INSR_MOUSE
ID INSR_MOUSE Reviewed; 1372 AA.
AC P15208; F8VPU4;
DT 01-APR-1990, integrated into UniProtKB/Swiss-Prot.
DT 03-OCT-2012, sequence version 2.
DT 03-AUG-2022, entry version 228.
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 Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=2557333; DOI=10.1016/s0021-9258(20)88221-0;
RA Flores-Riveros J.R., Sibley E., Kastelic T., Lane M.D.;
RT "Substrate phosphorylation catalyzed by the insulin receptor tyrosine
RT kinase. Kinetic correlation to autophosphorylation of specific sites in the
RT beta subunit.";
RL J. Biol. Chem. 264:21557-21572(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-33.
RX PubMed=2602374; DOI=10.1073/pnas.86.24.9732;
RA Sibley E., Kastelic T., Kelly T.J., Lane M.D.;
RT "Characterization of the mouse insulin receptor gene promoter.";
RL Proc. Natl. Acad. Sci. U.S.A. 86:9732-9736(1989).
RN [4]
RP INTERACTION WITH IRS1 AND IRS2, AND MUTAGENESIS OF TYR-989.
RX PubMed=8626379; DOI=10.1074/jbc.271.11.5980;
RA Sawka-Verhelle D., Tartare-Deckert S., White M.F., Van Obberghen E.;
RT "Insulin receptor substrate-2 binds to the insulin receptor through its
RT phosphotyrosine-binding domain and through a newly identified domain
RT comprising amino acids 591-786.";
RL J. Biol. Chem. 271:5980-5983(1996).
RN [5]
RP INTERACTION WITH SORBS1.
RX PubMed=9447983; DOI=10.1128/mcb.18.2.872;
RA Ribon V., Printen J.A., Hoffman N.G., Kay B.K., Saltiel A.R.;
RT "A novel, multifunctional c-Cbl binding protein in insulin receptor
RT signaling in 3T3-L1 adipocytes.";
RL Mol. Cell. Biol. 18:872-879(1998).
RN [6]
RP MUTAGENESIS OF TYR-989.
RX PubMed=10207032; DOI=10.1074/jbc.274.17.12075;
RA Chaika O.V., Chaika N., Volle D.J., Hayashi H., Ebina Y., Wang L.M.,
RA Pierce J.H., Lewis R.E.;
RT "Mutation of tyrosine 960 within the insulin receptor juxtamembrane domain
RT impairs glucose transport but does not inhibit ligand-mediated
RT phosphorylation of insulin receptor substrate-2 in 3T3-L1 adipocytes.";
RL J. Biol. Chem. 274:12075-12080(1999).
RN [7]
RP INTERACTION WITH SOCS3.
RX PubMed=10821852; DOI=10.1074/jbc.275.21.15985;
RA Emanuelli B., Peraldi P., Filloux C., Sawka-Verhelle D., Hilton D.,
RA Van Obberghen E.;
RT "SOCS-3 is an insulin-induced negative regulator of insulin signaling.";
RL J. Biol. Chem. 275:15985-15991(2000).
RN [8]
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 [9]
RP INTERACTION WITH SOCS1 AND SOCS3.
RX PubMed=15169905; DOI=10.1128/mcb.24.12.5434-5446.2004;
RA Ueki K., Kondo T., Kahn C.R.;
RT "Suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 cause insulin
RT resistance through inhibition of tyrosine phosphorylation of insulin
RT receptor substrate proteins by discrete mechanisms.";
RL Mol. Cell. Biol. 24:5434-5446(2004).
RN [10]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-445.
RC TISSUE=Myoblast;
RX PubMed=19656770; DOI=10.1074/mcp.m900195-mcp200;
RA Gundry R.L., Raginski K., Tarasova Y., Tchernyshyov I., Bausch-Fluck D.,
RA Elliott S.T., Boheler K.R., Van Eyk J.E., Wollscheid B.;
RT "The mouse C2C12 myoblast cell surface N-linked glycoproteome:
RT identification, glycosite occupancy, and membrane orientation.";
RL Mol. Cell. Proteomics 8:2555-2569(2009).
RN [11]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-445.
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 [12]
RP INTERACTION WITH ARRB2.
RX PubMed=19122674; DOI=10.1038/nature07617;
RA Luan B., Zhao J., Wu H., Duan B., Shu G., Wang X., Li D., Jia W., Kang J.,
RA Pei G.;
RT "Deficiency of a beta-arrestin-2 signal complex contributes to insulin
RT resistance.";
RL Nature 457:1146-1149(2009).
RN [13]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Brown adipose tissue, Heart, Kidney, Liver, Lung, and
RC Pancreas;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [14]
RP INTERACTION WITH LMBRD1.
RX PubMed=24078630; DOI=10.1074/jbc.m113.479527;
RA Tseng L.T., Lin C.L., Tzen K.Y., Chang S.C., Chang M.F.;
RT "LMBD1 protein serves as a specific adaptor for insulin receptor
RT internalization.";
RL J. Biol. Chem. 288:32424-32432(2013).
RN [15]
RP FUNCTION, INTERACTION WITH SORL1, AND SUBCELLULAR LOCATION.
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).
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). When present in a hybrid receptor with IGF1R,
CC binds IGF1 (By similarity). In adipocytes, inhibits lipolysis
CC (PubMed:27322061). {ECO:0000250, ECO:0000269|PubMed:27322061}.
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 -!- 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 (By similarity). Interacts with
CC PTPRF (By similarity). Interacts with ATIC; ATIC together with
CC PRKAA2/AMPK2 and HACD3/PTPLAD1 is proposed to be part of a signaling
CC netwok regulating INSR autophosphorylation and endocytosis (By
CC similarity). {ECO:0000250, ECO:0000250|UniProtKB:P15127}.
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 (By similarity). Activated form of INSR interacts (via Tyr-
CC 989) with the PTB/PID domains of IRS1 and SHC1. The sequences
CC surrounding the phosphorylated NPXY motif contribute differentially to
CC either IRS1 or SHC1 recognition. Interacts (via tyrosines in the C-
CC terminus) with IRS2 (via PTB domain and 591-786 AA); the 591-786 would
CC be the primary anchor of IRS2 to INSR while the PTB domain would have a
CC stabilizing action on the interaction with INSR. Interacts with the SH2
CC domains of the 85 kDa regulatory subunit of PI3K (PIK3R1) in vitro,
CC when autophosphorylated on tyrosine residues. Interacts with SOCS7 (By
CC similarity). Interacts (via the phosphorylated Tyr-989), with SOCS3.
CC Interacts (via the phosphorylated Tyr-1175, Tyr-1179, Tyr-1180) with
CC SOCS1. Interacts with CAV2 (tyrosine-phosphorylated form); the
CC interaction is increased with 'Tyr-27'phosphorylation of CAV2 (By
CC similarity). Interacts with ARRB2. Interacts with GRB10; this
CC interaction blocks the association between IRS1/IRS2 and INSR,
CC significantly reduces insulin-stimulated tyrosine phosphorylation of
CC IRS1 and IRS2 and thus decreases insulin signaling (By similarity).
CC Interacts with GRB7 (By similarity). Interacts with PDPK1 (By
CC similarity). Interacts (via Tyr-1180) with GRB14 (via BPS domain); this
CC interaction protects the tyrosines in the activation loop from
CC dephosphorylation, but promotes dephosphorylation of Tyr-989, this
CC results in decreased interaction with, and phosphorylation of, IRS1 (By
CC similarity). Interacts (via subunit alpha) with ENPP1 (via 485-599 AA);
CC this interaction blocks autophosphorylation (By similarity). Interacts
CC with PTPRE; this interaction is dependent of Tyr-1175, Tyr-1179 and
CC Tyr-1180 of the INSR (By similarity). Interacts with STAT5B (via SH2
CC domain) (By similarity). Interacts with PTPRF (By similarity).
CC Interacts with the insulin receptor SORL1; this interaction strongly
CC increases its surface exposure, hence strengthens insulin signal
CC reception (PubMed:27322061). Interacts (tyrosine phosphorylated) with
CC CCDC88A/GIV (via SH2-like region); binding requires autophosphorylation
CC of the INSR C-terminal region (By similarity). Interacts with GNAI3;
CC the interaction is probably mediated by CCDC88A/GIV (By similarity).
CC Interacts with LMBRD1 (PubMed:24078630). {ECO:0000250,
CC ECO:0000250|UniProtKB:P06213, ECO:0000269|PubMed:24078630,
CC ECO:0000269|PubMed:27322061}.
CC -!- INTERACTION:
CC P15208; P49817: Cav1; NbExp=2; IntAct=EBI-6999015, EBI-1161338;
CC P15208; Q60760: Grb10; NbExp=6; IntAct=EBI-6999015, EBI-861810;
CC P15208; Q1XH17: Trim72; NbExp=2; IntAct=EBI-6999015, EBI-16034016;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:27322061};
CC Single-pass type I membrane protein {ECO:0000305}. Recycling endosome
CC membrane {ECO:0000269|PubMed:27322061}. Late endosome
CC {ECO:0000269|PubMed:27322061}. Lysosome {ECO:0000305|PubMed:27322061}.
CC Note=Binding of insulin to INSR induces internalization and lysosomal
CC degradation of the receptor, a means for down-regulating this signaling
CC pathway after stimulation. In the presence of SORL1, internalized INSR
CC molecules are redirected back to the cell surface, thereby preventing
CC their lysosomal catabolism and strengthening insulin signal reception.
CC {ECO:0000269|PubMed:27322061}.
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 (By similarity).
CC {ECO:0000250}.
CC -!- PTM: Autophosphorylated on tyrosine residues in response to insulin (By
CC similarity). Phosphorylation of Tyr-989 is required for IRS1-, SHC1-,
CC and STAT5B-binding (By similarity). Dephosphorylated by PTPRE on Tyr-
CC 989, Tyr-1175, Tyr-1179 and Tyr-1180 residues (By similarity).
CC Dephosphorylated by PTPRF and PTPN1 (By similarity). Dephosphorylated
CC by PTPN2; down-regulates insulin-induced signaling. {ECO:0000250,
CC ECO:0000269|PubMed:12612081}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein
CC kinase family. Insulin receptor subfamily. {ECO:0000255|PROSITE-
CC ProRule:PRU00159}.
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DR EMBL; J05149; AAA39318.1; -; mRNA.
DR EMBL; AC168068; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; M28869; AAA39319.1; -; Genomic_DNA.
DR CCDS; CCDS22059.1; -.
DR PIR; A34157; A34157.
DR RefSeq; NP_034698.2; NM_010568.3.
DR PDB; 1LK2; X-ray; 1.35 A; P=423-430.
DR PDB; 7SL1; EM; 3.40 A; A/B=1-1372.
DR PDB; 7SL2; EM; 3.60 A; A/B=1-1372.
DR PDB; 7SL3; EM; 3.40 A; A/B=1-1372.
DR PDB; 7SL4; EM; 5.00 A; A/B=1-1372.
DR PDB; 7SL6; EM; 3.70 A; A/B=1-1372.
DR PDB; 7SL7; EM; 3.10 A; A/B=1-1372.
DR PDB; 7STH; EM; 3.50 A; A/B=1-1372.
DR PDB; 7STI; EM; 4.90 A; A/B=1-1372.
DR PDB; 7STJ; EM; 4.40 A; A/B=1-1372.
DR PDB; 7STK; EM; 4.00 A; A/B=1-1372.
DR PDBsum; 1LK2; -.
DR PDBsum; 7SL1; -.
DR PDBsum; 7SL2; -.
DR PDBsum; 7SL3; -.
DR PDBsum; 7SL4; -.
DR PDBsum; 7SL6; -.
DR PDBsum; 7SL7; -.
DR PDBsum; 7STH; -.
DR PDBsum; 7STI; -.
DR PDBsum; 7STJ; -.
DR PDBsum; 7STK; -.
DR AlphaFoldDB; P15208; -.
DR BMRB; P15208; -.
DR SMR; P15208; -.
DR BioGRID; 200774; 28.
DR CORUM; P15208; -.
DR DIP; DIP-41452N; -.
DR IntAct; P15208; 21.
DR MINT; P15208; -.
DR STRING; 10090.ENSMUSP00000088837; -.
DR BindingDB; P15208; -.
DR ChEMBL; CHEMBL3187; -.
DR CarbonylDB; P15208; -.
DR GlyConnect; 2393; 7 N-Linked glycans (4 sites).
DR GlyGen; P15208; 18 sites, 7 N-linked glycans (4 sites).
DR iPTMnet; P15208; -.
DR PhosphoSitePlus; P15208; -.
DR jPOST; P15208; -.
DR MaxQB; P15208; -.
DR PaxDb; P15208; -.
DR PeptideAtlas; P15208; -.
DR PRIDE; P15208; -.
DR ProteomicsDB; 267252; -.
DR Antibodypedia; 3403; 2147 antibodies from 53 providers.
DR DNASU; 16337; -.
DR Ensembl; ENSMUST00000091291; ENSMUSP00000088837; ENSMUSG00000005534.
DR GeneID; 16337; -.
DR KEGG; mmu:16337; -.
DR UCSC; uc009krc.2; mouse.
DR CTD; 3643; -.
DR MGI; MGI:96575; Insr.
DR VEuPathDB; HostDB:ENSMUSG00000005534; -.
DR eggNOG; KOG4258; Eukaryota.
DR GeneTree; ENSGT00940000155404; -.
DR HOGENOM; CLU_000288_166_0_1; -.
DR InParanoid; P15208; -.
DR OMA; QYIPDDW; -.
DR PhylomeDB; P15208; -.
DR TreeFam; TF351636; -.
DR BRENDA; 2.7.10.1; 3474.
DR Reactome; R-MMU-6811558; PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling.
DR Reactome; R-MMU-74713; IRS activation.
DR Reactome; R-MMU-74749; Signal attenuation.
DR Reactome; R-MMU-74751; Insulin receptor signalling cascade.
DR Reactome; R-MMU-74752; Signaling by Insulin receptor.
DR Reactome; R-MMU-77387; Insulin receptor recycling.
DR BioGRID-ORCS; 16337; 2 hits in 74 CRISPR screens.
DR ChiTaRS; Insr; mouse.
DR EvolutionaryTrace; P15208; -.
DR PRO; PR:P15208; -.
DR Proteomes; UP000000589; Chromosome 8.
DR RNAct; P15208; protein.
DR Bgee; ENSMUSG00000005534; Expressed in pigmented layer of retina and 215 other tissues.
DR ExpressionAtlas; P15208; baseline and differential.
DR Genevisible; P15208; MM.
DR GO; GO:0030424; C:axon; IBA:GO_Central.
DR GO; GO:0005901; C:caveola; IDA:MGI.
DR GO; GO:0044297; C:cell body; ISO:MGI.
DR GO; GO:0031410; C:cytoplasmic vesicle; ISO:MGI.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0030425; C:dendrite; ISO:MGI.
DR GO; GO:0032590; C:dendrite membrane; ISO:MGI.
DR GO; GO:0005768; C:endosome; ISO:MGI.
DR GO; GO:0009897; C:external side of plasma membrane; ISO:MGI.
DR GO; GO:0005899; C:insulin receptor complex; ISO:MGI.
DR GO; GO:0005887; C:integral component of plasma membrane; ISO:MGI.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; ISO:MGI.
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:0043025; C:neuronal cell body; ISO:MGI.
DR GO; GO:0032809; C:neuronal cell body membrane; ISO:MGI.
DR GO; GO:0005635; C:nuclear envelope; ISO:MGI.
DR GO; GO:0031981; C:nuclear lumen; ISO:MGI.
DR GO; GO:0005634; C:nucleus; ISO:MGI.
DR GO; GO:0005886; C:plasma membrane; IDA:MGI.
DR GO; GO:0043235; C:receptor complex; ISO:MGI.
DR GO; GO:0055038; C:recycling endosome membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0045202; C:synapse; ISO:MGI.
DR GO; GO:0060417; C:yolk; ISO:MGI.
DR GO; GO:0043423; F:3-phosphoinositide-dependent protein kinase binding; ISO:MGI.
DR GO; GO:0001540; F:amyloid-beta binding; ISO:MGI.
DR GO; GO:0005524; F:ATP binding; ISO:MGI.
DR GO; GO:0038024; F:cargo receptor activity; ISO:MGI.
DR GO; GO:0005525; F:GTP binding; ISO:MGI.
DR GO; GO:0042802; F:identical protein binding; ISO:MGI.
DR GO; GO:0043559; F:insulin binding; ISS:UniProtKB.
DR GO; GO:0005009; F:insulin receptor activity; ISS:UniProtKB.
DR GO; GO:0043560; F:insulin receptor substrate binding; ISS:UniProtKB.
DR GO; GO:0031994; F:insulin-like growth factor I binding; ISO:MGI.
DR GO; GO:0031995; F:insulin-like growth factor II binding; ISO:MGI.
DR GO; GO:0005159; F:insulin-like growth factor receptor binding; ISO:MGI.
DR GO; GO:0031405; F:lipoic acid binding; ISO:MGI.
DR GO; GO:0043548; F:phosphatidylinositol 3-kinase binding; ISS:UniProtKB.
DR GO; GO:0019904; F:protein domain specific binding; ISO:MGI.
DR GO; GO:0004672; F:protein kinase activity; ISO:MGI.
DR GO; GO:0019901; F:protein kinase binding; ISO:MGI.
DR GO; GO:0019903; F:protein phosphatase binding; ISO:MGI.
DR GO; GO:0004713; F:protein tyrosine kinase activity; ISO:MGI.
DR GO; GO:0044877; F:protein-containing complex binding; ISO:MGI.
DR GO; GO:0051425; F:PTB domain binding; ISS:UniProtKB.
DR GO; GO:0005198; F:structural molecule activity; ISO:MGI.
DR GO; GO:0004714; F:transmembrane receptor protein tyrosine kinase activity; IBA:GO_Central.
DR GO; GO:0032147; P:activation of protein kinase activity; ISO:MGI.
DR GO; GO:0032148; P:activation of protein kinase B activity; ISO:MGI.
DR GO; GO:0030325; P:adrenal gland development; IGI:CACAO.
DR GO; GO:0097242; P:amyloid-beta clearance; ISO:MGI.
DR GO; GO:0009887; P:animal organ morphogenesis; IMP:MGI.
DR GO; GO:0071363; P:cellular response to growth factor stimulus; IDA:MGI.
DR GO; GO:0032869; P:cellular response to insulin stimulus; ISO:MGI.
DR GO; GO:0097062; P:dendritic spine maintenance; ISO:MGI.
DR GO; GO:0008544; P:epidermis development; IMP:MGI.
DR GO; GO:0031017; P:exocrine pancreas development; IMP:MGI.
DR GO; GO:0007186; P:G protein-coupled receptor signaling pathway; ISO:MGI.
DR GO; GO:0042593; P:glucose homeostasis; ISO:MGI.
DR GO; GO:0003007; P:heart morphogenesis; ISO:MGI.
DR GO; GO:0008286; P:insulin receptor signaling pathway; IMP:MGI.
DR GO; GO:0008584; P:male gonad development; IGI:CACAO.
DR GO; GO:0030238; P:male sex determination; IMP:MGI.
DR GO; GO:2000252; P:negative regulation of feeding behavior; ISO:MGI.
DR GO; GO:0010629; P:negative regulation of gene expression; ISO:MGI.
DR GO; GO:0001933; P:negative regulation of protein phosphorylation; ISO:MGI.
DR GO; GO:0032410; P:negative regulation of transporter activity; ISO:MGI.
DR GO; GO:1990535; P:neuron projection maintenance; ISO:MGI.
DR GO; GO:0038083; P:peptidyl-tyrosine autophosphorylation; IDA:MGI.
DR GO; GO:0018108; P:peptidyl-tyrosine phosphorylation; ISO:MGI.
DR GO; GO:0030335; P:positive regulation of cell migration; ISO:MGI.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; ISO:MGI.
DR GO; GO:0048639; P:positive regulation of developmental growth; ISO:MGI.
DR GO; GO:0046326; P:positive regulation of glucose import; ISO:MGI.
DR GO; GO:0045725; P:positive regulation of glycogen biosynthetic process; IMP:BHF-UCL.
DR GO; GO:0045821; P:positive regulation of glycolytic process; ISO:MGI.
DR GO; GO:0010560; P:positive regulation of glycoprotein biosynthetic process; ISO:MGI.
DR GO; GO:0033674; P:positive regulation of kinase activity; IBA:GO_Central.
DR GO; GO:0043406; P:positive regulation of MAP kinase activity; ISO:MGI.
DR GO; GO:0043410; P:positive regulation of MAPK cascade; ISO:MGI.
DR GO; GO:0051446; P:positive regulation of meiotic cell cycle; IGI:CACAO.
DR GO; GO:0045840; P:positive regulation of mitotic nuclear division; IMP:MGI.
DR GO; GO:0045429; P:positive regulation of nitric oxide biosynthetic process; ISO:MGI.
DR GO; GO:0014068; P:positive regulation of phosphatidylinositol 3-kinase signaling; IBA:GO_Central.
DR GO; GO:0042327; P:positive regulation of phosphorylation; ISO:MGI.
DR GO; GO:0051897; P:positive regulation of protein kinase B signaling; ISO:MGI.
DR GO; GO:0001934; P:positive regulation of protein phosphorylation; ISO:MGI.
DR GO; GO:0043243; P:positive regulation of protein-containing complex disassembly; ISO:MGI.
DR GO; GO:0002092; P:positive regulation of receptor internalization; ISO:MGI.
DR GO; GO:0060267; P:positive regulation of respiratory burst; ISO:MGI.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IGI:CACAO.
DR GO; GO:0046777; P:protein autophosphorylation; ISS:UniProtKB.
DR GO; GO:0006468; P:protein phosphorylation; ISO:MGI.
DR GO; GO:0006898; P:receptor-mediated endocytosis; ISO:MGI.
DR GO; GO:0045995; P:regulation of embryonic development; ISO:MGI.
DR GO; GO:2000194; P:regulation of female gonad development; IGI:CACAO.
DR GO; GO:0010310; P:regulation of hydrogen peroxide metabolic process; ISO:MGI.
DR GO; GO:0006355; P:regulation of transcription, DNA-templated; ISO:MGI.
DR GO; GO:0031667; P:response to nutrient levels; ISO:MGI.
DR GO; GO:0034612; P:response to tumor necrosis factor; ISO:MGI.
DR GO; GO:0007169; P:transmembrane receptor protein tyrosine kinase signaling pathway; IBA:GO_Central.
DR GO; GO:0046718; P:viral entry into host cell; ISO:MGI.
DR CDD; cd00063; FN3; 2.
DR CDD; cd00064; FU; 1.
DR Gene3D; 2.60.40.10; -; 3.
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; PF00041; fn3; 1.
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; 1.
DR SMART; SM00219; TyrKc; 1.
DR SUPFAM; SSF49265; SSF49265; 3.
DR SUPFAM; SSF56112; SSF56112; 1.
DR SUPFAM; SSF57184; SSF57184; 1.
DR PROSITE; PS50853; FN3; 3.
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; ATP-binding; Cell membrane;
KW Cleavage on pair of basic residues; Disulfide bond; Endosome; Glycoprotein;
KW Kinase; Lysosome; Membrane; Nucleotide-binding; Phosphoprotein; Receptor;
KW Reference proteome; Repeat; Signal; Transferase; Transmembrane;
KW Transmembrane helix; Tyrosine-protein kinase.
FT SIGNAL 1..27
FT CHAIN 28..748
FT /note="Insulin receptor subunit alpha"
FT /id="PRO_0000016693"
FT CHAIN 753..1372
FT /note="Insulin receptor subunit beta"
FT /id="PRO_0000016695"
FT TOPO_DOM 28..748
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TOPO_DOM 753..946
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 947..967
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 968..1372
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT DOMAIN 626..728
FT /note="Fibronectin type-III 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316"
FT DOMAIN 744..838
FT /note="Fibronectin type-III 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316"
FT DOMAIN 843..937
FT /note="Fibronectin type-III 3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316"
FT DOMAIN 1013..1288
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 688..709
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 735..743
FT /note="Insulin-binding"
FT /evidence="ECO:0000250"
FT REGION 986..989
FT /note="Important for interaction with IRS1, SHC1 and
FT STAT5B"
FT /evidence="ECO:0000250"
FT REGION 1349..1372
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1351..1354
FT /note="PIK3R1 binding"
FT /evidence="ECO:0000250"
FT ACT_SITE 1149
FT /note="Proton donor/acceptor"
FT /evidence="ECO:0000250"
FT BINDING 1023
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 1047
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT BINDING 1094..1100
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 1153..1154
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 1167
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT SITE 66
FT /note="Insulin-binding"
FT /evidence="ECO:0000250"
FT MOD_RES 400
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P06213"
FT MOD_RES 401
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:P06213"
FT MOD_RES 407
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P06213"
FT MOD_RES 989
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P06213"
FT MOD_RES 1175
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P06213"
FT MOD_RES 1179
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P06213"
FT MOD_RES 1180
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P06213"
FT MOD_RES 1345
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P06213"
FT MOD_RES 1351
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P06213"
FT CARBOHYD 43
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 52
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
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:0000255"
FT CARBOHYD 242
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 282
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
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:0000255"
FT CARBOHYD 424
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 445
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:19349973,
FT ECO:0000269|PubMed:19656770"
FT CARBOHYD 541
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 635
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 653
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 700
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 759
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 772
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 910
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 923
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 35..53
FT /evidence="ECO:0000250"
FT DISULFID 153..182
FT /evidence="ECO:0000250"
FT DISULFID 186..209
FT /evidence="ECO:0000250"
FT DISULFID 196..215
FT /evidence="ECO:0000250"
FT DISULFID 219..228
FT /evidence="ECO:0000250"
FT DISULFID 223..234
FT /evidence="ECO:0000250"
FT DISULFID 235..243
FT /evidence="ECO:0000250"
FT DISULFID 239..252
FT /evidence="ECO:0000250"
FT DISULFID 255..264
FT /evidence="ECO:0000250"
FT DISULFID 268..280
FT /evidence="ECO:0000250"
FT DISULFID 286..311
FT /evidence="ECO:0000250"
FT DISULFID 293..301
FT /evidence="ECO:0000250"
FT DISULFID 315..328
FT /evidence="ECO:0000250"
FT DISULFID 331..335
FT /evidence="ECO:0000250"
FT DISULFID 339..360
FT /evidence="ECO:0000250"
FT DISULFID 462..495
FT /evidence="ECO:0000250"
FT DISULFID 551
FT /note="Interchain"
FT /evidence="ECO:0000250"
FT DISULFID 676..889
FT /evidence="ECO:0000250"
FT DISULFID 815..824
FT /evidence="ECO:0000250"
FT MUTAGEN 989
FT /note="Y->F: Abolishes interaction with IRS1 but not with
FT IRS2."
FT /evidence="ECO:0000269|PubMed:10207032,
FT ECO:0000269|PubMed:8626379"
FT CONFLICT 1089
FT /note="T -> M (in Ref. 1; AAA39318)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 1372 AA; 155610 MW; B0FA7DBD2AD4646A CRC64;
MGFGRGCETT AVPLLVAVAA LLVGTAGHLY PGEVCPGMDI RNNLTRLHEL ENCSVIEGHL
QILLMFKTRP EDFRDLSFPK LIMITDYLLL FRVYGLESLK DLFPNLTVIR GSRLFFNYAL
VIFEMVHLKE LGLYNLMNIT RGSVRIEKNN ELCYLATIDW SRILDSVEDN YIVLNKDDNE
ECGDVCPGTA KGKTNCPATV INGQFVERCW THSHCQKVCP TICKSHGCTA EGLCCHKECL
GNCSEPDDPT KCVACRNFYL DGQCVETCPP PYYHFQDWRC VNFSFCQDLH FKCRNSRKPG
CHQYVIHNNK CIPECPSGYT MNSSNLMCTP CLGPCPKVCQ ILEGEKTIDS VTSAQELRGC
TVINGSLIIN IRGGNNLAAE LEANLGLIEE ISGFLKIRRS YALVSLSFFR KLHLIRGETL
EIGNYSFYAL DNQNLRQLWD WSKHNLTITQ GKLFFHYNPK LCLSEIHKME EVSGTKGRQE
RNDIALKTNG DQASCENELL KFSFIRTSFD KILLRWEPYW PPDFRDLLGF MLFYKEAPYQ
NVTEFDGQDA CGSNSWTVVD IDPPQRSNDP KSQTPSHPGW LMRGLKPWTQ YAIFVKTLVT
FSDERRTYGA KSDIIYVQTD ATNPSVPLDP ISVSNSSSQI ILKWKPPSDP NGNITHYLVY
WERQAEDSEL FELDYCLKGL KLPSRTWSPP FESDDSQKHN QSEYDDSASE CCSCPKTDSQ
ILKELEESSF RKTFEDYLHN VVFVPRPSRK RRSLEEVGNV TATTLTLPDF PNVSSTIVPT
SQEEHRPFEK VVNKESLVIS GLRHFTGYRI ELQACNQDSP DERCSVAAYV SARTMPEAKA
DDIVGPVTHE IFENNVVHLM WQEPKEPNGL IVLYEVSYRR YGDEELHLCV SRKHFALERG
CRLRGLSPGN YSVRVRATSL AGNGSWTEPT YFYVTDYLDV PSNIAKIIIG PLIFVFLFSV
VIGSIYLFLR KRQPDGPMGP LYASSNPEYL SASDVFPSSV YVPDEWEVPR EKITLLRELG
QGSFGMVYEG NAKDIIKGEA ETRVAVKTVN ESASLRERIE FLNEASVMKG FTCHHVVRLL
GVVSKGQPTL VVMELMAHGD LKSHLRSLRP DAENNPGRPP PTLQEMIQMT AEIADGMAYL
NAKKFVHRDL AARNCMVAHD FTVKIGDFGM TRDIYETDYY RKGGKGLLPV RWMSPESLKD
GVFTASSDMW SFGVVLWEIT SLAEQPYQGL SNEQVLKFVM DGGYLDPPDN CPERLTDLMR
MCWQFNPKMR PTFLEIVNLL KDDLHPSFPE VSFFYSEENK APESEELEME FEDMENVPLD
RSSHCQREEA GGREGGSSLS IKRTYDEHIP YTHMNGGKKN GRVLTLPRSN PS
