INSR_HUMAN
ID INSR_HUMAN Reviewed; 1382 AA.
AC P06213; Q17RW0; Q59H98; Q9UCB7; Q9UCB8; Q9UCB9;
DT 01-JAN-1988, integrated into UniProtKB/Swiss-Prot.
DT 05-OCT-2010, sequence version 4.
DT 03-AUG-2022, entry version 277.
DE RecName: Full=Insulin receptor;
DE Short=IR;
DE EC=2.7.10.1;
DE AltName: CD_antigen=CD220;
DE Contains:
DE RecName: Full=Insulin receptor subunit alpha;
DE Contains:
DE RecName: Full=Insulin receptor subunit beta;
DE Flags: Precursor;
GN Name=INSR;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM LONG), AND VARIANTS GLY-2; HIS-171;
RP THR-448 AND LYS-492.
RX PubMed=2859121; DOI=10.1016/0092-8674(85)90334-4;
RA Ebina Y., Ellis L., Jarnagin K., Edery M., Graf L., Clauser E., Ou J.-H.,
RA Masiarz F., Kan Y.W., Goldfine I.D., Roth R.A., Rutter W.J.;
RT "The human insulin receptor cDNA: the structural basis for hormone-
RT activated transmembrane signalling.";
RL Cell 40:747-758(1985).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM SHORT), PROTEIN SEQUENCE OF 28-49 AND
RP 763-782, GLYCOSYLATION AT ASN-43 AND ASN-769, AND VARIANT GLY-2.
RX PubMed=2983222; DOI=10.1038/313756a0;
RA Ullrich A., Bell J.R., Chen E.Y., Herrera R., Petruzzelli L.M., Dull T.J.,
RA Gray A., Coussens L., Liao Y.-C., Tsubokawa M., Mason A., Seeburg P.H.,
RA Grunfeld C., Rosen O.M., Ramachandran J.;
RT "Human insulin receptor and its relationship to the tyrosine kinase family
RT of oncogenes.";
RL Nature 313:756-761(1985).
RN [3]
RP SEQUENCE REVISION TO 899-900.
RA Chen E.Y.;
RL Submitted (JUL-1985) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT GLY-2.
RC TISSUE=Fetal liver;
RX PubMed=2210055; DOI=10.2337/diacare.39.1.123;
RA Seino S., Seino M., Bell G.I.;
RT "Human insulin-receptor gene. Partial sequence and amplification of exons
RT by polymerase chain reaction.";
RL Diabetes 39:123-128(1990).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057824; DOI=10.1038/nature02399;
RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E.,
RA Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A.,
RA Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S.,
RA Carrano A.V., Caoile C., Chan Y.M., Christensen M., Cleland C.A.,
RA Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J.,
RA Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M.,
RA Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W.,
RA Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V.,
RA Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D.,
RA McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I.,
RA Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L.,
RA Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A.,
RA She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M.,
RA Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J.,
RA Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E.,
RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M.,
RA Rubin E.M., Lucas S.M.;
RT "The DNA sequence and biology of human chromosome 19.";
RL Nature 428:529-535(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM SHORT), AND VARIANT GLY-2.
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-33, AND VARIANT GLY-2.
RX PubMed=3680248; DOI=10.1016/s0021-9258(18)47714-9;
RA Araki E., Shimada F., Uzawa H., Mori M., Ebina Y.;
RT "Characterization of the promoter region of the human insulin receptor
RT gene. Evidence for promoter activity.";
RL J. Biol. Chem. 262:16186-16191(1987).
RN [8]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-33, AND VARIANT GLY-2.
RX PubMed=2806055; DOI=10.1016/0168-8227(89)90085-5;
RA Araki E., Shimada F., Fukushima H., Mori M., Shichiri M., Ebina Y.;
RT "Characterization of the promoter region of the human insulin receptor
RT gene.";
RL Diabetes Res. Clin. Pract. 7:S31-S33(1989).
RN [9]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-33, AND VARIANT GLY-2.
RX PubMed=2777789; DOI=10.1016/s0021-9258(18)71612-8;
RA Tewari D.S., Cook D.M., Taub R.;
RT "Characterization of the promoter region and 3' end of the human insulin
RT receptor gene.";
RL J. Biol. Chem. 264:16238-16245(1989).
RN [10]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-33, AND VARIANT GLY-2.
RC TISSUE=Skin fibroblast;
RX PubMed=2280779; DOI=10.1210/mend-4-4-647;
RA McKeon C., Moncada V., Pham T., Salvatore P., Kadowaki T., Accili D.,
RA Taylor S.I.;
RT "Structural and functional analysis of the insulin receptor promoter.";
RL Mol. Endocrinol. 4:647-656(1990).
RN [11]
RP PROTEIN SEQUENCE OF 28-44; 192-205; 299-314; 610-627 AND 763-780, ACTIVITY
RP REGULATION, AND SUBUNIT.
RC TISSUE=Placenta;
RX PubMed=2211730; DOI=10.1016/s0021-9258(17)44805-8;
RA Xu Q.-Y., Paxton R.J., Fujita-Yamaguchi Y.;
RT "Substructural analysis of the insulin receptor by microsequence analyses
RT of limited tryptic fragments isolated by sodium dodecyl sulfate-
RT polyacrylamide gel electrophoresis in the absence or presence of
RT dithiothreitol.";
RL J. Biol. Chem. 265:18673-18681(1990).
RN [12]
RP PROTEIN SEQUENCE OF 28-45 AND 763-782, FUNCTION, AND FORMATION OF A HYBRID
RP RECEPTOR WITH IGF1R.
RC TISSUE=Placenta;
RX PubMed=8257688; DOI=10.1021/bi00212a019;
RA Kasuya J., Paz I.B., Maddux B.A., Goldfine I.D., Hefta S.A.,
RA Fujita-Yamaguchi Y.;
RT "Characterization of human placental insulin-like growth factor-I/insulin
RT hybrid receptors by protein microsequencing and purification.";
RL Biochemistry 32:13531-13536(1993).
RN [13]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 538-1382 (ISOFORM SHORT).
RC TISSUE=Brain;
RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.,
RA Ohara O., Nagase T., Kikuno R.F.;
RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases.
RN [14]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 728-772 (ISOFORM LONG), AND ALTERNATIVE
RP SPLICING.
RX PubMed=2538124; DOI=10.1016/0006-291x(89)92439-x;
RA Seino S., Bell G.I.;
RT "Alternative splicing of human insulin receptor messenger RNA.";
RL Biochem. Biophys. Res. Commun. 159:312-316(1989).
RN [15]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 744-823 (ISOFORM LONG), TISSUE SPECIFICITY,
RP LIGAND-BINDING, AND AUTOPHOSPHORYLATION.
RX PubMed=2369896; DOI=10.1002/j.1460-2075.1990.tb07416.x;
RA Mosthaf L., Grako K., Dull T.J., Coussens L., Ullrich A., McClain D.A.;
RT "Functionally distinct insulin receptors generated by tissue-specific
RT alternative splicing.";
RL EMBO J. 9:2409-2413(1990).
RN [16]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 895-1085.
RX PubMed=2566545; DOI=10.2337/diab.38.6.737;
RA Elbein S.C.;
RT "Molecular and clinical characterization of an insertional polymorphism of
RT the insulin-receptor gene.";
RL Diabetes 38:737-743(1989).
RN [17]
RP PROTEIN SEQUENCE OF 927-956; 981-1019; 1182-1194 AND 1352-1369, AND
RP PHOSPHORYLATION AT TYR-999; TYR-1355 AND TYR-1361.
RC TISSUE=Placenta;
RX PubMed=3166375; DOI=10.1042/bj2520607;
RA Tavare J.M., Denton R.M.;
RT "Studies on the autophosphorylation of the insulin receptor from human
RT placenta. Analysis of the sites phosphorylated by two-dimensional peptide
RT mapping.";
RL Biochem. J. 252:607-615(1988).
RN [18]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1006-1123.
RX PubMed=2544997; DOI=10.1126/science.2544997;
RA Taira M., Taira M., Hashimoto N., Shimada F., Suzuki Y., Kanatsuka A.,
RA Nakamura F., Ebina Y., Tatibana M., Makino H.;
RT "Human diabetes associated with a deletion of the tyrosine kinase domain of
RT the insulin receptor.";
RL Science 245:63-66(1989).
RN [19]
RP PARTIAL PROTEIN SEQUENCE.
RX PubMed=3447155;
RA Fujita-Yamaguchi Y., Hawke D., Shively J.E., Choi S.;
RT "Partial amino acid sequence analyses of human placental insulin
RT receptor.";
RL Protein Seq. Data Anal. 1:3-6(1987).
RN [20]
RP MUTAGENESIS OF LYS-1057.
RX PubMed=3101064; DOI=10.1073/pnas.84.3.704;
RA Ebina Y., Araki E., Taira M., Shimada F., Mori M., Craik C.S., Siddle K.,
RA Pierce S.B., Roth R.A., Rutter W.J.;
RT "Replacement of lysine residue 1030 in the putative ATP-binding region of
RT the insulin receptor abolishes insulin- and antibody-stimulated glucose
RT uptake and receptor kinase activity.";
RL Proc. Natl. Acad. Sci. U.S.A. 84:704-708(1987).
RN [21]
RP MUTAGENESIS OF TYR-999.
RX PubMed=2842060; DOI=10.1016/s0092-8674(88)80008-4;
RA White M.F., Livingston J.N., Backer J.M., Lauris V., Dull T.J., Ullrich A.,
RA Kahn C.R.;
RT "Mutation of the insulin receptor at tyrosine 960 inhibits signal
RT transmission but does not affect its tyrosine kinase activity.";
RL Cell 54:641-649(1988).
RN [22]
RP AUTOPHOSPHORYLATION.
RX PubMed=1321605; DOI=10.1016/s0006-291x(05)80799-5;
RA Dickens M., Tavare J.M.;
RT "Analysis of the order of autophosphorylation of human insulin receptor
RT tyrosines 1158, 1162 and 1163.";
RL Biochem. Biophys. Res. Commun. 186:244-250(1992).
RN [23]
RP DISULFIDE BONDS, AND GLYCOSYLATION AT ASN-541.
RX PubMed=1472036; DOI=10.1016/0006-291x(92)92250-2;
RA Schaeffer L., Ljungqvist L.;
RT "Identification of a disulfide bridge connecting the alpha-subunits of the
RT extracellular domain of the insulin receptor.";
RL Biochem. Biophys. Res. Commun. 189:650-653(1992).
RN [24]
RP FUNCTION, AND FORMATION OF A HYBRID RECEPTOR WITH IGF1R.
RX PubMed=8452530; DOI=10.1042/bj2900419;
RA Soos M.A., Field C.E., Siddle K.;
RT "Purified hybrid insulin/insulin-like growth factor-I receptors bind
RT insulin-like growth factor-I, but not insulin, with high affinity.";
RL Biochem. J. 290:419-426(1993).
RN [25]
RP FUNCTION, AND INTERACTION WITH PIK3R1.
RX PubMed=8276809; DOI=10.1016/s0021-9258(17)42304-0;
RA Van Horn D.J., Myers M.G. Jr., Backer J.M.;
RT "Direct activation of the phosphatidylinositol 3'-kinase by the insulin
RT receptor.";
RL J. Biol. Chem. 269:29-32(1994).
RN [26]
RP INTERACTION WITH IRS1 AND SHC1, AND MUTAGENESIS OF LEU-991; TYR-992;
RP ASN-996; 996-ASN-PRO-997; PRO-997; TYR-999; LEU-1000 AND ALA-1002.
RX PubMed=7559478; DOI=10.1074/jbc.270.40.23258;
RA He W., O'Neill T.J., Gustafson T.A.;
RT "Distinct modes of interaction of SHC and insulin receptor substrate-1 with
RT the insulin receptor NPEY region via non-SH2 domains.";
RL J. Biol. Chem. 270:23258-23262(1995).
RN [27]
RP INTERACTION WITH IRS1; SHC1 AND PIK3R1, AND MUTAGENESIS OF ASN-996;
RP PRO-997; GLU-998; TYR-999 AND LYS-1057.
RX PubMed=7537849; DOI=10.1128/mcb.15.5.2500;
RA Gustafson T.A., He W., Craparo A., Schaub C.D., O'Neill T.J.;
RT "Phosphotyrosine-dependent interaction of SHC and insulin receptor
RT substrate 1 with the NPEY motif of the insulin receptor via a novel non-SH2
RT domain.";
RL Mol. Cell. Biol. 15:2500-2508(1995).
RN [28]
RP FORMATION OF A HYBRID RECEPTOR WITH IGF1R, AND TISSUE SPECIFICITY.
RX PubMed=9355755; DOI=10.1042/bj3270209;
RA Bailyes E.M., Nave B.T., Soos M.A., Orr S.R., Hayward A.C., Siddle K.;
RT "Insulin receptor/IGF-I receptor hybrids are widely distributed in
RT mammalian tissues: quantification of individual receptor species by
RT selective immunoprecipitation and immunoblotting.";
RL Biochem. J. 327:209-215(1997).
RN [29]
RP FUNCTION IN PHOSPHORYLATION OF STAT5B, MUTAGENESIS OF TYR-999, AND
RP INTERACTION WITH STAT5B; IRS1 AND IRS2.
RX PubMed=9428692; DOI=10.1111/j.1432-1033.1997.0411a.x;
RA Sawka-Verhelle D., Filloux C., Tartare-Deckert S., Mothe I.,
RA Van Obberghen E.;
RT "Identification of Stat 5B as a substrate of the insulin receptor.";
RL Eur. J. Biochem. 250:411-417(1997).
RN [30]
RP INTERACTION WITH PTPRF.
RX PubMed=8995282; DOI=10.1074/jbc.272.11.7519;
RA Ahmad F., Goldstein B.J.;
RT "Functional association between the insulin receptor and the transmembrane
RT protein-tyrosine phosphatase LAR in intact cells.";
RL J. Biol. Chem. 272:448-457(1997).
RN [31]
RP INTERACTION WITH PTPRE, AND DEPHOSPHORYLATION BY PTPRE.
RX PubMed=8999839; DOI=10.1074/jbc.272.3.1639;
RA Bandyopadhyay D., Kusari A., Kenner K.A., Liu F., Chernoff J.,
RA Gustafson T.A., Kusari J.;
RT "Protein-tyrosine phosphatase 1B complexes with the insulin receptor in
RT vivo and is tyrosine-phosphorylated in the presence of insulin.";
RL J. Biol. Chem. 272:1639-1645(1997).
RN [32]
RP FORMATION OF A HYBRID RECEPTOR WITH IGF1R, AND TISSUE SPECIFICITY.
RX PubMed=9202395; DOI=10.1016/s0303-7207(97)04050-1;
RA Federici M., Porzio O., Zucaro L., Fusco A., Borboni P., Lauro D.,
RA Sesti G.;
RT "Distribution of insulin/insulin-like growth factor-I hybrid receptors in
RT human tissues.";
RL Mol. Cell. Endocrinol. 129:121-126(1997).
RN [33]
RP TISSUE SPECIFICITY, AND FUNCTION AS RECEPTOR FOR IGFII (ISOFORM SHORT).
RX PubMed=10207053; DOI=10.1128/mcb.19.5.3278;
RA Frasca F., Pandini G., Scalia P., Sciacca L., Mineo R., Costantino A.,
RA Goldfine I.D., Belfiore A., Vigneri R.;
RT "Insulin receptor isoform A, a newly recognized, high-affinity insulin-like
RT growth factor II receptor in fetal and cancer cells.";
RL Mol. Cell. Biol. 19:3278-3288(1999).
RN [34]
RP INTERACTION WITH ENPP1, AND ACTIVITY REGULATION.
RX PubMed=10615944; DOI=10.2337/diabetes.49.1.13;
RA Maddux B.A., Goldfine I.D.;
RT "Membrane glycoprotein PC-1 inhibition of insulin receptor function occurs
RT via direct interaction with the receptor alpha-subunit.";
RL Diabetes 49:13-19(2000).
RN [35]
RP PHOSPHORYLATION, AND DEPHOSPHORYLATION BY PTPN1 AND PTPN2.
RX PubMed=10734133; DOI=10.1074/jbc.275.13.9792;
RA Waelchli S., Curchod M.L., Gobert R.P., Arkinstall S.,
RA Hooft van Huijsduijnen R.;
RT "Identification of tyrosine phosphatases that dephosphorylate the insulin
RT receptor. A brute force approach based on 'substrate-trapping' mutants.";
RL J. Biol. Chem. 275:9792-9796(2000).
RN [36]
RP INTERACTION WITH GRB7, AND MUTAGENESIS OF LYS-1057; TYR-1189 AND TYR-1190.
RX PubMed=10803466; DOI=10.1038/sj.onc.1203469;
RA Kasus-Jacobi A., Bereziat V., Perdereau D., Girard J., Burnol A.F.;
RT "Evidence for an interaction between the insulin receptor and Grb7. A role
RT for two of its binding domains, PIR and SH2.";
RL Oncogene 19:2052-2059(2000).
RN [37]
RP INTERACTION WITH SORBS1.
RX PubMed=11374898; DOI=10.1006/geno.2001.6541;
RA Lin W.-H., Huang C.-J., Liu M.-W., Chang H.-M., Chen Y.-J., Tai T.-Y.,
RA Chuang L.-M.;
RT "Cloning, mapping, and characterization of the human sorbin and SH3 domain
RT containing 1 (SORBS1) gene: a protein associated with c-Abl during insulin
RT signaling in the hepatoma cell line Hep3B.";
RL Genomics 74:12-20(2001).
RN [38]
RP CATALYTIC ACTIVITY, MUTAGENESIS OF ASP-1159 AND ARG-1163, AND ACTIVITY
RP REGULATION.
RX PubMed=11598120; DOI=10.1074/jbc.m107236200;
RA Ablooglu A.J., Frankel M., Rusinova E., Ross J.B., Kohanski R.A.;
RT "Multiple activation loop conformations and their regulatory properties in
RT the insulin receptor's kinase domain.";
RL J. Biol. Chem. 276:46933-46940(2001).
RN [39]
RP INTERACTION WITH GRB14, AND ACTIVITY REGULATION.
RX PubMed=11726652; DOI=10.1074/jbc.m106574200;
RA Bereziat V., Kasus-Jacobi A., Perdereau D., Cariou B., Girard J.,
RA Burnol A.F.;
RT "Inhibition of insulin receptor catalytic activity by the molecular adapter
RT Grb14.";
RL J. Biol. Chem. 277:4845-4852(2002).
RN [40]
RP FUNCTION, AND FORMATION OF A HYBRID RECEPTOR WITH IGF1R.
RX PubMed=12138094; DOI=10.1074/jbc.m202766200;
RA Pandini G., Frasca F., Mineo R., Sciacca L., Vigneri R., Belfiore A.;
RT "Insulin/insulin-like growth factor I hybrid receptors have different
RT biological characteristics depending on the insulin receptor isoform
RT involved.";
RL J. Biol. Chem. 277:39684-39695(2002).
RN [41]
RP INTERACTION WITH GRB10, AND ACTIVITY REGULATION.
RX PubMed=12493740; DOI=10.1074/jbc.m208518200;
RA Wick K.R., Werner E.D., Langlais P., Ramos F.J., Dong L.Q., Shoelson S.E.,
RA Liu F.;
RT "Grb10 inhibits insulin-stimulated insulin receptor substrate (IRS)-
RT phosphatidylinositol 3-kinase/Akt signaling pathway by disrupting the
RT association of IRS-1/IRS-2 with the insulin receptor.";
RL J. Biol. Chem. 278:8460-8467(2003).
RN [42]
RP PHOSPHORYLATION, AND DEPHOSPHORYLATION BY PTPN2.
RX PubMed=12612081; DOI=10.1128/mcb.23.6.2096-2108.2003;
RA Galic S., Klingler-Hoffmann M., Fodero-Tavoletti M.T., Puryer M.A.,
RA Meng T.C., Tonks N.K., Tiganis T.;
RT "Regulation of insulin receptor signaling by the protein tyrosine
RT phosphatase TCPTP.";
RL Mol. Cell. Biol. 23:2096-2108(2003).
RN [43]
RP INTERACTION WITH SOCS7.
RX PubMed=16127460; DOI=10.1172/jci23853;
RA Banks A.S., Li J., McKeag L., Hribal M.L., Kashiwada M., Accili D.,
RA Rothman P.B.;
RT "Deletion of SOCS7 leads to enhanced insulin action and enlarged islets of
RT Langerhans.";
RL J. Clin. Invest. 115:2462-2471(2005).
RN [44]
RP FUNCTION IN PHOSPHORYLATION OF PDPK1, AND INTERACTION WITH PDPK1.
RX PubMed=16314505; DOI=10.1128/mcb.25.24.10803-10814.2005;
RA Fiory F., Alberobello A.T., Miele C., Oriente F., Esposito I., Corbo V.,
RA Ruvo M., Tizzano B., Rasmussen T.E., Gammeltoft S., Formisano P.,
RA Beguinot F.;
RT "Tyrosine phosphorylation of phosphoinositide-dependent kinase 1 by the
RT insulin receptor is necessary for insulin metabolic signaling.";
RL Mol. Cell. Biol. 25:10803-10814(2005).
RN [45]
RP DEPHOSPHORYLATION BY PTPRE.
RX PubMed=15738637; DOI=10.2108/zsj.22.169;
RA Nakagawa Y., Aoki N., Aoyama K., Shimizu H., Shimano H., Yamada N.,
RA Miyazaki H.;
RT "Receptor-type protein tyrosine phosphatase epsilon (PTPepsilonM) is a
RT negative regulator of insulin signaling in primary hepatocytes and liver.";
RL Zool. Sci. 22:169-175(2005).
RN [46]
RP FUNCTION, AND FORMATION OF A HYBRID RECEPTOR WITH IGF1R.
RX PubMed=16831875; DOI=10.1074/jbc.m605189200;
RA Slaaby R., Schaeffer L., Lautrup-Larsen I., Andersen A.S., Shaw A.C.,
RA Mathiasen I.S., Brandt J.;
RT "Hybrid receptors formed by insulin receptor (IR) and insulin-like growth
RT factor I receptor (IGF-IR) have low insulin and high IGF-1 affinity
RT irrespective of the IR splice variant.";
RL J. Biol. Chem. 281:25869-25874(2006).
RN [47]
RP REVIEW ON SIGNALING PATHWAYS.
RX PubMed=16493415; DOI=10.1038/nrm1837;
RA Taniguchi C.M., Emanuelli B., Kahn C.R.;
RT "Critical nodes in signalling pathways: insights into insulin action.";
RL Nat. Rev. Mol. Cell Biol. 7:85-96(2006).
RN [48]
RP REVIEW ON REGULATION OF INSR FUNCTION.
RX PubMed=17347799; DOI=10.1007/s00018-007-6359-9;
RA Youngren J.F.;
RT "Regulation of insulin receptor function.";
RL Cell. Mol. Life Sci. 64:873-891(2007).
RN [49]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-400; TYR-401 AND SER-407, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [50]
RP DOMAIN, AND INSULIN-BINDING SITE.
RX PubMed=19459609; DOI=10.1021/bi900261q;
RA Menting J.G., Ward C.W., Margetts M.B., Lawrence M.C.;
RT "A thermodynamic study of ligand binding to the first three domains of the
RT human insulin receptor: relationship between the receptor alpha-chain C-
RT terminal peptide and the site 1 insulin mimetic peptides.";
RL Biochemistry 48:5492-5500(2009).
RN [51]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-242 AND ASN-541.
RC TISSUE=Liver;
RX PubMed=19159218; DOI=10.1021/pr8008012;
RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.;
RT "Glycoproteomics analysis of human liver tissue by combination of multiple
RT enzyme digestion and hydrazide chemistry.";
RL J. Proteome Res. 8:651-661(2009).
RN [52]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [53]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-445 AND ASN-920.
RC TISSUE=Leukemic T-cell;
RX PubMed=19349973; DOI=10.1038/nbt.1532;
RA Wollscheid B., Bausch-Fluck D., Henderson C., O'Brien R., Bibel M.,
RA Schiess R., Aebersold R., Watts J.D.;
RT "Mass-spectrometric identification and relative quantification of N-linked
RT cell surface glycoproteins.";
RL Nat. Biotechnol. 27:378-386(2009).
RN [54]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [55]
RP INTERACTION WITH CCDC88A AND GNAI3.
RX PubMed=25187647; DOI=10.1091/mbc.e14-05-0978;
RA Lin C., Ear J., Midde K., Lopez-Sanchez I., Aznar N., Garcia-Marcos M.,
RA Kufareva I., Abagyan R., Ghosh P.;
RT "Structural basis for activation of trimeric Gi proteins by multiple growth
RT factor receptors via GIV/Girdin.";
RL Mol. Biol. Cell 25:3654-3671(2014).
RN [56]
RP INTERACTION WITH SORL1.
RX PubMed=27322061; DOI=10.1172/jci84708;
RA Schmidt V., Schulz N., Yan X., Schuermann A., Kempa S., Kern M.,
RA Blueher M., Poy M.N., Olivecrona G., Willnow T.E.;
RT "SORLA facilitates insulin receptor signaling in adipocytes and exacerbates
RT obesity.";
RL J. Clin. Invest. 126:2706-2720(2016).
RN [57]
RP SUBUNIT.
RX PubMed=27617429; DOI=10.1038/nsmb.3292;
RA Menting J.G., Gajewiak J., MacRaild C.A., Chou D.H., Disotuar M.M.,
RA Smith N.A., Miller C., Erchegyi J., Rivier J.E., Olivera B.M., Forbes B.E.,
RA Smith B.J., Norton R.S., Safavi-Hemami H., Lawrence M.C.;
RT "A minimized human insulin-receptor-binding motif revealed in a Conus
RT geographus venom insulin.";
RL Nat. Struct. Mol. Biol. 23:916-920(2016).
RN [58]
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 1005-1310.
RX PubMed=7997262; DOI=10.1038/372746a0;
RA Hubbard S.R., Wei L., Ellis L., Hendrickson W.A.;
RT "Crystal structure of the tyrosine kinase domain of the human insulin
RT receptor.";
RL Nature 372:746-754(1994).
RN [59]
RP X-RAY CRYSTALLOGRAPHY (1.90 ANGSTROMS) OF 1005-1310 IN COMPLEX WITH ATP
RP ANALOG AND IRS1 PEPTIDE, CATALYTIC ACTIVITY, ACTIVE SITE,
RP AUTOPHOSPHORYLATION, AND PHOSPHORYLATION AT TYR-1185; TYR-1189 AND
RP TYR-1190.
RX PubMed=9312016; DOI=10.1093/emboj/16.18.5572;
RA Hubbard S.R.;
RT "Crystal structure of the activated insulin receptor tyrosine kinase in
RT complex with peptide substrate and ATP analog.";
RL EMBO J. 16:5572-5581(1997).
RN [60]
RP X-RAY CRYSTALLOGRAPHY (2.40 ANGSTROMS) OF 1005-1310 IN COMPLEX WITH ATP
RP ANALOG, AND CATALYTIC ACTIVITY.
RX PubMed=11124964; DOI=10.1074/jbc.m010161200;
RA Till J.H., Ablooglu A.J., Frankel M., Bishop S.M., Kohanski R.A.,
RA Hubbard S.R.;
RT "Crystallographic and solution studies of an activation loop mutant of the
RT insulin receptor tyrosine kinase: insights into kinase mechanism.";
RL J. Biol. Chem. 276:10049-10055(2001).
RN [61]
RP X-RAY CRYSTALLOGRAPHY (1.90 ANGSTROMS) OF 1005-1298 OF MUTANT ASN-1159,
RP CATALYTIC ACTIVITY, AUTOPHOSPHORYLATION, AND MUTAGENESIS OF TYR-1011.
RX PubMed=12707268; DOI=10.1074/jbc.m302425200;
RA Li S., Covino N.D., Stein E.G., Till J.H., Hubbard S.R.;
RT "Structural and biochemical evidence for an autoinhibitory role for
RT tyrosine 984 in the juxtamembrane region of the insulin receptor.";
RL J. Biol. Chem. 278:26007-26014(2003).
RN [62]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 1005-1310 IN COMPLEX WITH ATP
RP ANALOG AND SH2B2, AND PHOSPHORYLATION AT TYR-1185; TYR-1189 AND TYR-1190.
RX PubMed=14690593; DOI=10.1016/s1097-2765(03)00487-8;
RA Hu J., Liu J., Ghirlando R., Saltiel A.R., Hubbard S.R.;
RT "Structural basis for recruitment of the adaptor protein APS to the
RT activated insulin receptor.";
RL Mol. Cell 12:1379-1389(2003).
RN [63]
RP X-RAY CRYSTALLOGRAPHY (3.20 ANGSTROMS) OF 1005-1310 IN COMPLEX WITH GRB14,
RP INTERACTION WITH GRB14, AUTOPHOSPHORYLATION, AND PHOSPHORYLATION AT
RP TYR-1185; TYR-1189 AND TYR-1190.
RX PubMed=16246733; DOI=10.1016/j.molcel.2005.09.001;
RA Depetris R.S., Hu J., Gimpelevich I., Holt L.J., Daly R.J., Hubbard S.R.;
RT "Structural basis for inhibition of the insulin receptor by the adaptor
RT protein Grb14.";
RL Mol. Cell 20:325-333(2005).
RN [64]
RP X-RAY CRYSTALLOGRAPHY (2.30 ANGSTROMS) OF 1005-1310 IN COMPLEX WITH PTPN1,
RP AND PHOSPHORYLATION AT TYR-1185; TYR-1189 AND TYR-1190.
RX PubMed=16271887; DOI=10.1016/j.str.2005.07.019;
RA Li S., Depetris R.S., Barford D., Chernoff J., Hubbard S.R.;
RT "Crystal structure of a complex between protein tyrosine phosphatase 1B and
RT the insulin receptor tyrosine kinase.";
RL Structure 13:1643-1651(2005).
RN [65]
RP X-RAY CRYSTALLOGRAPHY (3.8 ANGSTROMS) OF 28-943 IN COMPLEX WITH INSULIN
RP ANALOG, DOMAIN, AND DISULFIDE BONDS.
RX PubMed=16957736; DOI=10.1038/nature05106;
RA McKern N.M., Lawrence M.C., Streltsov V.A., Lou M.Z., Adams T.E.,
RA Lovrecz G.O., Elleman T.C., Richards K.M., Bentley J.D., Pilling P.A.,
RA Hoyne P.A., Cartledge K.A., Pham T.M., Lewis J.L., Sankovich S.E.,
RA Stoichevska V., Da Silva E., Robinson C.P., Frenkel M.J., Sparrow L.G.,
RA Fernley R.T., Epa V.C., Ward C.W.;
RT "Structure of the insulin receptor ectodomain reveals a folded-over
RT conformation.";
RL Nature 443:218-221(2006).
RN [66]
RP X-RAY CRYSTALLOGRAPHY (2.32 ANGSTROMS) OF 28-512, GLYCOSYLATION AT ASN-43;
RP ASN-52; ASN-138; ASN-242; ASN-282; ASN-364; ASN-424 AND ASN-445, AND
RP DISULFIDE BONDS.
RX PubMed=16894147; DOI=10.1073/pnas.0605395103;
RA Lou M., Garrett T.P., McKern N.M., Hoyne P.A., Epa V.C., Bentley J.D.,
RA Lovrecz G.O., Cosgrove L.J., Frenkel M.J., Ward C.W.;
RT "The first three domains of the insulin receptor differ structurally from
RT the insulin-like growth factor 1 receptor in the regions governing ligand
RT specificity.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:12429-12434(2006).
RN [67]
RP X-RAY CRYSTALLOGRAPHY (1.65 ANGSTROMS) OF 1005-1310 IN COMPLEX WITH ATP AND
RP IRS2, CATALYTIC ACTIVITY, PHOSPHORYLATION AT TYR-1185; TYR-1189 AND
RP TYR-1190, AND INTERACTION WITH IRS2.
RX PubMed=18278056; DOI=10.1038/nsmb.1388;
RA Wu J., Tseng Y.D., Xu C.F., Neubert T.A., White M.F., Hubbard S.R.;
RT "Structural and biochemical characterization of the KRLB region in insulin
RT receptor substrate-2.";
RL Nat. Struct. Mol. Biol. 15:251-258(2008).
RN [68]
RP X-RAY CRYSTALLOGRAPHY (3.25 ANGSTROMS) OF 1009-1310 IN COMPLEX WITH
RP INHIBITORY PEPTIDE, AND PHOSPHORYLATION AT TYR-1185; TYR-1189 AND TYR-1190.
RX PubMed=18767165; DOI=10.1002/prot.22207;
RA Katayama N., Orita M., Yamaguchi T., Hisamichi H., Kuromitsu S.,
RA Kurihara H., Sakashita H., Matsumoto Y., Fujita S., Niimi T.;
RT "Identification of a key element for hydrogen-bonding patterns between
RT protein kinases and their inhibitors.";
RL Proteins 73:795-801(2008).
RN [69]
RP X-RAY CRYSTALLOGRAPHY (2.20 ANGSTROMS) OF 1005-1310 IN COMPLEX WITH
RP SYNTHETIC INHIBITOR, AND CATALYTIC ACTIVITY.
RX PubMed=19071018; DOI=10.1016/j.bmcl.2008.11.077;
RA Chamberlain S.D., Redman A.M., Wilson J.W., Deanda F., Shotwell J.B.,
RA Gerding R., Lei H., Yang B., Stevens K.L., Hassell A.M., Shewchuk L.M.,
RA Leesnitzer M.A., Smith J.L., Sabbatini P., Atkins C., Groy A., Rowand J.L.,
RA Kumar R., Mook R.A. Jr., Moorthy G., Patnaik S.;
RT "Optimization of 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidine IGF-1R
RT tyrosine kinase inhibitors towards JNK selectivity.";
RL Bioorg. Med. Chem. Lett. 19:360-364(2009).
RN [70]
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 1005-1310 IN COMPLEX WITH
RP SYNTHETIC INHIBITOR, AND CATALYTIC ACTIVITY.
RX PubMed=19056263; DOI=10.1016/j.bmcl.2008.11.046;
RA Chamberlain S.D., Wilson J.W., Deanda F., Patnaik S., Redman A.M., Yang B.,
RA Shewchuk L., Sabbatini P., Leesnitzer M.A., Groy A., Atkins C., Gerding R.,
RA Hassell A.M., Lei H., Mook R.A. Jr., Moorthy G., Rowand J.L., Stevens K.L.,
RA Kumar R., Shotwell J.B.;
RT "Discovery of 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidines: potent
RT inhibitors of the IGF-1R receptor tyrosine kinase.";
RL Bioorg. Med. Chem. Lett. 19:469-473(2009).
RN [71]
RP X-RAY CRYSTALLOGRAPHY (2.60 ANGSTROMS) OF 1017-1322 IN COMPLEX WITH
RP SYNTHETIC INHIBITOR, AND CATALYTIC ACTIVITY.
RX PubMed=19394223; DOI=10.1016/j.bmcl.2008.12.110;
RA Patnaik S., Stevens K.L., Gerding R., Deanda F., Shotwell J.B., Tang J.,
RA Hamajima T., Nakamura H., Leesnitzer M.A., Hassell A.M., Shewchuck L.M.,
RA Kumar R., Lei H., Chamberlain S.D.;
RT "Discovery of 3,5-disubstituted-1H-pyrrolo[2,3-b]pyridines as potent
RT inhibitors of the insulin-like growth factor-1 receptor (IGF-1R) tyrosine
RT kinase.";
RL Bioorg. Med. Chem. Lett. 19:3136-3140(2009).
RN [72]
RP X-RAY CRYSTALLOGRAPHY (3.80 ANGSTROMS) OF 28-956, INSULIN-BINDING REGION,
RP AND DISULFIDE BONDS.
RX PubMed=20348418; DOI=10.1073/pnas.1001813107;
RA Smith B.J., Huang K., Kong G., Chan S.J., Nakagawa S., Menting J.G.,
RA Hu S.Q., Whittaker J., Steiner D.F., Katsoyannis P.G., Ward C.W.,
RA Weiss M.A., Lawrence M.C.;
RT "Structural resolution of a tandem hormone-binding element in the insulin
RT receptor and its implications for design of peptide agonists.";
RL Proc. Natl. Acad. Sci. U.S.A. 107:6771-6776(2010).
RN [73]
RP X-RAY CRYSTALLOGRAPHY (3.9 ANGSTROMS) OF 28-620 IN COMPLEX WITH INSULIN,
RP DOMAIN, GLYCOSYLATION AT ASN-43; ASN-52; ASN-138; ASN-242 AND ASN-282, AND
RP DISULFIDE BONDS.
RX PubMed=23302862; DOI=10.1038/nature11781;
RA Menting J.G., Whittaker J., Margetts M.B., Whittaker L.J., Kong G.K.,
RA Smith B.J., Watson C.J., Zakova L., Kletvikova E., Jiracek J., Chan S.J.,
RA Steiner D.F., Dodson G.G., Brzozowski A.M., Weiss M.A., Ward C.W.,
RA Lawrence M.C.;
RT "How insulin engages its primary binding site on the insulin receptor.";
RL Nature 493:241-245(2013).
RN [74]
RP VARIANT IRAN TYPE A SER-762.
RX PubMed=3283938; DOI=10.1126/science.3283938;
RA Yoshimasa Y., Seino S., Whittaker J., Kakehi T., Kosaki A., Kuzuya H.,
RA Imura H., Bell G.I., Steiner D.F.;
RT "Insulin-resistant diabetes due to a point mutation that prevents insulin
RT proreceptor processing.";
RL Science 240:784-787(1988).
RN [75]
RP VARIANT LEPRCH GLU-487.
RX PubMed=2834824; DOI=10.1126/science.2834824;
RA Kadowaki T., Bevins C., Cama A., Ojamaa K., Marcus-Samuels B., Kadowaki H.,
RA Beitz L., McKeon C., Taylor S.I.;
RT "Two mutant alleles of the insulin receptor gene in a patient with extreme
RT insulin resistance.";
RL Science 240:787-790(1988).
RN [76]
RP VARIANT LEPRCH PRO-260.
RX PubMed=2479553; DOI=10.1002/j.1460-2075.1989.tb08387.x;
RA Klinkhamer M.P., Groen N.A., van der Zon G.C.M., Lindhout D.,
RA Sandkuyl L.A., Krans H.M.J., Moeller W., Maassen J.A.;
RT "A leucine-to-proline mutation in the insulin receptor in a family with
RT insulin resistance.";
RL EMBO J. 8:2503-2507(1989).
RN [77]
RP VARIANT IRAN TYPE A VAL-1035.
RX PubMed=2544998; DOI=10.1126/science.2544998;
RA Odawara M., Kadowaki T., Yamamoto R., Shibasaki Y., Tobe K., Accili D.,
RA Bevins C., Mikami Y., Matsuura N., Akanuma Y., Takaku F., Taylor S.I.,
RA Kasuga M.;
RT "Human diabetes associated with a mutation in the tyrosine kinase domain of
RT the insulin receptor.";
RL Science 245:66-68(1989).
RN [78]
RP VARIANT IRAN TYPE A THR-1161.
RX PubMed=2168397; DOI=10.1016/s0021-9258(18)77212-8;
RA Moller D.E., Yokota A., White M.F., Pazianos A.G., Flier J.S.;
RT "A naturally occurring mutation of insulin receptor alanine 1134 impairs
RT tyrosine kinase function and is associated with dominantly inherited
RT insulin resistance.";
RL J. Biol. Chem. 265:14979-14985(1990).
RN [79]
RP CHARACTERIZATION OF VARIANT RMS LYS-42.
RX PubMed=2121734; DOI=10.1016/s0021-9258(17)30636-1;
RA Kadowaki T., Kadowaki H., Accili D., Taylor S.I.;
RT "Substitution of lysine for asparagine at position 15 in the alpha-subunit
RT of the human insulin receptor. A mutation that impairs transport of
RT receptors to the cell surface and decreases the affinity of insulin
RT binding.";
RL J. Biol. Chem. 265:19143-19150(1990).
RN [80]
RP VARIANT RMS LYS-42, VARIANT LEPRCH ARG-236, AND VARIANT IRAN TYPE A
RP SER-489.
RX PubMed=2365819; DOI=10.1172/jci114693;
RA Kadowaki T., Kadowaki H., Rechler M.M., Serrano-Rios M., Roth J.,
RA Gorden P., Taylor S.I.;
RT "Five mutant alleles of the insulin receptor gene in patients with genetic
RT forms of insulin resistance.";
RL J. Clin. Invest. 86:254-264(1990).
RN [81]
RP VARIANT IRAN TYPE A SER-1227.
RX PubMed=1963473; DOI=10.1210/mend-4-8-1183;
RA Moller D.E., Yokota A., Ginsberg-Fellner F., Flier J.S.;
RT "Functional properties of a naturally occurring Trp1200-->Ser1200 mutation
RT of the insulin receptor.";
RL Mol. Endocrinol. 4:1183-1191(1990).
RN [82]
RP VARIANT GLU-1095.
RX PubMed=2040394; DOI=10.2337/diab.40.6.777;
RA O'Rahilly S., Choi W.H., Patel P., Turner R.C., Flier J.S., Moller D.E.;
RT "Detection of mutations in insulin-receptor gene in NIDDM patients by
RT analysis of single-stranded conformation polymorphisms.";
RL Diabetes 40:777-782(1991).
RN [83]
RP VARIANT IRAN TYPE A GLN-1020.
RX PubMed=2002058; DOI=10.1016/s0021-9258(19)67781-1;
RA Kusari J., Takata Y., Hatada E., Freidenberg G., Kolterman O.,
RA Olefsky J.M.;
RT "Insulin resistance and diabetes due to different mutations in the tyrosine
RT kinase domain of both insulin receptor gene alleles.";
RL J. Biol. Chem. 266:5260-5267(1991).
RN [84]
RP VARIANT INS RESISTANCE ILE-1180.
RX PubMed=1890161; DOI=10.1210/jcem-73-4-894;
RA Cama A., de la Luz Sierra M., Ottini L., Kadowaki T., Gorden P.,
RA Imperato-Mcginley J., Taylor S.I.;
RT "A mutation in the tyrosine kinase domain of the insulin receptor
RT associated with insulin resistance in an obese woman.";
RL J. Clin. Endocrinol. Metab. 73:894-901(1991).
RN [85]
RP VARIANTS LEPRCH ALA-55 AND ARG-393.
RX PubMed=1607067; DOI=10.2337/diab.41.4.408;
RA Barbetti F., Gejman P.V., Taylor S.I., Raben N., Cama A., Bonora E.,
RA Pizzo P., Moghetti P., Muggeo M., Roth J.;
RT "Detection of mutations in insulin receptor gene by denaturing gradient gel
RT electrophoresis.";
RL Diabetes 41:408-415(1992).
RN [86]
RP VARIANT NIDDM GLN-1191.
RX PubMed=1607076; DOI=10.2337/diab.41.4.521;
RA Cocozza S., Porcellini A., Riccardi G., Monticelli A., Condorelli G.,
RA Ferrara A., Pianese L., Miele C., Capaldo B., Beguinot F., Varrone S.;
RT "NIDDM associated with mutation in tyrosine kinase domain of insulin
RT receptor gene.";
RL Diabetes 41:521-526(1992).
RN [87]
RP VARIANT IRAN TYPE A LEU-1205.
RX PubMed=1563582; DOI=10.1007/bf00400927;
RA Kim H., Kadowaki H., Sakura H., Odawara M., Momomura K., Takahashi Y.,
RA Miyazaki Y., Ohtani T., Akanuma Y., Yazaki Y., Kasuga M., Taylor S.I.,
RA Kadowaki T.;
RT "Detection of mutations in the insulin receptor gene in patients with
RT insulin resistance by analysis of single-stranded conformational
RT polymorphisms.";
RL Diabetologia 35:261-266(1992).
RN [88]
RP VARIANT LEPRCH ARG-58.
RX PubMed=1730625; DOI=10.1016/s0021-9258(18)48459-1;
RA van der Vorm E.R., van der Zon G.C.M., Moeller W., Krans H.M.J.,
RA Lindhout D., Maassen J.A.;
RT "An Arg for Gly substitution at position 31 in the insulin receptor, linked
RT to insulin resistance, inhibits receptor processing and transport.";
RL J. Biol. Chem. 267:66-71(1992).
RN [89]
RP VARIANT NIDDM GLN-1158.
RX PubMed=1470163;
RA Kasuga M., Kishimoto M., Hashiramoto M., Yonezawa K., Kazumi T., Hagino H.,
RA Shii K.;
RT "Insulin receptor Arg1131-->Gln: a novel mutation in the catalytic loop of
RT insulin receptor observed in insulin resistant diabetes.";
RL Nihon Geka Gakkai Zasshi 93:968-971(1992).
RN [90]
RP VARIANT MET-1012.
RX PubMed=8432414; DOI=10.2337/diab.42.3.429;
RA Elbein S.C., Sorensen L.K., Schumacher M.C.;
RT "Methionine for valine substitution in exon 17 of the insulin receptor gene
RT in a pedigree with familial NIDDM.";
RL Diabetes 42:429-434(1993).
RN [91]
RP VARIANT IRAN TYPE A ASP-1075.
RX PubMed=8243830; DOI=10.2337/diab.42.12.1837;
RA Haruta T., Takata Y., Iwanishi M., Maegawa H., Imamura T., Egawa K.,
RA Itazu T., Kobayashi M.;
RT "Ala1048-->Asp mutation in the kinase domain of insulin receptor causes
RT defective kinase activity and insulin resistance.";
RL Diabetes 42:1837-1844(1993).
RN [92]
RP VARIANT MET-1012.
RX PubMed=8458533; DOI=10.1007/bf00400701;
RA van der Vorm E.R., Kuipers A., Bonenkamp J.W., Kleijer W.J.,
RA van Maldergem L., Herwig J., Maassen J.A.;
RT "Patients with lipodystrophic diabetes mellitus of the Seip-Berardinelli
RT type, express normal insulin receptors.";
RL Diabetologia 36:172-174(1993).
RN [93]
RP VARIANT INS RESISTANCE LEU-1220.
RX PubMed=8390949; DOI=10.1007/bf00402277;
RA Iwanishi M., Haruta T., Takata Y., Ishibashi O., Sasaoka T., Egawa K.,
RA Imamura T., Naitou K., Itazu T., Kobayashi M.;
RT "A mutation (Trp1193-->Leu1193) in the tyrosine kinase domain of the
RT insulin receptor associated with type A syndrome of insulin resistance.";
RL Diabetologia 36:414-422(1993).
RN [94]
RP VARIANT INS RESISTANCE LEU-220.
RX PubMed=8242067; DOI=10.1093/hmg/2.9.1437;
RA Carrera P., Cordera R., Ferrari M., Cremonesi L., Taramelli R.,
RA Andraghetti G., Carducci C., Dozio N., Pozza G., Taylor S.I., Micossi P.,
RA Barbetti F.;
RT "Substitution of Leu for Pro-193 in the insulin receptor in a patient with
RT a genetic form of severe insulin resistance.";
RL Hum. Mol. Genet. 2:1437-1441(1993).
RN [95]
RP CHARACTERIZATION OF VARIANT IRAN TYPE A GLU-1162.
RX PubMed=8096518; DOI=10.1016/s0021-9258(18)53063-5;
RA Cama A., de la Luz Sierra M., Quon M.J., Ottini L., Gorden P., Taylor S.I.;
RT "Substitution of glutamic acid for alanine 1135 in the putative 'catalytic
RT loop' of the tyrosine kinase domain of the human insulin receptor. A
RT mutation that impairs proteolytic processing into subunits and inhibits
RT receptor tyrosine kinase activity.";
RL J. Biol. Chem. 268:8060-8069(1993).
RN [96]
RP VARIANT IRAN TYPE A VAL-409.
RX PubMed=8388389; DOI=10.1016/s0021-9258(18)82120-2;
RA Lebrun C., Baron V., Kaliman P., Gautier N., Dolais-Kitabgi J.,
RA Taylor S.I., Accili D., van Obberghen E.;
RT "Antibodies to the extracellular receptor domain restore the hormone-
RT insensitive kinase and conformation of the mutant insulin receptor valine
RT 382.";
RL J. Biol. Chem. 268:11272-11277(1993).
RN [97]
RP VARIANT LEPRCH MET-146.
RX PubMed=8326490; DOI=10.1136/jmg.30.6.470;
RA Al-Gazali L.I., Khalil M., Devadas K.;
RT "A syndrome of insulin resistance resembling leprechaunism in five sibs of
RT consanguineous parents.";
RL J. Med. Genet. 30:470-475(1993).
RN [98]
RP VARIANT LEPRCH PRO-113.
RX PubMed=8419945; DOI=10.1073/pnas.90.1.60;
RA Longo N., Langley S.D., Griffin L.D., Elsas L.J.;
RT "Activation of glucose transport by a natural mutation in the human insulin
RT receptor.";
RL Proc. Natl. Acad. Sci. U.S.A. 90:60-64(1993).
RN [99]
RP VARIANT IRAN TYPE A GLN-1201.
RX PubMed=8288049; DOI=10.2337/diab.43.2.247;
RA Moller D.E., Cohen O., Yamaguchi Y., Assiz R., Grigorescu F., Eberle A.,
RA Morrow L.A., Moses A.C., Flier J.S.;
RT "Prevalence of mutations in the insulin receptor gene in subjects with
RT features of the type A syndrome of insulin resistance.";
RL Diabetes 43:247-255(1994).
RN [100]
RP VARIANT RMS SYNDROME LEU-350, VARIANTS IRAN TYPE A LEU-1205 AND GLN-1378,
RP AND VARIANT MET-1012.
RX PubMed=8314008; DOI=10.2337/diab.43.3.357;
RA Krook A., Kumar S., Laing I., Boulton A.J., Wass J.A., O'Rahilly S.;
RT "Molecular scanning of the insulin receptor gene in syndromes of insulin
RT resistance.";
RL Diabetes 43:357-368(1994).
RN [101]
RP CHARACTERIZATION OF VARIANT IRAN TYPE A GLN-1201.
RX PubMed=8082780; DOI=10.1016/0014-5793(94)00876-0;
RA Moritz W., Froesch E.R., Boeni-Schnetzler M.;
RT "Functional properties of a heterozygous mutation (Arg1174-->Gln) in the
RT tyrosine kinase domain of the insulin receptor from a type A insulin
RT resistant patient.";
RL FEBS Lett. 351:276-280(1994).
RN [102]
RP VARIANT LEPRCH SER-439.
RX PubMed=8188715; DOI=10.1016/s0021-9258(17)36788-1;
RA van der Vorm E.R., Kuipers A., Kielkopf-Renner S., Krans H.M.J., Moller W.,
RA Maassen J.A.;
RT "A mutation in the insulin receptor that impairs proreceptor processing but
RT not insulin binding.";
RL J. Biol. Chem. 269:14297-14302(1994).
RN [103]
RP CHARACTERIZATION OF VARIANTS IRAN TYPE A ASP-1206 AND LEU-1220.
RX PubMed=7983039; DOI=10.1016/s0021-9258(18)47384-x;
RA Imamura T., Takata Y., Sasaoka T., Takada Y., Morioka H., Haruta T.,
RA Sawa T., Iwanishi M., Hu Y.G., Suzuki Y., Hamada J., Kobayashi M.;
RT "Two naturally occurring mutations in the kinase domain of insulin receptor
RT accelerate degradation of the insulin receptor and impair the kinase
RT activity.";
RL J. Biol. Chem. 269:31019-31027(1994).
RN [104]
RP VARIANT LEPRCH MET-146.
RX PubMed=7815442; DOI=10.1136/jmg.31.9.715;
RA Hone J., Accili D., al-Gazali L.I., Lestringant G., Orban T., Taylor S.I.;
RT "Homozygosity for a new mutation (Ile119-->Met) in the insulin receptor
RT gene in five sibs with familial insulin resistance.";
RL J. Med. Genet. 31:715-716(1994).
RN [105]
RP VARIANT NIDDM ALA-858, AND VARIANT CYS-1361.
RX PubMed=7657032; DOI=10.2337/diab.44.9.1081;
RA Kan M., Kanai F., Iida M., Jinnouchi H., Todaka M., Imanaka T., Ito K.,
RA Nishioka Y., Ohnishi T., Kamohara S., Hayashi H., Murakami T., Kagawa S.,
RA Sano H., Hashimoto N., Yoshida S., Makino H., Ebina Y.;
RT "Frequency of mutations of insulin receptor gene in Japanese patients with
RT NIDDM.";
RL Diabetes 44:1081-1086(1995).
RN [106]
RP VARIANT LEPRCH ASN-308 DEL.
RX PubMed=7538143; DOI=10.1210/jcem.80.5.7538143;
RA Longo N., Langley S.D., Griffin L.D., Elsas L.J.;
RT "Two mutations in the insulin receptor gene of a patient with
RT leprechaunism: application to prenatal diagnosis.";
RL J. Clin. Endocrinol. Metab. 80:1496-1501(1995).
RN [107]
RP VARIANT PHE-1023.
RX PubMed=8890729; DOI=10.1530/eje.0.1350357;
RA Moritz W., Boeni-Schnetzler M., Stevens W., Froesch E.R., Levy J.R.;
RT "In-frame exon 2 deletion in insulin receptor RNA in a family with extreme
RT insulin resistance in association with defective insulin binding: a case
RT report.";
RL Eur. J. Endocrinol. 135:357-363(1996).
RN [108]
RP VARIANT LEPRCH ASN-308 DEL.
RX PubMed=8636294; DOI=10.1210/jcem.81.2.8636294;
RA Desbois-Mouthon C., Sert-Langeron C., Magre J., Oreal E., Blivet M.J.,
RA Flori E., Besmond C., Capeau J., Caron M.;
RT "Deletion of Asn281 in the alpha-subunit of the human insulin receptor
RT causes constitutive activation of the receptor and insulin
RT desensitization.";
RL J. Clin. Endocrinol. Metab. 81:719-727(1996).
RN [109]
RP VARIANT MET-1012.
RX PubMed=9199575; DOI=10.1086/515464;
RA Hansen L., Hansen T., Clausen J.O., Echwald S.M., Urhammer S.A.,
RA Rasmussen S.K., Pedersen O.;
RT "The Val985Met insulin-receptor variant in the Danish Caucasian population:
RT lack of associations with non-insulin-dependent diabetes mellitus or
RT insulin resistance.";
RL Am. J. Hum. Genet. 60:1532-1535(1997).
RN [110]
RP VARIANTS IRAN TYPE A GLY-86 AND PRO-89.
RX PubMed=9175790; DOI=10.1006/bbrc.1997.6695;
RA Rouard M., Macari F., Bouix O., Lautier C., Brun J.F., Lefebvre P.,
RA Renard E., Bringer J., Jaffiol C., Grigorescu F.;
RT "Identification of two novel insulin receptor mutations, Asp59Gly and
RT Leu62Pro, in type A syndrome of extreme insulin resistance.";
RL Biochem. Biophys. Res. Commun. 234:764-768(1997).
RN [111]
RP CHARACTERIZATION OF VARIANT LEPRCH MET-937.
RX PubMed=9299395; DOI=10.1006/bbrc.1997.7181;
RA Kadowaki H., Takahashi Y., Ando A., Momomura K., Kaburagi Y., Quin J.D.,
RA MacCuish A.C., Koda N., Fukushima Y., Taylor S.I., Akanuma Y., Yazaki Y.,
RA Kadowaki T.;
RT "Four mutant alleles of the insulin receptor gene associated with genetic
RT syndromes of extreme insulin resistance.";
RL Biochem. Biophys. Res. Commun. 237:516-520(1997).
RN [112]
RP VARIANTS LEPRCH TRP-1119 AND LYS-1206.
RX PubMed=9249867;
RX DOI=10.1002/(sici)1097-0223(199707)17:7<657::aid-pd132>3.0.co;2-8;
RA Desbois-Mouthon C., Girodon E., Ghanem N., Caron M., Pennerath A.,
RA Conteville P., Magre J., Besmond C., Goossens M., Capeau J., Amselem S.;
RT "Molecular analysis of the insulin receptor gene for prenatal diagnosis of
RT leprechaunism in two families.";
RL Prenat. Diagn. 17:657-663(1997).
RN [113]
RP VARIANTS LEPRCH TYR-301 AND TRP-1201.
RX PubMed=9703342; DOI=10.2337/diab.47.8.1362;
RA Whitehead J.P., Soos M.A., Jackson R., Tasic V., Kocova M., O'Rahilly S.;
RT "Multiple molecular mechanisms of insulin receptor dysfunction in a patient
RT with Donohue syndrome.";
RL Diabetes 47:1362-1364(1998).
RN [114]
RP VARIANTS RMS THR-1143 AND TRP-1158.
RX PubMed=10443650; DOI=10.1210/jcem.84.8.5902;
RA Longo N., Wang Y., Pasquali M.;
RT "Progressive decline in insulin levels in Rabson-Mendenhall syndrome.";
RL J. Clin. Endocrinol. Metab. 84:2623-2629(1999).
RN [115]
RP VARIANTS IRAN TYPE A LEU-167 AND VAL-1055.
RX PubMed=10733238; DOI=10.1034/j.1399-0004.2000.570110.x;
RA Rique S., Nogues C., Ibanez L., Marcos M.V., Ferragut J., Carrascosa A.,
RA Potau N.;
RT "Identification of three novel mutations in the insulin receptor gene in
RT type A insulin resistant patients.";
RL Clin. Genet. 57:67-69(2000).
RN [116]
RP VARIANT IRAN TYPE A TYR-280.
RX PubMed=11260230; DOI=10.1034/j.1399-0004.2001.590309.x;
RA Osawa H., Nishimiya T., Ochi M., Niiya T., Onuma H., Kitamuro F., Kaino Y.,
RA Kida K., Makino H.;
RT "Identification of novel C253Y missense and Y864X nonsense mutations in the
RT insulin receptor gene in type A insulin-resistant patients.";
RL Clin. Genet. 59:194-197(2001).
RN [117]
RP VARIANT IRAN TYPE A CYS-279.
RX PubMed=12107746; DOI=10.1007/s00125-002-0798-5;
RA Hamer I., Foti M., Emkey R., Cordier-Bussat M., Philippe J., De Meyts P.,
RA Maeder C., Kahn C.R., Carpentier J.-L.;
RT "An arginine to cysteine(252) mutation in insulin receptors from a patient
RT with severe insulin resistance inhibits receptor internalisation but
RT preserves signalling events.";
RL Diabetologia 45:657-667(2002).
RN [118]
RP CHARACTERIZATION OF VARIANTS LEPRCH PRO-113; VAL-119; ASN-308 DEL; THR-925
RP AND TRP-926, AND VARIANTS RMS THR-997; THR-1143; TRP-1158 AND TRP-1201.
RX PubMed=12023989; DOI=10.1093/hmg/11.12.1465;
RA Longo N., Wang Y., Smith S.A., Langley S.D., DiMeglio L.A.,
RA Giannella-Neto D.;
RT "Genotype-phenotype correlation in inherited severe insulin resistance.";
RL Hum. Mol. Genet. 11:1465-1475(2002).
RN [119]
RP VARIANT LEPRCH VAL-362 DEL.
RX PubMed=12538626; DOI=10.1210/en.2002-220815;
RA George S., Johansen A., Soos M.A., Mortensen H., Gammeltoft S., Saudek V.,
RA Siddle K., Hansen L., O'Rahilly S.;
RT "Deletion of V335 from the L2 domain of the insulin receptor results in a
RT conformationally abnormal receptor that is unable to bind insulin and
RT causes Donohue's syndrome in a human subject.";
RL Endocrinology 144:631-637(2003).
RN [120]
RP VARIANT IRAN TYPE A HIS-279, VARIANTS LEPRCH GLN-120; LEU-350; ASP-458 AND
RP TRP-1119, CHARACTERIZATION OF VARIANT IRAN TYPE A HIS-279, AND
RP CHARACTERIZATION OF VARIANTS LEPRCH GLN-120 AND ASP-458.
RX PubMed=12970295; DOI=10.1210/jc.2003-030034;
RA Maassen J.A., Tobias E.S., Kayserilli H., Tukel T., Yuksel-Apak M.,
RA D'Haens E., Kleijer W.J., Fery F., van der Zon G.C.M.;
RT "Identification and functional assessment of novel and known insulin
RT receptor mutations in five patients with syndromes of severe insulin
RT resistance.";
RL J. Clin. Endocrinol. Metab. 88:4251-4257(2003).
RN [121]
RP VARIANT HHF5 GLN-1201.
RX PubMed=15161766; DOI=10.2337/diabetes.53.6.1592;
RA Hoejlund K., Hansen T., Lajer M., Henriksen J.E., Levin K., Lindholm J.,
RA Pedersen O., Bech-Nielsen H.;
RT "A novel syndrome of autosomal-dominant hyperinsulinemic hypoglycemia
RT linked to a mutation in the human insulin receptor gene.";
RL Diabetes 53:1592-1598(2004).
RN [122]
RP VARIANTS RMS ARG-236 AND SER-386, AND CHARACTERIZATION OF VARIANTS RMS
RP ARG-236 AND SER-386.
RX PubMed=17201797; DOI=10.1111/j.1365-2265.2006.02678.x;
RA Tuthill A., Semple R.K., Day R., Soos M.A., Sweeney E., Seymour P.J.,
RA Didi M., O'Rahilly S.;
RT "Functional characterization of a novel insulin receptor mutation
RT contributing to Rabson-Mendenhall syndrome.";
RL Clin. Endocrinol. (Oxf.) 66:21-26(2007).
RN [123]
RP VARIANTS [LARGE SCALE ANALYSIS] ARG-228; ARG-695; SER-811; MET-1012;
RP VAL-1065 AND ALA-1282.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G.,
RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S.,
RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G.,
RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K.,
RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D.,
RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R.,
RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A.,
RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F.,
RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F.,
RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G.,
RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R.,
RA Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
RN [124]
RP VARIANTS LEPRCH CYS-818 AND 890-ARG--SER-1382 DEL.
RX PubMed=22768670; DOI=10.1515/jpem-2011-0448;
RA Nobile S., Semple R.K., Carnielli V.P.;
RT "A novel mutation of the insulin receptor gene in a preterm infant with
RT Donohue syndrome and heart failure.";
RL J. Pediatr. Endocrinol. Metab. 25:363-366(2012).
RN [125]
RP VARIANTS LEPRCH THR-56 AND TYR-286, AND CHARACTERIZATION OF VARIANTS LEPRCH
RP THR-56 AND TYR-286.
RX PubMed=24498630; DOI=10.1002/mgg3.43;
RA Falik Zaccai T.C., Kalfon L., Klar A., Elisha M.B., Hurvitz H.,
RA Weingarten G., Chechik E., Fleisher Sheffer V., Haj Yahya R., Meidan G.,
RA Gross-Kieselstein E., Bauman D., Hershkovitz S., Yaron Y., Orr-Urtreger A.,
RA Wertheimer E.;
RT "Two novel mutations identified in familial cases with Donohue syndrome.";
RL Mol. Genet. Genomic Med. 2:64-72(2014).
RN [126]
RP VARIANTS RMS CYS-256; LEU-635; ILE-835; VAL-842; LEU-874; SER-878 AND
RP 999-TYR--SER-1382 DEL, VARIANTS IRAN TYPE A ASP-489 AND MET-1054, VARIANTS
RP LEPRCH PHE-657; ARG-659 AND CYS-818, CHARACTERIZATION OF VARIANTS LEPRCH
RP PHE-657; ARG-659; CYS-818; THR-925; TRP-926 AND MET-937, AND
RP CHARACTERIZATION OF VARIANTS RMS LEU-635; ILE-835; VAL-842; LEU-874 AND
RP SER-878.
RX PubMed=28765322; DOI=10.2337/db17-0301;
RA Hosoe J., Kadowaki H., Miya F., Aizu K., Kawamura T., Miyata I.,
RA Satomura K., Ito T., Hara K., Tanaka M., Ishiura H., Tsuji S., Suzuki K.,
RA Takakura M., Boroevich K.A., Tsunoda T., Yamauchi T., Shojima N.,
RA Kadowaki T.;
RT "Structural Basis and Genotype-Phenotype Correlations of INSR Mutations
RT Causing Severe Insulin Resistance.";
RL Diabetes 66:2713-2723(2017).
CC -!- FUNCTION: Receptor tyrosine kinase which mediates the pleiotropic
CC actions of insulin. Binding of insulin leads to phosphorylation of
CC several intracellular substrates, including, insulin receptor
CC substrates (IRS1, 2, 3, 4), SHC, GAB1, CBL and other signaling
CC intermediates. Each of these phosphorylated proteins serve as docking
CC proteins for other signaling proteins that contain Src-homology-2
CC domains (SH2 domain) that specifically recognize different
CC phosphotyrosine residues, including the p85 regulatory subunit of PI3K
CC and SHP2. Phosphorylation of IRSs proteins lead to the activation of
CC two main signaling pathways: the PI3K-AKT/PKB pathway, which is
CC responsible for most of the metabolic actions of insulin, and the Ras-
CC MAPK pathway, which regulates expression of some genes and cooperates
CC with the PI3K pathway to control cell growth and differentiation.
CC Binding of the SH2 domains of PI3K to phosphotyrosines on IRS1 leads to
CC the activation of PI3K and the generation of phosphatidylinositol-(3,
CC 4, 5)-triphosphate (PIP3), a lipid second messenger, which activates
CC several PIP3-dependent serine/threonine kinases, such as PDPK1 and
CC subsequently AKT/PKB. The net effect of this pathway is to produce a
CC translocation of the glucose transporter SLC2A4/GLUT4 from cytoplasmic
CC vesicles to the cell membrane to facilitate glucose transport.
CC Moreover, upon insulin stimulation, activated AKT/PKB is responsible
CC for: anti-apoptotic effect of insulin by inducing phosphorylation of
CC BAD; regulates the expression of gluconeogenic and lipogenic enzymes by
CC controlling the activity of the winged helix or forkhead (FOX) class of
CC transcription factors. Another pathway regulated by PI3K-AKT/PKB
CC activation is mTORC1 signaling pathway which regulates cell growth and
CC metabolism and integrates signals from insulin. AKT mediates insulin-
CC stimulated protein synthesis by phosphorylating TSC2 thereby activating
CC mTORC1 pathway. The Ras/RAF/MAP2K/MAPK pathway is mainly involved in
CC mediating cell growth, survival and cellular differentiation of
CC insulin. Phosphorylated IRS1 recruits GRB2/SOS complex, which triggers
CC the activation of the Ras/RAF/MAP2K/MAPK pathway. In addition to
CC binding insulin, the insulin receptor can bind insulin-like growth
CC factors (IGFI and IGFII). Isoform Short has a higher affinity for IGFII
CC binding. When present in a hybrid receptor with IGF1R, binds IGF1.
CC PubMed:12138094 shows that hybrid receptors composed of IGF1R and INSR
CC isoform Long are activated with a high affinity by IGF1, with low
CC affinity by IGF2 and not significantly activated by insulin, and that
CC hybrid receptors composed of IGF1R and INSR isoform Short are activated
CC by IGF1, IGF2 and insulin. In contrast, PubMed:16831875 shows that
CC hybrid receptors composed of IGF1R and INSR isoform Long and hybrid
CC receptors composed of IGF1R and INSR isoform Short have similar binding
CC characteristics, both bind IGF1 and have a low affinity for insulin. In
CC adipocytes, inhibits lipolysis (By similarity).
CC {ECO:0000250|UniProtKB:P15208, ECO:0000269|PubMed:12138094,
CC ECO:0000269|PubMed:16314505, ECO:0000269|PubMed:16831875,
CC ECO:0000269|PubMed:8257688, ECO:0000269|PubMed:8276809,
CC ECO:0000269|PubMed:8452530, ECO:0000269|PubMed:9428692}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl-
CC [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA-
CC COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858,
CC ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.1;
CC Evidence={ECO:0000255|PROSITE-ProRule:PRU10028,
CC ECO:0000269|PubMed:11124964, ECO:0000269|PubMed:11598120,
CC ECO:0000269|PubMed:12707268, ECO:0000269|PubMed:18278056,
CC ECO:0000269|PubMed:19056263, ECO:0000269|PubMed:19071018,
CC ECO:0000269|PubMed:19394223, ECO:0000269|PubMed:9312016};
CC -!- ACTIVITY REGULATION: Activated in response to insulin.
CC Autophosphorylation activates the kinase activity. PTPN1, PTPRE and
CC PTPRF dephosphorylate important tyrosine residues, thereby reducing
CC INSR activity. Inhibited by ENPP1. GRB10 and GRB14 inhibit the
CC catalytic activity of the INSR, they block access of substrates to the
CC activated receptor. SOCS1 and SOCS3 act as negative regulators of INSR
CC activity, they bind to the activated INRS and interfere with the
CC phosphorylation of INSR substrates. {ECO:0000269|PubMed:10615944,
CC ECO:0000269|PubMed:11598120, ECO:0000269|PubMed:11726652,
CC ECO:0000269|PubMed:12493740, ECO:0000269|PubMed:2211730}.
CC -!- SUBUNIT: Tetramer of 2 alpha and 2 beta chains linked by disulfide
CC bonds. The alpha chains carry the insulin-binding regions, while the
CC beta chains carry the kinase domain. Forms a hybrid receptor with
CC IGF1R, the hybrid is a tetramer consisting of 1 alpha chain and 1 beta
CC chain of INSR and 1 alpha chain and 1 beta chain of IGF1R. Interacts
CC with SORBS1 but dissociates from it following insulin stimulation.
CC Binds SH2B2. Activated form of INSR interacts (via Tyr-999) with the
CC PTB/PID domains of IRS1 and SHC1. The sequences surrounding the
CC phosphorylated NPXY motif contribute differentially to either IRS1 or
CC SHC1 recognition. Interacts (via tyrosines in the C-terminus) with IRS2
CC (via PTB domain and 591-786 AA); the 591-786 would be the primary
CC anchor of IRS2 to INSR while the PTB domain would have a stabilizing
CC action on the interaction with INSR. Interacts with the SH2 domains of
CC the 85 kDa regulatory subunit of PI3K (PIK3R1) in vitro, when
CC autophosphorylated on tyrosine residues. Interacts with SOCS7.
CC Interacts (via the phosphorylated Tyr-999), with SOCS3. Interacts (via
CC the phosphorylated Tyr-1185, Tyr-1189, Tyr-1190) with SOCS1. Interacts
CC with CAV2 (tyrosine-phosphorylated form); the interaction is increased
CC with 'Tyr-27'phosphorylation of CAV2 (By similarity). Interacts with
CC ARRB2 (By similarity). Interacts with GRB10; this interaction blocks
CC the association between IRS1/IRS2 and INSR, significantly reduces
CC insulin-stimulated tyrosine phosphorylation of IRS1 and IRS2 and thus
CC decreases insulin signaling. Interacts with GRB7. Interacts with PDPK1.
CC Interacts (via Tyr-1190) with GRB14 (via BPS domain); this interaction
CC protects the tyrosines in the activation loop from dephosphorylation,
CC but promotes dephosphorylation of Tyr-999, this results in decreased
CC interaction with, and phosphorylation of, IRS1. Interacts (via subunit
CC alpha) with ENPP1 (via 485-599 AA); this interaction blocks
CC autophosphorylation. Interacts with PTPRE; this interaction is
CC dependent of Tyr-1185, Tyr-1189 and Tyr-1190 of the INSR. Interacts
CC with STAT5B (via SH2 domain). Interacts with PTPRF. Interacts with
CC ATIC; ATIC together with PRKAA2/AMPK2 and HACD3/PTPLAD1 is proposed to
CC be part of a signaling netwok regulating INSR autophosphorylation and
CC endocytosis (By similarity). Interacts with the cone snail venom
CC insulin Con-Ins G1 (PubMed:27617429). Interacts with the insulin
CC receptor SORL1; this interaction strongly increases its surface
CC exposure, hence strengthens insulin signal reception (PubMed:27322061).
CC Interacts (tyrosine phosphorylated) with CCDC88A/GIV (via SH2-like
CC region); binding requires autophosphorylation of the INSR C-terminal
CC region (PubMed:25187647). Interacts with GNAI3; the interaction is
CC probably mediated by CCDC88A/GIV (PubMed:25187647). Interacts with
CC LMBRD1 (By similarity). {ECO:0000250, ECO:0000250|UniProtKB:P15127,
CC ECO:0000250|UniProtKB:P15208, ECO:0000269|PubMed:10615944,
CC ECO:0000269|PubMed:10803466, ECO:0000269|PubMed:11124964,
CC ECO:0000269|PubMed:11374898, ECO:0000269|PubMed:11726652,
CC ECO:0000269|PubMed:12493740, ECO:0000269|PubMed:14690593,
CC ECO:0000269|PubMed:16127460, ECO:0000269|PubMed:16246733,
CC ECO:0000269|PubMed:16271887, ECO:0000269|PubMed:16314505,
CC ECO:0000269|PubMed:16957736, ECO:0000269|PubMed:18278056,
CC ECO:0000269|PubMed:18767165, ECO:0000269|PubMed:19056263,
CC ECO:0000269|PubMed:19071018, ECO:0000269|PubMed:19394223,
CC ECO:0000269|PubMed:2211730, ECO:0000269|PubMed:23302862,
CC ECO:0000269|PubMed:25187647, ECO:0000269|PubMed:27322061,
CC ECO:0000269|PubMed:27617429, ECO:0000269|PubMed:7537849,
CC ECO:0000269|PubMed:7559478, ECO:0000269|PubMed:8276809,
CC ECO:0000269|PubMed:8995282, ECO:0000269|PubMed:8999839,
CC ECO:0000269|PubMed:9312016, ECO:0000269|PubMed:9428692}.
CC -!- INTERACTION:
CC P06213; Q99490: AGAP2; NbExp=2; IntAct=EBI-475899, EBI-2361824;
CC P06213; Q8NEJ0: DUSP18; NbExp=2; IntAct=EBI-475899, EBI-10698945;
CC P06213; Q13322: GRB10; NbExp=3; IntAct=EBI-475899, EBI-80275;
CC P06213; P05019: IGF1; NbExp=4; IntAct=EBI-475899, EBI-7902275;
CC P06213; P35568: IRS1; NbExp=3; IntAct=EBI-475899, EBI-517592;
CC P06213; Q15323: KRT31; NbExp=3; IntAct=EBI-475899, EBI-948001;
CC P06213; P27986: PIK3R1; NbExp=3; IntAct=EBI-475899, EBI-79464;
CC P06213; P19174: PLCG1; NbExp=9; IntAct=EBI-475899, EBI-79387;
CC P06213; P18031: PTPN1; NbExp=32; IntAct=EBI-475899, EBI-968788;
CC P06213; Q06124: PTPN11; NbExp=2; IntAct=EBI-475899, EBI-297779;
CC P06213; Q15256: PTPRR; NbExp=2; IntAct=EBI-475899, EBI-2265659;
CC P06213; Q9NRF2: SH2B1; NbExp=6; IntAct=EBI-475899, EBI-310491;
CC P06213; P29353: SHC1; NbExp=2; IntAct=EBI-475899, EBI-78835;
CC P06213; P01317: INS; Xeno; NbExp=5; IntAct=EBI-475899, EBI-3989070;
CC P06213; P35570: Irs1; Xeno; NbExp=5; IntAct=EBI-475899, EBI-520230;
CC P06213-1; P32121: ARRB2; NbExp=2; IntAct=EBI-15558981, EBI-714559;
CC P06213-1; P06213-1: INSR; NbExp=4; IntAct=EBI-15558981, EBI-15558981;
CC P06213-1; P18031: PTPN1; NbExp=2; IntAct=EBI-15558981, EBI-968788;
CC P06213-1; Q92485-2: SMPDL3B; NbExp=2; IntAct=EBI-15558981, EBI-21501656;
CC P06213-1; P81122: Irs2; Xeno; NbExp=8; IntAct=EBI-15558981, EBI-1369862;
CC P06213-1; Q1XH17: Trim72; Xeno; NbExp=2; IntAct=EBI-15558981, EBI-16034016;
CC P06213-2; P01308: INS; NbExp=6; IntAct=EBI-9984921, EBI-7090529;
CC P06213-2; Q13257: MAD2L1; NbExp=3; IntAct=EBI-9984921, EBI-78203;
CC P06213-2; Q92485-2: SMPDL3B; NbExp=2; IntAct=EBI-9984921, EBI-21501656;
CC P06213-2; P01317: INS; Xeno; NbExp=2; IntAct=EBI-9984921, EBI-3989070;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:P15208};
CC Single-pass type I membrane protein {ECO:0000305}. Late endosome
CC {ECO:0000250|UniProtKB:P15208}. Lysosome
CC {ECO:0000250|UniProtKB:P15208}. Note=Binding of insulin to INSR induces
CC internalization and lysosomal degradation of the receptor, a means for
CC down-regulating this signaling pathway after stimulation. In the
CC presence of SORL1, internalized INSR molecules are redirected back to
CC the cell surface, thereby preventing their lysosomal catabolism and
CC strengthening insulin signal reception. {ECO:0000250|UniProtKB:P15208}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=Long; Synonyms=HIR-B;
CC IsoId=P06213-1; Sequence=Displayed;
CC Name=Short; Synonyms=HIR-A;
CC IsoId=P06213-2; Sequence=VSP_002898;
CC -!- TISSUE SPECIFICITY: Isoform Long and isoform Short are predominantly
CC expressed in tissue targets of insulin metabolic effects: liver,
CC adipose tissue and skeletal muscle but are also expressed in the
CC peripheral nerve, kidney, pulmonary alveoli, pancreatic acini, placenta
CC vascular endothelium, fibroblasts, monocytes, granulocytes,
CC erythrocytes and skin. Isoform Short is preferentially expressed in
CC fetal cells such as fetal fibroblasts, muscle, liver and kidney. Found
CC as a hybrid receptor with IGF1R in muscle, heart, kidney, adipose
CC tissue, skeletal muscle, hepatoma, fibroblasts, spleen and placenta (at
CC protein level). Overexpressed in several tumors, including breast,
CC colon, lung, ovary, and thyroid carcinomas.
CC {ECO:0000269|PubMed:10207053, ECO:0000269|PubMed:2369896,
CC ECO:0000269|PubMed:9202395, ECO:0000269|PubMed:9355755}.
CC -!- DOMAIN: The tetrameric insulin receptor binds insulin via non-identical
CC regions from two alpha chains, primarily via the C-terminal region of
CC the first INSR alpha chain. Residues from the leucine-rich N-terminus
CC of the other INSR alpha chain also contribute to this insulin binding
CC site. A secondary insulin-binding site is formed by residues at the
CC junction of fibronectin type-III domain 1 and 2.
CC {ECO:0000269|PubMed:16957736, ECO:0000269|PubMed:19459609,
CC ECO:0000269|PubMed:23302862}.
CC -!- PTM: After being transported from the endoplasmic reticulum to the
CC Golgi apparatus, the single glycosylated precursor is further
CC glycosylated and then cleaved, followed by its transport to the plasma
CC membrane. {ECO:0000269|PubMed:1472036, ECO:0000269|PubMed:16894147,
CC ECO:0000269|PubMed:19159218, ECO:0000269|PubMed:19349973,
CC ECO:0000269|PubMed:23302862, ECO:0000269|PubMed:2983222}.
CC -!- PTM: Autophosphorylated on tyrosine residues in response to insulin.
CC Phosphorylation of Tyr-999 is required for binding to IRS1, SHC1 and
CC STAT5B. Dephosphorylated by PTPRE at Tyr-999, Tyr-1185, Tyr-1189 and
CC Tyr-1190. Dephosphorylated by PTPRF and PTPN1. Dephosphorylated by
CC PTPN2; down-regulates insulin-induced signaling.
CC {ECO:0000269|PubMed:10734133, ECO:0000269|PubMed:12612081,
CC ECO:0000269|PubMed:14690593, ECO:0000269|PubMed:16246733,
CC ECO:0000269|PubMed:16271887, ECO:0000269|PubMed:18278056,
CC ECO:0000269|PubMed:18767165, ECO:0000269|PubMed:3166375,
CC ECO:0000269|PubMed:9312016}.
CC -!- DISEASE: Rabson-Mendenhall syndrome (RMS) [MIM:262190]: Severe insulin
CC resistance syndrome characterized by insulin-resistant diabetes
CC mellitus with pineal hyperplasia and somatic abnormalities. Typical
CC features include coarse, senile-appearing facies, dental and skin
CC abnormalities, abdominal distension, and phallic enlargement.
CC Inheritance is autosomal recessive. {ECO:0000269|PubMed:10443650,
CC ECO:0000269|PubMed:12023989, ECO:0000269|PubMed:17201797,
CC ECO:0000269|PubMed:2121734, ECO:0000269|PubMed:2365819,
CC ECO:0000269|PubMed:28765322, ECO:0000269|PubMed:8314008}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- DISEASE: Leprechaunism (LEPRCH) [MIM:246200]: Represents the most
CC severe form of insulin resistance syndrome, characterized by
CC intrauterine and postnatal growth retardation and death in early
CC infancy. Inheritance is autosomal recessive.
CC {ECO:0000269|PubMed:12023989, ECO:0000269|PubMed:12538626,
CC ECO:0000269|PubMed:12970295, ECO:0000269|PubMed:1607067,
CC ECO:0000269|PubMed:1730625, ECO:0000269|PubMed:22768670,
CC ECO:0000269|PubMed:2365819, ECO:0000269|PubMed:24498630,
CC ECO:0000269|PubMed:2479553, ECO:0000269|PubMed:2834824,
CC ECO:0000269|PubMed:28765322, ECO:0000269|PubMed:7538143,
CC ECO:0000269|PubMed:7815442, ECO:0000269|PubMed:8188715,
CC ECO:0000269|PubMed:8326490, ECO:0000269|PubMed:8419945,
CC ECO:0000269|PubMed:8636294, ECO:0000269|PubMed:9249867,
CC ECO:0000269|PubMed:9299395, ECO:0000269|PubMed:9703342}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- DISEASE: Diabetes mellitus, non-insulin-dependent (NIDDM) [MIM:125853]:
CC A multifactorial disorder of glucose homeostasis caused by a lack of
CC sensitivity to the body's own insulin. Affected individuals usually
CC have an obese body habitus and manifestations of a metabolic syndrome
CC characterized by diabetes, insulin resistance, hypertension and
CC hypertriglyceridemia. The disease results in long-term complications
CC that affect the eyes, kidneys, nerves, and blood vessels.
CC {ECO:0000269|PubMed:1470163, ECO:0000269|PubMed:1607076,
CC ECO:0000269|PubMed:7657032}. Note=The gene represented in this entry
CC may be involved in disease pathogenesis.
CC -!- DISEASE: Familial hyperinsulinemic hypoglycemia 5 (HHF5) [MIM:609968]:
CC Familial hyperinsulinemic hypoglycemia [MIM:256450], also referred to
CC as congenital hyperinsulinism, nesidioblastosis, or persistent
CC hyperinsulinemic hypoglycemia of infancy (PPHI), is the most common
CC cause of persistent hypoglycemia in infancy and is due to defective
CC negative feedback regulation of insulin secretion by low glucose
CC levels. {ECO:0000269|PubMed:15161766}. Note=The disease is caused by
CC variants affecting the gene represented in this entry.
CC -!- DISEASE: Insulin-resistant diabetes mellitus with acanthosis nigricans
CC type A (IRAN type A) [MIM:610549]: Characterized by the association of
CC severe insulin resistance (manifested by marked hyperinsulinemia and a
CC failure to respond to exogenous insulin) with the skin lesion
CC acanthosis nigricans and ovarian hyperandrogenism in adolescent female
CC subjects. Women frequently present with hirsutism, acne, amenorrhea or
CC oligomenorrhea, and virilization. This syndrome is different from the
CC type B that has been demonstrated to be secondary to the presence of
CC circulating autoantibodies against the insulin receptor.
CC {ECO:0000269|PubMed:10733238, ECO:0000269|PubMed:11260230,
CC ECO:0000269|PubMed:12107746, ECO:0000269|PubMed:12970295,
CC ECO:0000269|PubMed:1563582, ECO:0000269|PubMed:1963473,
CC ECO:0000269|PubMed:2002058, ECO:0000269|PubMed:2168397,
CC ECO:0000269|PubMed:2365819, ECO:0000269|PubMed:2544998,
CC ECO:0000269|PubMed:28765322, ECO:0000269|PubMed:3283938,
CC ECO:0000269|PubMed:8243830, ECO:0000269|PubMed:8288049,
CC ECO:0000269|PubMed:8314008, ECO:0000269|PubMed:8388389,
CC ECO:0000269|PubMed:9175790}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein
CC kinase family. Insulin receptor subfamily. {ECO:0000255|PROSITE-
CC ProRule:PRU00159}.
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Insulin receptor entry;
CC URL="https://en.wikipedia.org/wiki/Insulin_receptor";
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
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DR EMBL; M10051; AAA59174.1; -; mRNA.
DR EMBL; X02160; CAA26096.1; -; mRNA.
DR EMBL; M32972; AAA59452.1; -; Genomic_DNA.
DR EMBL; M23100; AAA59452.1; JOINED; Genomic_DNA.
DR EMBL; M32823; AAA59452.1; JOINED; Genomic_DNA.
DR EMBL; M32824; AAA59452.1; JOINED; Genomic_DNA.
DR EMBL; M32825; AAA59452.1; JOINED; Genomic_DNA.
DR EMBL; M32826; AAA59452.1; JOINED; Genomic_DNA.
DR EMBL; M32827; AAA59452.1; JOINED; Genomic_DNA.
DR EMBL; M32828; AAA59452.1; JOINED; Genomic_DNA.
DR EMBL; M32829; AAA59452.1; JOINED; Genomic_DNA.
DR EMBL; M32830; AAA59452.1; JOINED; Genomic_DNA.
DR EMBL; M32831; AAA59452.1; JOINED; Genomic_DNA.
DR EMBL; M32832; AAA59452.1; JOINED; Genomic_DNA.
DR EMBL; M32833; AAA59452.1; JOINED; Genomic_DNA.
DR EMBL; M32834; AAA59452.1; JOINED; Genomic_DNA.
DR EMBL; M32835; AAA59452.1; JOINED; Genomic_DNA.
DR EMBL; M32836; AAA59452.1; JOINED; Genomic_DNA.
DR EMBL; M32837; AAA59452.1; JOINED; Genomic_DNA.
DR EMBL; M32838; AAA59452.1; JOINED; Genomic_DNA.
DR EMBL; M32839; AAA59452.1; JOINED; Genomic_DNA.
DR EMBL; M32840; AAA59452.1; JOINED; Genomic_DNA.
DR EMBL; M32841; AAA59452.1; JOINED; Genomic_DNA.
DR EMBL; M32842; AAA59452.1; JOINED; Genomic_DNA.
DR EMBL; AC010311; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC010526; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC010606; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC125387; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC117172; AAI17173.1; -; mRNA.
DR EMBL; J03466; AAA59175.1; -; Genomic_DNA.
DR EMBL; J05043; AAA59190.1; -; Genomic_DNA.
DR EMBL; M76592; AAC37604.1; -; Genomic_DNA.
DR EMBL; AB208861; BAD92098.1; -; mRNA.
DR EMBL; M24555; AAA59178.1; -; mRNA.
DR EMBL; M29929; AAA59176.1; -; Genomic_DNA.
DR EMBL; M29930; AAA59177.1; -; Genomic_DNA.
DR EMBL; M27197; AAA86791.1; -; Genomic_DNA.
DR EMBL; M27195; AAA86791.1; JOINED; Genomic_DNA.
DR CCDS; CCDS12176.1; -. [P06213-1]
DR CCDS; CCDS42487.1; -. [P06213-2]
DR PIR; A37348; INHUR.
DR RefSeq; NP_000199.2; NM_000208.3. [P06213-1]
DR RefSeq; NP_001073285.1; NM_001079817.2. [P06213-2]
DR PDB; 1GAG; X-ray; 2.70 A; A=1005-1310.
DR PDB; 1I44; X-ray; 2.40 A; A=1005-1310.
DR PDB; 1IR3; X-ray; 1.90 A; A=1005-1310.
DR PDB; 1IRK; X-ray; 2.10 A; A=1005-1310.
DR PDB; 1P14; X-ray; 1.90 A; A=1005-1310.
DR PDB; 1RQQ; X-ray; 2.60 A; A/B=1005-1310.
DR PDB; 2AUH; X-ray; 3.20 A; A=1005-1310.
DR PDB; 2B4S; X-ray; 2.30 A; B/D=1005-1310.
DR PDB; 2HR7; X-ray; 2.32 A; A/B=28-512.
DR PDB; 2MFR; NMR; -; A=940-988.
DR PDB; 2Z8C; X-ray; 3.25 A; A=1008-1310.
DR PDB; 3BU3; X-ray; 1.65 A; A=1005-1310.
DR PDB; 3BU5; X-ray; 2.10 A; A=1005-1310.
DR PDB; 3BU6; X-ray; 1.95 A; A=1005-1310.
DR PDB; 3EKK; X-ray; 2.10 A; A=1005-1310.
DR PDB; 3EKN; X-ray; 2.20 A; A=1005-1310.
DR PDB; 3ETA; X-ray; 2.60 A; A/B=1017-1322.
DR PDB; 3W11; X-ray; 3.90 A; E=28-337, F=731-744.
DR PDB; 3W12; X-ray; 4.30 A; E=28-337, F=731-744.
DR PDB; 3W13; X-ray; 4.30 A; E=28-337, F=724-744.
DR PDB; 4IBM; X-ray; 1.80 A; A/B=1005-1310.
DR PDB; 4OGA; X-ray; 3.50 A; E=28-337, F=731-744.
DR PDB; 4XLV; X-ray; 2.30 A; A=983-1310.
DR PDB; 4XSS; X-ray; 3.00 A; E=28-337.
DR PDB; 4XST; X-ray; 3.00 A; E=28-337.
DR PDB; 4ZXB; X-ray; 3.30 A; E=28-956.
DR PDB; 5E1S; X-ray; 2.26 A; A=1005-1310.
DR PDB; 5HHW; X-ray; 1.79 A; A=1005-1310.
DR PDB; 5J3H; X-ray; 3.27 A; E=28-337.
DR PDB; 5KQV; X-ray; 4.40 A; E/F=28-746.
DR PDB; 5U1M; X-ray; 1.80 A; B=991-999.
DR PDB; 6HN4; EM; 4.20 A; E/F=28-955.
DR PDB; 6HN5; EM; 3.20 A; E/F=28-955.
DR PDB; 6PXV; EM; 3.20 A; A/C=28-1382.
DR PDB; 6PXW; EM; 3.10 A; A/B=28-1382.
DR PDB; 6SOF; EM; 4.30 A; A/C=28-746, B/D=795-956.
DR PDB; 6VEP; X-ray; 2.90 A; E/K/Q/W=28-337, F/L/R/X=731-746.
DR PDB; 6VEQ; X-ray; 3.25 A; E/K=28-337, F/L=731-746.
DR PDB; 7BW7; EM; 4.10 A; A/C=28-1382.
DR PDB; 7BW8; EM; 3.80 A; A/C=28-1382.
DR PDB; 7BWA; EM; 4.90 A; A/C=28-1382.
DR PDB; 7KD6; X-ray; 2.60 A; E/K/Q/W=28-337.
DR PDB; 7MQO; EM; 3.40 A; E/F=28-956.
DR PDB; 7MQR; EM; 4.10 A; E/F=28-955.
DR PDB; 7MQS; EM; 4.40 A; E/F=28-955.
DR PDB; 7PG0; EM; 7.60 A; A/B=1-1382.
DR PDB; 7PG2; EM; 6.70 A; A/B=1-1382.
DR PDB; 7PG3; EM; 7.30 A; A/B=1-1382.
DR PDB; 7PG4; EM; 9.10 A; A/B=1-1382.
DR PDB; 7QID; EM; 5.00 A; A/C=28-746, B/D=763-956.
DR PDBsum; 1GAG; -.
DR PDBsum; 1I44; -.
DR PDBsum; 1IR3; -.
DR PDBsum; 1IRK; -.
DR PDBsum; 1P14; -.
DR PDBsum; 1RQQ; -.
DR PDBsum; 2AUH; -.
DR PDBsum; 2B4S; -.
DR PDBsum; 2HR7; -.
DR PDBsum; 2MFR; -.
DR PDBsum; 2Z8C; -.
DR PDBsum; 3BU3; -.
DR PDBsum; 3BU5; -.
DR PDBsum; 3BU6; -.
DR PDBsum; 3EKK; -.
DR PDBsum; 3EKN; -.
DR PDBsum; 3ETA; -.
DR PDBsum; 3W11; -.
DR PDBsum; 3W12; -.
DR PDBsum; 3W13; -.
DR PDBsum; 4IBM; -.
DR PDBsum; 4OGA; -.
DR PDBsum; 4XLV; -.
DR PDBsum; 4XSS; -.
DR PDBsum; 4XST; -.
DR PDBsum; 4ZXB; -.
DR PDBsum; 5E1S; -.
DR PDBsum; 5HHW; -.
DR PDBsum; 5J3H; -.
DR PDBsum; 5KQV; -.
DR PDBsum; 5U1M; -.
DR PDBsum; 6HN4; -.
DR PDBsum; 6HN5; -.
DR PDBsum; 6PXV; -.
DR PDBsum; 6PXW; -.
DR PDBsum; 6SOF; -.
DR PDBsum; 6VEP; -.
DR PDBsum; 6VEQ; -.
DR PDBsum; 7BW7; -.
DR PDBsum; 7BW8; -.
DR PDBsum; 7BWA; -.
DR PDBsum; 7KD6; -.
DR PDBsum; 7MQO; -.
DR PDBsum; 7MQR; -.
DR PDBsum; 7MQS; -.
DR PDBsum; 7PG0; -.
DR PDBsum; 7PG2; -.
DR PDBsum; 7PG3; -.
DR PDBsum; 7PG4; -.
DR PDBsum; 7QID; -.
DR AlphaFoldDB; P06213; -.
DR BMRB; P06213; -.
DR SASBDB; P06213; -.
DR SMR; P06213; -.
DR BioGRID; 109854; 185.
DR CORUM; P06213; -.
DR DIP; DIP-480N; -.
DR ELM; P06213; -.
DR IntAct; P06213; 84.
DR MINT; P06213; -.
DR STRING; 9606.ENSP00000303830; -.
DR BindingDB; P06213; -.
DR ChEMBL; CHEMBL1981; -.
DR DrugBank; DB08513; [4-({5-(AMINOCARBONYL)-4-[(3-METHYLPHENYL)AMINO]PYRIMIDIN-2-YL}AMINO)PHENYL]ACETIC ACID.
DR DrugBank; DB03909; Adenosine-5'-[Beta, Gamma-Methylene]Triphosphate.
DR DrugBank; DB05120; AT1391.
DR DrugBank; DB15399; BMS-754807.
DR DrugBank; DB12267; Brigatinib.
DR DrugBank; DB09129; Chromic chloride.
DR DrugBank; DB12010; Fostamatinib.
DR DrugBank; DB11564; Insulin argine.
DR DrugBank; DB01306; Insulin aspart.
DR DrugBank; DB09456; Insulin beef.
DR DrugBank; DB09564; Insulin degludec.
DR DrugBank; DB01307; Insulin detemir.
DR DrugBank; DB00047; Insulin glargine.
DR DrugBank; DB01309; Insulin glulisine.
DR DrugBank; DB00030; Insulin human.
DR DrugBank; DB00046; Insulin lispro.
DR DrugBank; DB11567; Insulin peglispro.
DR DrugBank; DB00071; Insulin pork.
DR DrugBank; DB11568; Insulin tregopil.
DR DrugBank; DB16637; KW-2450 free base.
DR DrugBank; DB06075; Linsitinib.
DR DrugBank; DB01277; Mecasermin.
DR DrugBank; DB14751; Mecasermin rinfabate.
DR DrugBank; DB05115; NN344.
DR DrugCentral; P06213; -.
DR GuidetoPHARMACOLOGY; 1800; -.
DR GlyConnect; 1402; 8 N-Linked glycans (6 sites).
DR GlyGen; P06213; 22 sites, 8 N-linked glycans (6 sites), 4 O-linked glycans (4 sites).
DR iPTMnet; P06213; -.
DR PhosphoSitePlus; P06213; -.
DR BioMuta; INSR; -.
DR DMDM; 308153655; -.
DR CPTAC; CPTAC-1771; -.
DR CPTAC; CPTAC-1772; -.
DR EPD; P06213; -.
DR jPOST; P06213; -.
DR MassIVE; P06213; -.
DR MaxQB; P06213; -.
DR PaxDb; P06213; -.
DR PeptideAtlas; P06213; -.
DR PRIDE; P06213; -.
DR ProteomicsDB; 51872; -. [P06213-1]
DR ProteomicsDB; 51873; -. [P06213-2]
DR ABCD; P06213; 3 sequenced antibodies.
DR Antibodypedia; 3403; 2147 antibodies from 53 providers.
DR DNASU; 3643; -.
DR Ensembl; ENST00000302850.10; ENSP00000303830.4; ENSG00000171105.14. [P06213-1]
DR Ensembl; ENST00000341500.9; ENSP00000342838.4; ENSG00000171105.14. [P06213-2]
DR GeneID; 3643; -.
DR KEGG; hsa:3643; -.
DR MANE-Select; ENST00000302850.10; ENSP00000303830.4; NM_000208.4; NP_000199.2.
DR UCSC; uc002mgd.2; human. [P06213-1]
DR CTD; 3643; -.
DR DisGeNET; 3643; -.
DR GeneCards; INSR; -.
DR GeneReviews; INSR; -.
DR HGNC; HGNC:6091; INSR.
DR HPA; ENSG00000171105; Low tissue specificity.
DR MalaCards; INSR; -.
DR MIM; 125853; phenotype.
DR MIM; 147670; gene.
DR MIM; 246200; phenotype.
DR MIM; 262190; phenotype.
DR MIM; 609968; phenotype.
DR MIM; 610549; phenotype.
DR neXtProt; NX_P06213; -.
DR OpenTargets; ENSG00000171105; -.
DR Orphanet; 263458; Hyperinsulinism due to INSR deficiency.
DR Orphanet; 2297; Insulin-resistance syndrome type A.
DR Orphanet; 508; Leprechaunism.
DR Orphanet; 769; Rabson-Mendenhall syndrome.
DR PharmGKB; PA202; -.
DR VEuPathDB; HostDB:ENSG00000171105; -.
DR eggNOG; KOG4258; Eukaryota.
DR GeneTree; ENSGT00940000155404; -.
DR HOGENOM; CLU_000288_166_0_1; -.
DR InParanoid; P06213; -.
DR OMA; QYIPDDW; -.
DR OrthoDB; 1567781at2759; -.
DR PhylomeDB; P06213; -.
DR TreeFam; TF351636; -.
DR BRENDA; 2.7.10.1; 2681.
DR PathwayCommons; P06213; -.
DR Reactome; R-HSA-6811558; PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling.
DR Reactome; R-HSA-74713; IRS activation.
DR Reactome; R-HSA-74749; Signal attenuation.
DR Reactome; R-HSA-74751; Insulin receptor signalling cascade.
DR Reactome; R-HSA-74752; Signaling by Insulin receptor.
DR Reactome; R-HSA-77387; Insulin receptor recycling.
DR SABIO-RK; P06213; -.
DR SignaLink; P06213; -.
DR SIGNOR; P06213; -.
DR BioGRID-ORCS; 3643; 13 hits in 1106 CRISPR screens.
DR ChiTaRS; INSR; human.
DR EvolutionaryTrace; P06213; -.
DR GeneWiki; Insulin_receptor; -.
DR GenomeRNAi; 3643; -.
DR Pharos; P06213; Tclin.
DR PRO; PR:P06213; -.
DR Proteomes; UP000005640; Chromosome 19.
DR RNAct; P06213; protein.
DR Bgee; ENSG00000171105; Expressed in buccal mucosa cell and 207 other tissues.
DR ExpressionAtlas; P06213; baseline and differential.
DR Genevisible; P06213; HS.
DR GO; GO:0030424; C:axon; IBA:GO_Central.
DR GO; GO:0005901; C:caveola; IDA:BHF-UCL.
DR GO; GO:0032590; C:dendrite membrane; ISS:ARUK-UCL.
DR GO; GO:0010008; C:endosome membrane; TAS:Reactome.
DR GO; GO:0009897; C:external side of plasma membrane; ISS:ARUK-UCL.
DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR GO; GO:0005899; C:insulin receptor complex; IDA:UniProtKB.
DR GO; GO:0005887; C:integral component of plasma membrane; IDA:BHF-UCL.
DR GO; GO:0005770; C:late endosome; IEA:UniProtKB-SubCell.
DR GO; GO:0005764; C:lysosome; IEA:UniProtKB-SubCell.
DR GO; GO:0016020; C:membrane; IDA:BHF-UCL.
DR GO; GO:0032809; C:neuronal cell body membrane; ISS:ARUK-UCL.
DR GO; GO:0005886; C:plasma membrane; IDA:ARUK-UCL.
DR GO; GO:0043235; C:receptor complex; IDA:MGI.
DR GO; GO:0001540; F:amyloid-beta binding; IPI:ARUK-UCL.
DR GO; GO:0005524; F:ATP binding; IDA:BHF-UCL.
DR GO; GO:0038024; F:cargo receptor activity; ISS:ARUK-UCL.
DR GO; GO:0005525; F:GTP binding; IDA:BHF-UCL.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0043559; F:insulin binding; IDA:UniProtKB.
DR GO; GO:0005009; F:insulin receptor activity; IDA:UniProtKB.
DR GO; GO:0043560; F:insulin receptor substrate binding; IPI:UniProtKB.
DR GO; GO:0031994; F:insulin-like growth factor I binding; IPI:BHF-UCL.
DR GO; GO:0031995; F:insulin-like growth factor II binding; IPI:BHF-UCL.
DR GO; GO:0005159; F:insulin-like growth factor receptor binding; IDA:BHF-UCL.
DR GO; GO:0043548; F:phosphatidylinositol 3-kinase binding; IPI:UniProtKB.
DR GO; GO:0019904; F:protein domain specific binding; IPI:CAFA.
DR GO; GO:0004713; F:protein tyrosine kinase activity; IDA:BHF-UCL.
DR GO; GO:0044877; F:protein-containing complex binding; IPI:ARUK-UCL.
DR GO; GO:0051425; F:PTB domain binding; IPI:UniProtKB.
DR GO; GO:0005198; F:structural molecule activity; IDA:UniProtKB.
DR GO; GO:0004714; F:transmembrane receptor protein tyrosine kinase activity; IBA:GO_Central.
DR GO; GO:0032147; P:activation of protein kinase activity; IMP:BHF-UCL.
DR GO; GO:0032148; P:activation of protein kinase B activity; IDA:BHF-UCL.
DR GO; GO:0030325; P:adrenal gland development; IEA:Ensembl.
DR GO; GO:0097242; P:amyloid-beta clearance; ISS:ARUK-UCL.
DR GO; GO:0005975; P:carbohydrate metabolic process; IEA:UniProtKB-KW.
DR GO; GO:0071363; P:cellular response to growth factor stimulus; IEA:Ensembl.
DR GO; GO:0032869; P:cellular response to insulin stimulus; IDA:BHF-UCL.
DR GO; GO:0097062; P:dendritic spine maintenance; ISS:ARUK-UCL.
DR GO; GO:0008544; P:epidermis development; IEA:Ensembl.
DR GO; GO:0031017; P:exocrine pancreas development; IEA:Ensembl.
DR GO; GO:0007186; P:G protein-coupled receptor signaling pathway; IDA:BHF-UCL.
DR GO; GO:0042593; P:glucose homeostasis; IMP:BHF-UCL.
DR GO; GO:0003007; P:heart morphogenesis; IMP:BHF-UCL.
DR GO; GO:0008286; P:insulin receptor signaling pathway; IDA:UniProtKB.
DR GO; GO:0007612; P:learning; TAS:ARUK-UCL.
DR GO; GO:0008584; P:male gonad development; IEA:Ensembl.
DR GO; GO:0030238; P:male sex determination; IEA:Ensembl.
DR GO; GO:0007613; P:memory; TAS:ARUK-UCL.
DR GO; GO:1990535; P:neuron projection maintenance; ISS:ARUK-UCL.
DR GO; GO:0038083; P:peptidyl-tyrosine autophosphorylation; IEA:Ensembl.
DR GO; GO:0018108; P:peptidyl-tyrosine phosphorylation; IDA:BHF-UCL.
DR GO; GO:0030335; P:positive regulation of cell migration; IMP:BHF-UCL.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; IDA:BHF-UCL.
DR GO; GO:0048639; P:positive regulation of developmental growth; IMP:BHF-UCL.
DR GO; GO:0046326; P:positive regulation of glucose import; IDA:BHF-UCL.
DR GO; GO:0045725; P:positive regulation of glycogen biosynthetic process; IDA:BHF-UCL.
DR GO; GO:0045821; P:positive regulation of glycolytic process; IMP:BHF-UCL.
DR GO; GO:0033674; P:positive regulation of kinase activity; IBA:GO_Central.
DR GO; GO:0043406; P:positive regulation of MAP kinase activity; IMP:BHF-UCL.
DR GO; GO:0043410; P:positive regulation of MAPK cascade; IDA:BHF-UCL.
DR GO; GO:0051446; P:positive regulation of meiotic cell cycle; IEA:Ensembl.
DR GO; GO:0045840; P:positive regulation of mitotic nuclear division; IMP:BHF-UCL.
DR GO; GO:0045429; P:positive regulation of nitric oxide biosynthetic process; IMP:BHF-UCL.
DR GO; GO:0014068; P:positive regulation of phosphatidylinositol 3-kinase signaling; IBA:GO_Central.
DR GO; GO:0051897; P:positive regulation of protein kinase B signaling; IMP:BHF-UCL.
DR GO; GO:0001934; P:positive regulation of protein phosphorylation; IDA:BHF-UCL.
DR GO; GO:0043243; P:positive regulation of protein-containing complex disassembly; ISS:ARUK-UCL.
DR GO; GO:0002092; P:positive regulation of receptor internalization; IDA:CACAO.
DR GO; GO:0060267; P:positive regulation of respiratory burst; IDA:BHF-UCL.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IEA:Ensembl.
DR GO; GO:0046777; P:protein autophosphorylation; IDA:BHF-UCL.
DR GO; GO:0006468; P:protein phosphorylation; TAS:ARUK-UCL.
DR GO; GO:0006898; P:receptor-mediated endocytosis; ISS:ARUK-UCL.
DR GO; GO:0045995; P:regulation of embryonic development; IMP:BHF-UCL.
DR GO; GO:2000194; P:regulation of female gonad development; IEA:Ensembl.
DR GO; GO:0006355; P:regulation of transcription, DNA-templated; IMP:BHF-UCL.
DR GO; GO:0007169; P:transmembrane receptor protein tyrosine kinase signaling pathway; IBA:GO_Central.
DR GO; GO:0150104; P:transport across blood-brain barrier; NAS:ARUK-UCL.
DR GO; GO:0046718; P:viral entry into host cell; IMP:BHF-UCL.
DR CDD; cd00063; FN3; 2.
DR CDD; cd00064; FU; 1.
DR Gene3D; 2.60.40.10; -; 4.
DR Gene3D; 3.80.20.20; -; 2.
DR InterPro; IPR003961; FN3_dom.
DR InterPro; IPR036116; FN3_sf.
DR InterPro; IPR006211; Furin-like_Cys-rich_dom.
DR InterPro; IPR006212; Furin_repeat.
DR InterPro; IPR009030; Growth_fac_rcpt_cys_sf.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR040969; Insulin_TMD.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR000494; Rcpt_L-dom.
DR InterPro; IPR036941; Rcpt_L-dom_sf.
DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
DR InterPro; IPR008266; Tyr_kinase_AS.
DR InterPro; IPR020635; Tyr_kinase_cat_dom.
DR InterPro; IPR016246; Tyr_kinase_insulin-like_rcpt.
DR InterPro; IPR002011; Tyr_kinase_rcpt_2_CS.
DR Pfam; PF00757; Furin-like; 1.
DR Pfam; PF17870; Insulin_TMD; 1.
DR Pfam; PF07714; PK_Tyr_Ser-Thr; 1.
DR Pfam; PF01030; Recep_L_domain; 2.
DR PIRSF; PIRSF000620; Insulin_receptor; 1.
DR PRINTS; PR00109; TYRKINASE.
DR SMART; SM00060; FN3; 3.
DR SMART; SM00261; FU; 2.
DR SMART; SM00219; TyrKc; 1.
DR SUPFAM; SSF49265; SSF49265; 3.
DR SUPFAM; SSF56112; SSF56112; 1.
DR SUPFAM; SSF57184; SSF57184; 1.
DR PROSITE; PS50853; FN3; 2.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00109; PROTEIN_KINASE_TYR; 1.
DR PROSITE; PS00239; RECEPTOR_TYR_KIN_II; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; ATP-binding; Carbohydrate metabolism;
KW Cell membrane; Cleavage on pair of basic residues; Diabetes mellitus;
KW Direct protein sequencing; Disease variant; Disulfide bond; Endosome;
KW Glycoprotein; Kinase; Lysosome; Membrane; Nucleotide-binding;
KW Phosphoprotein; Receptor; Reference proteome; Repeat; Signal; Transferase;
KW Transmembrane; Transmembrane helix; Tyrosine-protein kinase.
FT SIGNAL 1..27
FT /evidence="ECO:0000269|PubMed:2211730,
FT ECO:0000269|PubMed:2983222, ECO:0000269|PubMed:8257688"
FT CHAIN 28..758
FT /note="Insulin receptor subunit alpha"
FT /id="PRO_0000016687"
FT CHAIN 763..1382
FT /note="Insulin receptor subunit beta"
FT /id="PRO_0000016689"
FT TOPO_DOM 28..758
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TOPO_DOM 763..956
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 957..979
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 980..1382
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT DOMAIN 624..726
FT /note="Fibronectin type-III 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316"
FT DOMAIN 757..842
FT /note="Fibronectin type-III 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316"
FT DOMAIN 853..947
FT /note="Fibronectin type-III 3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316"
FT DOMAIN 1023..1298
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 686..708
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 733..741
FT /note="Insulin-binding"
FT REGION 746..766
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 999
FT /note="Important for interaction with IRS1, SHC1 and
FT STAT5B"
FT /evidence="ECO:0000269|PubMed:9428692"
FT REGION 1360..1382
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1361..1364
FT /note="PIK3R1-binding"
FT ACT_SITE 1159
FT /note="Proton donor/acceptor"
FT /evidence="ECO:0000269|PubMed:9312016"
FT BINDING 1033
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000269|PubMed:18278056"
FT BINDING 1057
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000269|PubMed:18278056"
FT BINDING 1104..1110
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000269|PubMed:18278056"
FT BINDING 1163..1164
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000269|PubMed:18278056"
FT BINDING 1177
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000269|PubMed:18278056"
FT SITE 66
FT /note="Insulin-binding"
FT /evidence="ECO:0000305"
FT MOD_RES 400
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648"
FT MOD_RES 401
FT /note="Phosphotyrosine"
FT /evidence="ECO:0007744|PubMed:18669648"
FT MOD_RES 407
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648"
FT MOD_RES 992
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000305"
FT MOD_RES 999
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000305|PubMed:3166375"
FT MOD_RES 1011
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000305"
FT MOD_RES 1185
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:14690593,
FT ECO:0000269|PubMed:16246733, ECO:0000269|PubMed:16271887,
FT ECO:0000269|PubMed:18278056, ECO:0000269|PubMed:18767165,
FT ECO:0000269|PubMed:3166375, ECO:0000269|PubMed:9312016"
FT MOD_RES 1189
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:14690593,
FT ECO:0000269|PubMed:16246733, ECO:0000269|PubMed:16271887,
FT ECO:0000269|PubMed:18278056, ECO:0000269|PubMed:18767165,
FT ECO:0000269|PubMed:3166375, ECO:0000269|PubMed:9312016"
FT MOD_RES 1190
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:14690593,
FT ECO:0000269|PubMed:16246733, ECO:0000269|PubMed:16271887,
FT ECO:0000269|PubMed:18278056, ECO:0000269|PubMed:18767165,
FT ECO:0000269|PubMed:3166375, ECO:0000269|PubMed:9312016"
FT MOD_RES 1355
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000305|PubMed:3166375"
FT MOD_RES 1361
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000305|PubMed:3166375"
FT CARBOHYD 43
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:16894147,
FT ECO:0000269|PubMed:23302862, ECO:0000269|PubMed:2983222"
FT CARBOHYD 52
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:16894147,
FT ECO:0000269|PubMed:23302862"
FT CARBOHYD 105
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 138
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:16894147,
FT ECO:0000269|PubMed:23302862"
FT CARBOHYD 242
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:16894147,
FT ECO:0000269|PubMed:19159218, ECO:0000269|PubMed:23302862"
FT CARBOHYD 282
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:16894147,
FT ECO:0000269|PubMed:23302862"
FT CARBOHYD 322
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 364
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:16894147"
FT CARBOHYD 424
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:16894147"
FT CARBOHYD 445
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:16894147,
FT ECO:0000269|PubMed:19349973"
FT CARBOHYD 541
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:1472036,
FT ECO:0000269|PubMed:19159218"
FT CARBOHYD 633
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 651
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 698
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 769
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:2983222"
FT CARBOHYD 782
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 920
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:19349973"
FT CARBOHYD 933
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 35..53
FT DISULFID 153..182
FT DISULFID 186..209
FT DISULFID 196..215
FT DISULFID 219..228
FT DISULFID 223..234
FT DISULFID 235..243
FT DISULFID 239..252
FT DISULFID 255..264
FT DISULFID 268..280
FT DISULFID 286..311
FT DISULFID 293..301
FT DISULFID 315..328
FT DISULFID 331..335
FT DISULFID 339..360
FT DISULFID 462..495
FT /evidence="ECO:0000269|PubMed:1472036"
FT DISULFID 551
FT /note="Interchain"
FT /evidence="ECO:0000269|PubMed:1472036"
FT DISULFID 674..899
FT DISULFID 825..834
FT VAR_SEQ 745..756
FT /note="Missing (in isoform Short)"
FT /evidence="ECO:0000303|PubMed:15489334,
FT ECO:0000303|PubMed:2983222, ECO:0000303|Ref.13"
FT /id="VSP_002898"
FT VARIANT 2
FT /note="A -> G (in dbSNP:rs7508518)"
FT /evidence="ECO:0000269|PubMed:15489334,
FT ECO:0000269|PubMed:2210055, ECO:0000269|PubMed:2280779,
FT ECO:0000269|PubMed:2777789, ECO:0000269|PubMed:2806055,
FT ECO:0000269|PubMed:2859121, ECO:0000269|PubMed:2983222,
FT ECO:0000269|PubMed:3680248"
FT /id="VAR_058395"
FT VARIANT 42
FT /note="N -> K (in RMS; impairs transport to the plasma
FT membrane and reduces the affinity to bind insulin;
FT dbSNP:rs121913143)"
FT /evidence="ECO:0000269|PubMed:2121734,
FT ECO:0000269|PubMed:2365819"
FT /id="VAR_004079"
FT VARIANT 55
FT /note="V -> A (in LEPRCH; Verona-1; dbSNP:rs121913152)"
FT /evidence="ECO:0000269|PubMed:1607067"
FT /id="VAR_004080"
FT VARIANT 56
FT /note="I -> T (in LEPRCH; abolishes post-translational
FT processing; dbSNP:rs1555689937)"
FT /evidence="ECO:0000269|PubMed:24498630"
FT /id="VAR_079535"
FT VARIANT 58
FT /note="G -> R (in LEPRCH; Helmond; inhibits processing and
FT transport; dbSNP:rs52836744)"
FT /evidence="ECO:0000269|PubMed:1730625"
FT /id="VAR_004081"
FT VARIANT 86
FT /note="D -> G (in IRAN type A)"
FT /evidence="ECO:0000269|PubMed:9175790"
FT /id="VAR_015907"
FT VARIANT 89
FT /note="L -> P (in IRAN type A)"
FT /evidence="ECO:0000269|PubMed:9175790"
FT /id="VAR_015908"
FT VARIANT 113
FT /note="R -> P (in LEPRCH; Atlanta-1; abolishes insulin
FT binding; dbSNP:rs121913153)"
FT /evidence="ECO:0000269|PubMed:12023989,
FT ECO:0000269|PubMed:8419945"
FT /id="VAR_004082"
FT VARIANT 119
FT /note="A -> V (in LEPRCH; markedly impairs insulin binding;
FT dbSNP:rs1347473020)"
FT /evidence="ECO:0000269|PubMed:12023989"
FT /id="VAR_015909"
FT VARIANT 120
FT /note="L -> Q (in LEPRCH; inhibits receptor processing)"
FT /evidence="ECO:0000269|PubMed:12970295"
FT /id="VAR_031518"
FT VARIANT 146
FT /note="I -> M (in LEPRCH; mild; dbSNP:rs121913159)"
FT /evidence="ECO:0000269|PubMed:7815442,
FT ECO:0000269|PubMed:8326490"
FT /id="VAR_015539"
FT VARIANT 167
FT /note="V -> L (in IRAN type A; dbSNP:rs938519025)"
FT /evidence="ECO:0000269|PubMed:10733238"
FT /id="VAR_015910"
FT VARIANT 171
FT /note="Y -> H (in dbSNP:rs1051692)"
FT /evidence="ECO:0000269|PubMed:2859121"
FT /id="VAR_058396"
FT VARIANT 220
FT /note="P -> L (in Ins resistance; severe;
FT dbSNP:rs749094324)"
FT /evidence="ECO:0000269|PubMed:8242067"
FT /id="VAR_004083"
FT VARIANT 228
FT /note="C -> R (in a gastric adenocarcinoma sample; somatic
FT mutation)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041429"
FT VARIANT 236
FT /note="H -> R (in RMS and LEPRCH; Winnipeg; may impair
FT receptor processing; dbSNP:rs121913145)"
FT /evidence="ECO:0000269|PubMed:17201797,
FT ECO:0000269|PubMed:2365819"
FT /id="VAR_004084"
FT VARIANT 256
FT /note="R -> C (in RMS; dbSNP:rs781007453)"
FT /evidence="ECO:0000269|PubMed:28765322"
FT /id="VAR_079536"
FT VARIANT 260
FT /note="L -> P (in LEPRCH; Geldeimalsen; dbSNP:rs121913141)"
FT /evidence="ECO:0000269|PubMed:2479553"
FT /id="VAR_004085"
FT VARIANT 279
FT /note="R -> C (in IRAN type A; inhibits receptor
FT internalization; dbSNP:rs1568470274)"
FT /evidence="ECO:0000269|PubMed:12107746"
FT /id="VAR_015540"
FT VARIANT 279
FT /note="R -> H (in IRAN type A; interferes with receptor
FT processing; dbSNP:rs1329693158)"
FT /evidence="ECO:0000269|PubMed:12970295"
FT /id="VAR_031519"
FT VARIANT 280
FT /note="C -> Y (in IRAN type A)"
FT /evidence="ECO:0000269|PubMed:11260230"
FT /id="VAR_015911"
FT VARIANT 286
FT /note="C -> Y (in LEPRCH; abolishes post-translational
FT processing)"
FT /evidence="ECO:0000269|PubMed:24498630"
FT /id="VAR_079537"
FT VARIANT 301
FT /note="C -> Y (in LEPRCH)"
FT /evidence="ECO:0000269|PubMed:9703342"
FT /id="VAR_015912"
FT VARIANT 308
FT /note="Missing (in LEPRCH; abolishes insulin binding)"
FT /evidence="ECO:0000269|PubMed:12023989,
FT ECO:0000269|PubMed:7538143, ECO:0000269|PubMed:8636294"
FT /id="VAR_015913"
FT VARIANT 350
FT /note="S -> L (in RMS and LEPRCH)"
FT /evidence="ECO:0000269|PubMed:12970295,
FT ECO:0000269|PubMed:8314008"
FT /id="VAR_015914"
FT VARIANT 362
FT /note="Missing (in LEPRCH)"
FT /evidence="ECO:0000269|PubMed:12538626"
FT /id="VAR_015541"
FT VARIANT 386
FT /note="G -> S (in RMS; may impair receptor processing;
FT dbSNP:rs764221583)"
FT /evidence="ECO:0000269|PubMed:17201797"
FT /id="VAR_031520"
FT VARIANT 393
FT /note="G -> R (in LEPRCH; Verona-1; dbSNP:rs267607184)"
FT /evidence="ECO:0000269|PubMed:1607067"
FT /id="VAR_004086"
FT VARIANT 409
FT /note="F -> V (in IRAN type A; dbSNP:rs121913142)"
FT /evidence="ECO:0000269|PubMed:8388389"
FT /id="VAR_004087"
FT VARIANT 439
FT /note="W -> S (in LEPRCH; impairs transport of the receptor
FT to the cell surface; dbSNP:rs121913158)"
FT /evidence="ECO:0000269|PubMed:8188715"
FT /id="VAR_015542"
FT VARIANT 448
FT /note="I -> T (in dbSNP:rs1051691)"
FT /evidence="ECO:0000269|PubMed:2859121"
FT /id="VAR_015915"
FT VARIANT 458
FT /note="N -> D (in LEPRCH; partially inhibits receptor
FT processing and autophosphorylation; strongly impairs ERK
FT phosphorylation; induces wild-type levels of IRS-1
FT phosphorylation; dbSNP:rs121913160)"
FT /evidence="ECO:0000269|PubMed:12970295"
FT /id="VAR_031521"
FT VARIANT 487
FT /note="K -> E (in LEPRCH; ARK-1; dbSNP:rs121913136)"
FT /evidence="ECO:0000269|PubMed:2834824"
FT /id="VAR_004088"
FT VARIANT 489
FT /note="N -> D (in IRAN type A; unknown pathological
FT significance; dbSNP:rs1135401742)"
FT /evidence="ECO:0000269|PubMed:28765322"
FT /id="VAR_079538"
FT VARIANT 489
FT /note="N -> S (in IRAN type A; dbSNP:rs121913147)"
FT /evidence="ECO:0000269|PubMed:2365819"
FT /id="VAR_004089"
FT VARIANT 492
FT /note="Q -> K"
FT /evidence="ECO:0000269|PubMed:2859121"
FT /id="VAR_015916"
FT VARIANT 635
FT /note="S -> L (in RMS; decreases post-translational
FT processing)"
FT /evidence="ECO:0000269|PubMed:28765322"
FT /id="VAR_079539"
FT VARIANT 657
FT /note="V -> F (in LEPRCH; impairs post-translational
FT processing; dbSNP:rs1135401737)"
FT /evidence="ECO:0000269|PubMed:28765322"
FT /id="VAR_079540"
FT VARIANT 659
FT /note="W -> R (in LEPRCH; impairs post-translational
FT processing)"
FT /evidence="ECO:0000269|PubMed:28765322"
FT /id="VAR_079541"
FT VARIANT 695
FT /note="Q -> R (in dbSNP:rs55906835)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041430"
FT VARIANT 762
FT /note="R -> S (in IRAN type A; dbSNP:rs121913138)"
FT /evidence="ECO:0000269|PubMed:3283938"
FT /id="VAR_004090"
FT VARIANT 811
FT /note="G -> S (in dbSNP:rs35045353)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041431"
FT VARIANT 818
FT /note="Y -> C (in LEPRCH; abolishes post-translational
FT processing)"
FT /evidence="ECO:0000269|PubMed:22768670,
FT ECO:0000269|PubMed:28765322"
FT /id="VAR_079542"
FT VARIANT 830
FT /note="P -> L (in dbSNP:rs2162771)"
FT /id="VAR_055986"
FT VARIANT 835
FT /note="S -> I (in RMS; impairs post-translational
FT processing; dbSNP:rs1135401739)"
FT /evidence="ECO:0000269|PubMed:28765322"
FT /id="VAR_079543"
FT VARIANT 842
FT /note="A -> V (in RMS; decreases post-translational
FT processing; dbSNP:rs1135401738)"
FT /evidence="ECO:0000269|PubMed:28765322"
FT /id="VAR_079544"
FT VARIANT 858
FT /note="T -> A (in NIDDM; dbSNP:rs182552223)"
FT /evidence="ECO:0000269|PubMed:7657032"
FT /id="VAR_015917"
FT VARIANT 874
FT /note="P -> L (in RMS; impairs post-translational
FT processing)"
FT /evidence="ECO:0000269|PubMed:28765322"
FT /id="VAR_079545"
FT VARIANT 878
FT /note="N -> S (in RMS; impairs post-translational
FT processing; dbSNP:rs887190835)"
FT /evidence="ECO:0000269|PubMed:28765322"
FT /id="VAR_079546"
FT VARIANT 890..1382
FT /note="Missing (in LEPRCH)"
FT /evidence="ECO:0000269|PubMed:22768670"
FT /id="VAR_079547"
FT VARIANT 925
FT /note="I -> T (in LEPRCH; abolishes post-translational
FT processing; abolishes insulin binding; dbSNP:rs1599881881)"
FT /evidence="ECO:0000269|PubMed:12023989,
FT ECO:0000269|PubMed:28765322"
FT /id="VAR_015918"
FT VARIANT 926
FT /note="R -> W (in LEPRCH; markedly impairs insulin
FT binding;impairs post-translational processing;
FT dbSNP:rs911929963)"
FT /evidence="ECO:0000269|PubMed:12023989,
FT ECO:0000269|PubMed:28765322"
FT /id="VAR_015919"
FT VARIANT 937
FT /note="T -> M (in LEPRCH; impaired receptor processing;
FT impairs post-translational processing)"
FT /evidence="ECO:0000269|PubMed:28765322,
FT ECO:0000269|PubMed:9299395"
FT /id="VAR_015920"
FT VARIANT 997
FT /note="P -> T (in RMS; reduces insulin binding)"
FT /evidence="ECO:0000269|PubMed:12023989"
FT /id="VAR_015921"
FT VARIANT 999..1382
FT /note="Missing (in RMS)"
FT /evidence="ECO:0000269|PubMed:28765322"
FT /id="VAR_079548"
FT VARIANT 1012
FT /note="V -> M (in dbSNP:rs1799816)"
FT /evidence="ECO:0000269|PubMed:17344846,
FT ECO:0000269|PubMed:8314008, ECO:0000269|PubMed:8432414,
FT ECO:0000269|PubMed:8458533, ECO:0000269|PubMed:9199575"
FT /id="VAR_004091"
FT VARIANT 1020
FT /note="R -> Q (in IRAN type A; dbSNP:rs121913148)"
FT /evidence="ECO:0000269|PubMed:2002058"
FT /id="VAR_004092"
FT VARIANT 1023
FT /note="I -> F"
FT /evidence="ECO:0000269|PubMed:8890729"
FT /id="VAR_015922"
FT VARIANT 1035
FT /note="G -> V (in IRAN type A; dbSNP:rs121913135)"
FT /evidence="ECO:0000269|PubMed:2544998"
FT /id="VAR_004093"
FT VARIANT 1054
FT /note="V -> M (in IRAN type A; unknown pathological
FT significance; dbSNP:rs1135401741)"
FT /evidence="ECO:0000269|PubMed:28765322"
FT /id="VAR_079549"
FT VARIANT 1055
FT /note="A -> V (in IRAN type A; dbSNP:rs1599874183)"
FT /evidence="ECO:0000269|PubMed:10733238"
FT /id="VAR_015923"
FT VARIANT 1065
FT /note="L -> V (in dbSNP:rs56395521)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041432"
FT VARIANT 1075
FT /note="A -> D (in IRAN type A)"
FT /evidence="ECO:0000269|PubMed:8243830"
FT /id="VAR_004094"
FT VARIANT 1095
FT /note="K -> E (in a NIDDM subject; dbSNP:rs909008899)"
FT /evidence="ECO:0000269|PubMed:2040394"
FT /id="VAR_015924"
FT VARIANT 1119
FT /note="R -> W (in LEPRCH; dbSNP:rs1229730671)"
FT /evidence="ECO:0000269|PubMed:12970295,
FT ECO:0000269|PubMed:9249867"
FT /id="VAR_015925"
FT VARIANT 1143
FT /note="I -> T (in RMS; reduces insulin binding)"
FT /evidence="ECO:0000269|PubMed:10443650,
FT ECO:0000269|PubMed:12023989"
FT /id="VAR_015926"
FT VARIANT 1158
FT /note="R -> Q (in NIDDM)"
FT /evidence="ECO:0000269|PubMed:1470163"
FT /id="VAR_015927"
FT VARIANT 1158
FT /note="R -> W (in RMS; abolishes insulin binding;
FT dbSNP:rs111993466)"
FT /evidence="ECO:0000269|PubMed:10443650,
FT ECO:0000269|PubMed:12023989"
FT /id="VAR_015928"
FT VARIANT 1161
FT /note="A -> T (in IRAN type A; dbSNP:rs121913139)"
FT /evidence="ECO:0000269|PubMed:2168397"
FT /id="VAR_004095"
FT VARIANT 1162
FT /note="A -> E (in IRAN type A; impairs proteolytic
FT processing; dbSNP:rs121913154)"
FT /evidence="ECO:0000269|PubMed:8096518"
FT /id="VAR_004096"
FT VARIANT 1180
FT /note="M -> I (in a patient with insulin resistance;
FT dbSNP:rs121913157)"
FT /evidence="ECO:0000269|PubMed:1890161"
FT /id="VAR_004097"
FT VARIANT 1191
FT /note="R -> Q (in NIDDM; dbSNP:rs121913150)"
FT /evidence="ECO:0000269|PubMed:1607076"
FT /id="VAR_004098"
FT VARIANT 1201
FT /note="R -> Q (in HHF5 and IRAN type A; interferes with
FT kinase activation by insulin; dbSNP:rs121913156)"
FT /evidence="ECO:0000269|PubMed:15161766,
FT ECO:0000269|PubMed:8082780, ECO:0000269|PubMed:8288049"
FT /id="VAR_015929"
FT VARIANT 1201
FT /note="R -> W (in LEPRCH and RMS; reduces insulin binding
FT possibly due to reduced receptor levels on the cell
FT surface; dbSNP:rs1568426700)"
FT /evidence="ECO:0000269|PubMed:12023989,
FT ECO:0000269|PubMed:9703342"
FT /id="VAR_015930"
FT VARIANT 1205
FT /note="P -> L (in IRAN type A; moderate;
FT dbSNP:rs1295645322)"
FT /evidence="ECO:0000269|PubMed:1563582,
FT ECO:0000269|PubMed:8314008"
FT /id="VAR_004099"
FT VARIANT 1206
FT /note="E -> D (in IRAN type A; accelerates degradation of
FT the protein and impairs kinase activity)"
FT /evidence="ECO:0000269|PubMed:7983039"
FT /id="VAR_015931"
FT VARIANT 1206
FT /note="E -> K (in LEPRCH)"
FT /evidence="ECO:0000269|PubMed:9249867"
FT /id="VAR_015932"
FT VARIANT 1220
FT /note="W -> L (in IRAN type A; accelerates degradation of
FT the protein and impairs kinase activity; dbSNP:rs52800171)"
FT /evidence="ECO:0000269|PubMed:7983039,
FT ECO:0000269|PubMed:8390949"
FT /id="VAR_004100"
FT VARIANT 1227
FT /note="W -> S (in IRAN type A; dbSNP:rs121913140)"
FT /evidence="ECO:0000269|PubMed:1963473"
FT /id="VAR_004101"
FT VARIANT 1282
FT /note="T -> A (in dbSNP:rs55875349)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041433"
FT VARIANT 1361
FT /note="Y -> C (in dbSNP:rs13306449)"
FT /evidence="ECO:0000269|PubMed:7657032"
FT /id="VAR_015933"
FT VARIANT 1378
FT /note="R -> Q (in IRAN type A; dbSNP:rs52826008)"
FT /evidence="ECO:0000269|PubMed:8314008"
FT /id="VAR_015934"
FT MUTAGEN 991
FT /note="L->A: Reduces interaction with IRS1 but has no
FT effect on interaction with SHC1."
FT /evidence="ECO:0000269|PubMed:7559478"
FT MUTAGEN 992
FT /note="Y->A: Reduces interaction with IRS1 but has no
FT effect on interaction with SHC1."
FT /evidence="ECO:0000269|PubMed:7559478"
FT MUTAGEN 996..997
FT /note="NP->AA: Abolishes interaction with IRS1. Severely
FT disrupts, but does not abolish interaction with SHC1."
FT /evidence="ECO:0000269|PubMed:7559478"
FT MUTAGEN 996
FT /note="N->A: Abolishes interaction with IRS1 and
FT significantly reduces interaction with SHC1. Has no effect
FT on interaction with PIK3R1."
FT /evidence="ECO:0000269|PubMed:7537849,
FT ECO:0000269|PubMed:7559478"
FT MUTAGEN 997
FT /note="P->A: Abolishes interaction with IRS1 and
FT significantly reduces interaction with SHC1. Has no effect
FT on interaction with PIK3R1."
FT /evidence="ECO:0000269|PubMed:7537849,
FT ECO:0000269|PubMed:7559478"
FT MUTAGEN 998
FT /note="E->A: Does not affect interaction with IRS1, SHC1 or
FT PIK3R1."
FT /evidence="ECO:0000269|PubMed:7537849"
FT MUTAGEN 999
FT /note="Y->E: Abolishes interaction with IRS1 and SHC1."
FT /evidence="ECO:0000269|PubMed:2842060,
FT ECO:0000269|PubMed:7537849, ECO:0000269|PubMed:7559478,
FT ECO:0000269|PubMed:9428692"
FT MUTAGEN 999
FT /note="Y->F: Has no effect on insulin-stimulated
FT autophosphorylation, but inhibits the biological activity
FT of the receptor. Abolishes interaction with IRS1 and almost
FT completely prevents interaction with SHC1. Has no effect on
FT interaction with PIK3R1. Abolishes interaction with
FT STAT5B."
FT /evidence="ECO:0000269|PubMed:2842060,
FT ECO:0000269|PubMed:7537849, ECO:0000269|PubMed:7559478,
FT ECO:0000269|PubMed:9428692"
FT MUTAGEN 1000
FT /note="L->A,R: Severely reduces interaction with SHC1. Has
FT no effect on interaction with IRS1."
FT /evidence="ECO:0000269|PubMed:7559478"
FT MUTAGEN 1002
FT /note="A->D: Reduces interaction with IRS1 but has no
FT effect on interaction with SHC1."
FT /evidence="ECO:0000269|PubMed:7559478"
FT MUTAGEN 1011
FT /note="Y->A: Increases kinase activity."
FT /evidence="ECO:0000269|PubMed:12707268"
FT MUTAGEN 1057
FT /note="K->A: Abolishes the kinase activity and abolishes
FT interaction with IRS1, SHC1, GRB7 and PIK3R1."
FT /evidence="ECO:0000269|PubMed:10803466,
FT ECO:0000269|PubMed:3101064, ECO:0000269|PubMed:7537849"
FT MUTAGEN 1057
FT /note="K->M,R: Abolishes the kinase activity."
FT /evidence="ECO:0000269|PubMed:10803466,
FT ECO:0000269|PubMed:3101064, ECO:0000269|PubMed:7537849"
FT MUTAGEN 1159
FT /note="D->N: Loss of kinase activity."
FT /evidence="ECO:0000269|PubMed:11598120"
FT MUTAGEN 1163
FT /note="R->Q: Loss of kinase activity."
FT /evidence="ECO:0000269|PubMed:11598120"
FT MUTAGEN 1189
FT /note="Y->F: Reduced interaction with GRB7."
FT /evidence="ECO:0000269|PubMed:10803466"
FT MUTAGEN 1190
FT /note="Y->F: Strongly reduced interaction with GRB7."
FT /evidence="ECO:0000269|PubMed:10803466"
FT CONFLICT 601
FT /note="D -> N (in Ref. 19; AA sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 830
FT /note="P -> E (in Ref. 19; AA sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 1278
FT /note="K -> N (in Ref. 2; CAA26096)"
FT /evidence="ECO:0000305"
FT STRAND 33..42
FT /evidence="ECO:0007829|PDB:2HR7"
FT HELIX 45..50
FT /evidence="ECO:0007829|PDB:2HR7"
FT STRAND 53..65
FT /evidence="ECO:0007829|PDB:2HR7"
FT HELIX 70..72
FT /evidence="ECO:0007829|PDB:2HR7"
FT TURN 73..75
FT /evidence="ECO:0007829|PDB:2HR7"
FT STRAND 83..86
FT /evidence="ECO:0007829|PDB:2HR7"
FT STRAND 88..93
FT /evidence="ECO:0007829|PDB:2HR7"
FT TURN 100..102
FT /evidence="ECO:0007829|PDB:2HR7"
FT STRAND 115..117
FT /evidence="ECO:0007829|PDB:6PXW"
FT STRAND 118..124
FT /evidence="ECO:0007829|PDB:2HR7"
FT STRAND 141..149
FT /evidence="ECO:0007829|PDB:2HR7"
FT HELIX 160..162
FT /evidence="ECO:0007829|PDB:2HR7"
FT HELIX 167..169
FT /evidence="ECO:0007829|PDB:7KD6"
FT STRAND 171..175
FT /evidence="ECO:0007829|PDB:2HR7"
FT HELIX 176..178
FT /evidence="ECO:0007829|PDB:2HR7"
FT TURN 187..192
FT /evidence="ECO:0007829|PDB:2HR7"
FT STRAND 199..201
FT /evidence="ECO:0007829|PDB:2HR7"
FT STRAND 204..206
FT /evidence="ECO:0007829|PDB:2HR7"
FT STRAND 209..211
FT /evidence="ECO:0007829|PDB:2HR7"
FT HELIX 221..223
FT /evidence="ECO:0007829|PDB:2HR7"
FT STRAND 243..247
FT /evidence="ECO:0007829|PDB:2HR7"
FT STRAND 251..260
FT /evidence="ECO:0007829|PDB:2HR7"
FT STRAND 263..267
FT /evidence="ECO:0007829|PDB:2HR7"
FT STRAND 273..275
FT /evidence="ECO:0007829|PDB:2HR7"
FT TURN 276..278
FT /evidence="ECO:0007829|PDB:2HR7"
FT STRAND 279..281
FT /evidence="ECO:0007829|PDB:2HR7"
FT HELIX 283..295
FT /evidence="ECO:0007829|PDB:2HR7"
FT STRAND 298..300
FT /evidence="ECO:0007829|PDB:2HR7"
FT STRAND 305..307
FT /evidence="ECO:0007829|PDB:2HR7"
FT STRAND 310..314
FT /evidence="ECO:0007829|PDB:2HR7"
FT STRAND 319..321
FT /evidence="ECO:0007829|PDB:2HR7"
FT TURN 323..325
FT /evidence="ECO:0007829|PDB:7KD6"
FT STRAND 327..330
FT /evidence="ECO:0007829|PDB:2HR7"
FT STRAND 332..334
FT /evidence="ECO:0007829|PDB:2HR7"
FT STRAND 338..348
FT /evidence="ECO:0007829|PDB:2HR7"
FT HELIX 351..355
FT /evidence="ECO:0007829|PDB:2HR7"
FT TURN 356..359
FT /evidence="ECO:0007829|PDB:2HR7"
FT STRAND 361..369
FT /evidence="ECO:0007829|PDB:2HR7"
FT STRAND 373..375
FT /evidence="ECO:0007829|PDB:6HN5"
FT HELIX 377..385
FT /evidence="ECO:0007829|PDB:2HR7"
FT STRAND 390..393
FT /evidence="ECO:0007829|PDB:2HR7"
FT STRAND 395..399
FT /evidence="ECO:0007829|PDB:2HR7"
FT STRAND 404..406
FT /evidence="ECO:0007829|PDB:2HR7"
FT TURN 422..424
FT /evidence="ECO:0007829|PDB:2HR7"
FT STRAND 425..430
FT /evidence="ECO:0007829|PDB:2HR7"
FT STRAND 437..439
FT /evidence="ECO:0007829|PDB:4ZXB"
FT TURN 441..443
FT /evidence="ECO:0007829|PDB:2HR7"
FT STRAND 447..450
FT /evidence="ECO:0007829|PDB:6HN5"
FT STRAND 452..458
FT /evidence="ECO:0007829|PDB:2HR7"
FT HELIX 463..472
FT /evidence="ECO:0007829|PDB:2HR7"
FT TURN 476..478
FT /evidence="ECO:0007829|PDB:2HR7"
FT TURN 481..483
FT /evidence="ECO:0007829|PDB:2HR7"
FT STRAND 486..490
FT /evidence="ECO:0007829|PDB:2HR7"
FT STRAND 498..500
FT /evidence="ECO:0007829|PDB:6PXW"
FT STRAND 502..507
FT /evidence="ECO:0007829|PDB:6PXW"
FT STRAND 512..516
FT /evidence="ECO:0007829|PDB:6PXW"
FT HELIX 524..526
FT /evidence="ECO:0007829|PDB:6PXW"
FT STRAND 527..534
FT /evidence="ECO:0007829|PDB:6PXW"
FT STRAND 538..540
FT /evidence="ECO:0007829|PDB:6PXW"
FT STRAND 552..554
FT /evidence="ECO:0007829|PDB:6HN5"
FT STRAND 557..561
FT /evidence="ECO:0007829|PDB:6PXW"
FT STRAND 570..573
FT /evidence="ECO:0007829|PDB:6HN5"
FT STRAND 578..580
FT /evidence="ECO:0007829|PDB:6PXW"
FT STRAND 588..597
FT /evidence="ECO:0007829|PDB:6PXW"
FT STRAND 601..603
FT /evidence="ECO:0007829|PDB:6PXW"
FT STRAND 608..610
FT /evidence="ECO:0007829|PDB:4ZXB"
FT STRAND 613..616
FT /evidence="ECO:0007829|PDB:6PXW"
FT STRAND 626..631
FT /evidence="ECO:0007829|PDB:6PXV"
FT STRAND 633..636
FT /evidence="ECO:0007829|PDB:6PXV"
FT STRAND 638..643
FT /evidence="ECO:0007829|PDB:6PXV"
FT STRAND 654..658
FT /evidence="ECO:0007829|PDB:6PXV"
FT HELIX 666..669
FT /evidence="ECO:0007829|PDB:6PXV"
FT HELIX 732..740
FT /evidence="ECO:0007829|PDB:6VEP"
FT STRAND 798..803
FT /evidence="ECO:0007829|PDB:6PXV"
FT STRAND 805..809
FT /evidence="ECO:0007829|PDB:6PXV"
FT STRAND 817..827
FT /evidence="ECO:0007829|PDB:6PXV"
FT STRAND 838..843
FT /evidence="ECO:0007829|PDB:6PXV"
FT STRAND 858..861
FT /evidence="ECO:0007829|PDB:6PXV"
FT STRAND 867..870
FT /evidence="ECO:0007829|PDB:6PXV"
FT STRAND 881..890
FT /evidence="ECO:0007829|PDB:6PXV"
FT STRAND 896..901
FT /evidence="ECO:0007829|PDB:6PXV"
FT HELIX 902..908
FT /evidence="ECO:0007829|PDB:6PXV"
FT STRAND 910..913
FT /evidence="ECO:0007829|PDB:6PXV"
FT STRAND 918..931
FT /evidence="ECO:0007829|PDB:6PXV"
FT STRAND 940..944
FT /evidence="ECO:0007829|PDB:6PXV"
FT HELIX 953..979
FT /evidence="ECO:0007829|PDB:2MFR"
FT STRAND 992..995
FT /evidence="ECO:0007829|PDB:5U1M"
FT TURN 1003..1005
FT /evidence="ECO:0007829|PDB:4XLV"
FT HELIX 1009..1011
FT /evidence="ECO:0007829|PDB:1IR3"
FT HELIX 1014..1016
FT /evidence="ECO:0007829|PDB:1IRK"
FT HELIX 1020..1022
FT /evidence="ECO:0007829|PDB:3BU3"
FT STRAND 1023..1031
FT /evidence="ECO:0007829|PDB:3BU3"
FT STRAND 1033..1043
FT /evidence="ECO:0007829|PDB:3BU3"
FT STRAND 1046..1048
FT /evidence="ECO:0007829|PDB:2Z8C"
FT STRAND 1050..1057
FT /evidence="ECO:0007829|PDB:3BU3"
FT HELIX 1065..1078
FT /evidence="ECO:0007829|PDB:3BU3"
FT STRAND 1089..1093
FT /evidence="ECO:0007829|PDB:3BU3"
FT STRAND 1095..1098
FT /evidence="ECO:0007829|PDB:3BU3"
FT STRAND 1100..1104
FT /evidence="ECO:0007829|PDB:3BU3"
FT HELIX 1111..1117
FT /evidence="ECO:0007829|PDB:3BU3"
FT STRAND 1119..1121
FT /evidence="ECO:0007829|PDB:3ETA"
FT HELIX 1133..1152
FT /evidence="ECO:0007829|PDB:3BU3"
FT STRAND 1154..1156
FT /evidence="ECO:0007829|PDB:2AUH"
FT HELIX 1162..1164
FT /evidence="ECO:0007829|PDB:3BU3"
FT STRAND 1165..1167
FT /evidence="ECO:0007829|PDB:3BU3"
FT STRAND 1173..1175
FT /evidence="ECO:0007829|PDB:3BU3"
FT STRAND 1181..1183
FT /evidence="ECO:0007829|PDB:1IRK"
FT TURN 1185..1187
FT /evidence="ECO:0007829|PDB:3BU3"
FT STRAND 1190..1192
FT /evidence="ECO:0007829|PDB:5HHW"
FT STRAND 1194..1198
FT /evidence="ECO:0007829|PDB:3BU3"
FT HELIX 1200..1202
FT /evidence="ECO:0007829|PDB:3BU3"
FT HELIX 1205..1210
FT /evidence="ECO:0007829|PDB:3BU3"
FT HELIX 1215..1230
FT /evidence="ECO:0007829|PDB:3BU3"
FT TURN 1236..1239
FT /evidence="ECO:0007829|PDB:3BU3"
FT HELIX 1242..1250
FT /evidence="ECO:0007829|PDB:3BU3"
FT HELIX 1263..1272
FT /evidence="ECO:0007829|PDB:3BU3"
FT HELIX 1277..1279
FT /evidence="ECO:0007829|PDB:3BU3"
FT HELIX 1283..1290
FT /evidence="ECO:0007829|PDB:3BU3"
FT HELIX 1291..1293
FT /evidence="ECO:0007829|PDB:5HHW"
FT HELIX 1298..1301
FT /evidence="ECO:0007829|PDB:3BU3"
FT TURN 1303..1305
FT /evidence="ECO:0007829|PDB:4XLV"
FT HELIX 1307..1309
FT /evidence="ECO:0007829|PDB:1I44"
SQ SEQUENCE 1382 AA; 156333 MW; 709A955660739066 CRC64;
MATGGRRGAA AAPLLVAVAA LLLGAAGHLY PGEVCPGMDI RNNLTRLHEL ENCSVIEGHL
QILLMFKTRP EDFRDLSFPK LIMITDYLLL FRVYGLESLK DLFPNLTVIR GSRLFFNYAL
VIFEMVHLKE LGLYNLMNIT RGSVRIEKNN ELCYLATIDW SRILDSVEDN YIVLNKDDNE
ECGDICPGTA KGKTNCPATV INGQFVERCW THSHCQKVCP TICKSHGCTA EGLCCHSECL
GNCSQPDDPT KCVACRNFYL DGRCVETCPP PYYHFQDWRC VNFSFCQDLH HKCKNSRRQG
CHQYVIHNNK CIPECPSGYT MNSSNLLCTP CLGPCPKVCH LLEGEKTIDS VTSAQELRGC
TVINGSLIIN IRGGNNLAAE LEANLGLIEE ISGYLKIRRS YALVSLSFFR KLRLIRGETL
EIGNYSFYAL DNQNLRQLWD WSKHNLTITQ GKLFFHYNPK LCLSEIHKME EVSGTKGRQE
RNDIALKTNG DQASCENELL KFSYIRTSFD KILLRWEPYW PPDFRDLLGF MLFYKEAPYQ
NVTEFDGQDA CGSNSWTVVD IDPPLRSNDP KSQNHPGWLM RGLKPWTQYA IFVKTLVTFS
DERRTYGAKS DIIYVQTDAT NPSVPLDPIS VSNSSSQIIL KWKPPSDPNG NITHYLVFWE
RQAEDSELFE LDYCLKGLKL PSRTWSPPFE SEDSQKHNQS EYEDSAGECC SCPKTDSQIL
KELEESSFRK TFEDYLHNVV FVPRKTSSGT GAEDPRPSRK RRSLGDVGNV TVAVPTVAAF
PNTSSTSVPT SPEEHRPFEK VVNKESLVIS GLRHFTGYRI ELQACNQDTP EERCSVAAYV
SARTMPEAKA DDIVGPVTHE IFENNVVHLM WQEPKEPNGL IVLYEVSYRR YGDEELHLCV
SRKHFALERG CRLRGLSPGN YSVRIRATSL AGNGSWTEPT YFYVTDYLDV PSNIAKIIIG
PLIFVFLFSV VIGSIYLFLR KRQPDGPLGP LYASSNPEYL SASDVFPCSV YVPDEWEVSR
EKITLLRELG QGSFGMVYEG NARDIIKGEA ETRVAVKTVN ESASLRERIE FLNEASVMKG
FTCHHVVRLL GVVSKGQPTL VVMELMAHGD LKSYLRSLRP EAENNPGRPP PTLQEMIQMA
AEIADGMAYL NAKKFVHRDL AARNCMVAHD FTVKIGDFGM TRDIYETDYY RKGGKGLLPV
RWMAPESLKD GVFTTSSDMW SFGVVLWEIT SLAEQPYQGL SNEQVLKFVM DGGYLDQPDN
CPERVTDLMR MCWQFNPKMR PTFLEIVNLL KDDLHPSFPE VSFFHSEENK APESEELEME
FEDMENVPLD RSSHCQREEA GGRDGGSSLG FKRSYEEHIP YTHMNGGKKN GRILTLPRSN
PS
