IRS4_MOUSE
ID IRS4_MOUSE Reviewed; 1216 AA.
AC Q9Z0Y7; A2BHF6; Q8BRB9;
DT 15-JAN-2008, integrated into UniProtKB/Swiss-Prot.
DT 15-JAN-2008, sequence version 2.
DT 03-AUG-2022, entry version 139.
DE RecName: Full=Insulin receptor substrate 4;
DE Short=IRS-4;
DE AltName: Full=Phosphoprotein of 160 kDa;
DE Short=pp160;
GN Name=Irs4;
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 [GENOMIC DNA], DEVELOPMENTAL STAGE, AND TISSUE
RP SPECIFICITY.
RC TISSUE=Liver;
RX PubMed=10067860; DOI=10.1210/endo.140.3.6578;
RA Fantin V.R., Lavan B.E., Wang Q., Jenkins N.A., Gilbert D.J.,
RA Copeland N.G., Keller S.R., Lienhard G.E.;
RT "Cloning, tissue expression, and chromosomal location of the mouse insulin
RT receptor substrate 4 gene.";
RL Endocrinology 140:1329-1337(1999).
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 [LARGE SCALE MRNA] OF 746-1216.
RC STRAIN=C57BL/6J; TISSUE=Embryo;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [4]
RP FUNCTION.
RX PubMed=10403832; DOI=10.1006/bbrc.1999.0967;
RA Fantin V.R., Keller S.R., Lienhard G.E., Wang L.-M.;
RT "Insulin receptor substrate 4 supports insulin- and interleukin 4-
RT stimulated proliferation of hematopoietic cells.";
RL Biochem. Biophys. Res. Commun. 260:718-723(1999).
RN [5]
RP TISSUE SPECIFICITY, FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=10644546; DOI=10.1152/ajpendo.2000.278.1.e127;
RA Fantin V.R., Wang Q., Lienhard G.E., Keller S.R.;
RT "Mice lacking insulin receptor substrate 4 exhibit mild defects in growth,
RT reproduction, and glucose homeostasis.";
RL Am. J. Physiol. 278:E127-E133(2000).
RN [6]
RP FUNCTION, AND INTERACTION WITH PIK3R1 AND GRB2.
RX PubMed=11113178; DOI=10.1128/mcb.21.1.26-38.2001;
RA Tsuruzoe K., Emkey R., Kriauciunas K.M., Ueki K., Kahn C.R.;
RT "Insulin receptor substrate 3 (IRS-3) and IRS-4 impair IRS-1- and IRS-2-
RT mediated signaling.";
RL Mol. Cell. Biol. 21:26-38(2001).
RN [7]
RP INTERACTION WITH SOCS6, AND IDENTIFICATION BY MASS SPECTROMETRY.
RX PubMed=12052866; DOI=10.1128/mcb.22.13.4567-4578.2002;
RA Krebs D.L., Uren R.T., Metcalf D., Rakar S., Zhang J.-G., Starr R.,
RA De Souza D.P., Hanzinikolas K., Eyles J., Connolly L.M., Simpson R.J.,
RA Nicola N.A., Nicholson S.E., Baca M., Hilton D.J., Alexander W.S.;
RT "SOCS-6 binds to insulin receptor substrate 4, and mice lacking the SOCS-6
RT gene exhibit mild growth retardation.";
RL Mol. Cell. Biol. 22:4567-4578(2002).
RN [8]
RP FUNCTION, INTERACTION WITH PHOSPHATIDYLINOSITOL 3-KINASE, AND
RP PHOSPHORYLATION.
RX PubMed=12618213; DOI=10.1016/s0898-6568(02)00113-4;
RA Ursoe B., Ilondo M.M., Holst P.A., Christoffersen C.T., Ouwens M.,
RA Giorgetti S., Van Obberghen E., Naor D., Tornqvist H., De Meyts P.;
RT "IRS-4 mediated mitogenic signalling by insulin and growth hormone in LB
RT cells, a murine T-cell lymphoma devoid of IGF-I receptors.";
RL Cell. Signal. 15:385-394(2003).
CC -!- FUNCTION: Acts as an interface between multiple growth factor receptors
CC possessing tyrosine kinase activity, such as insulin receptor, IGF1R
CC and FGFR1, and a complex network of intracellular signaling molecules
CC containing SH2 domains. Involved in the IGF1R mitogenic signaling
CC pathway. Promotes the AKT1 signaling pathway and BAD phosphorylation
CC during insulin stimulation without activation of RPS6KB1 or the
CC inhibition of apoptosis. Interaction with GRB2 enhances insulin-
CC stimulated mitogen-activated protein kinase activity. May be involved
CC in nonreceptor tyrosine kinase signaling in myoblasts. Plays a pivotal
CC role in the proliferation/differentiation of hepatoblastoma cell
CC through EPHB2 activation upon IGF1 stimulation. May play a role in the
CC signal transduction in response to insulin and to a lesser extent in
CC response to IL4 and GH on mitogenesis. Plays a role in growth,
CC reproduction and glucose homeostasis. May act as negative regulators of
CC the IGF1 signaling pathway by suppressing the function of IRS1 and
CC IRS2. {ECO:0000269|PubMed:10403832, ECO:0000269|PubMed:10644546,
CC ECO:0000269|PubMed:11113178, ECO:0000269|PubMed:12618213}.
CC -!- SUBUNIT: Interacts with CRK and CRKL. Interaction with CRK is stronger
CC than with CRKL. Interacts with CRK via the phosphorylated YXXM motifs.
CC Interacts with PLC-gamma, SHC1, PTK6, PPP4C and NISCH (By similarity).
CC Interacts with SOCS6 in response to stimulation with either insulin or
CC IGF1. Interacts with PIK3R1 and GRB2. {ECO:0000250,
CC ECO:0000269|PubMed:11113178, ECO:0000269|PubMed:12052866,
CC ECO:0000269|PubMed:12618213}.
CC -!- SUBCELLULAR LOCATION: Cell membrane; Peripheral membrane protein;
CC Cytoplasmic side.
CC -!- TISSUE SPECIFICITY: Expressed in skeletal muscle, brain, heart, kidney
CC and liver. {ECO:0000269|PubMed:10067860, ECO:0000269|PubMed:10644546}.
CC -!- DEVELOPMENTAL STAGE: First detected from days 15 and 17 embryos.
CC {ECO:0000269|PubMed:10067860}.
CC -!- PTM: Phosphorylated on tyrosine residues in response to both insulin
CC and IGF1 signaling. Phosphorylated on Tyr-894 in response to FGF2
CC signaling. Phosphorylation of Tyr-894 is required for GRB2,
CC phospholipase C-gamma and phosphatidylinositol 3-kinase interaction (By
CC similarity). {ECO:0000250}.
CC -!- DISRUPTION PHENOTYPE: Slight defects in growth, reproduction and
CC glucose homeostasis. {ECO:0000269|PubMed:10644546}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAC32246.1; Type=Erroneous initiation; Evidence={ECO:0000305};
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DR EMBL; AF087797; AAD17797.1; -; Genomic_DNA.
DR EMBL; BX571779; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AK045172; BAC32246.1; ALT_INIT; mRNA.
DR CCDS; CCDS30445.1; -.
DR RefSeq; NP_034702.2; NM_010572.2.
DR AlphaFoldDB; Q9Z0Y7; -.
DR SMR; Q9Z0Y7; -.
DR BioGRID; 200791; 5.
DR IntAct; Q9Z0Y7; 1.
DR MINT; Q9Z0Y7; -.
DR STRING; 10090.ENSMUSP00000067085; -.
DR iPTMnet; Q9Z0Y7; -.
DR PhosphoSitePlus; Q9Z0Y7; -.
DR PaxDb; Q9Z0Y7; -.
DR PRIDE; Q9Z0Y7; -.
DR ProteomicsDB; 301669; -.
DR Antibodypedia; 15310; 172 antibodies from 31 providers.
DR DNASU; 16370; -.
DR Ensembl; ENSMUST00000067841; ENSMUSP00000067085; ENSMUSG00000054667.
DR GeneID; 16370; -.
DR KEGG; mmu:16370; -.
DR UCSC; uc009ulp.1; mouse.
DR CTD; 8471; -.
DR MGI; MGI:1338009; Irs4.
DR VEuPathDB; HostDB:ENSMUSG00000054667; -.
DR eggNOG; ENOG502SD84; Eukaryota.
DR GeneTree; ENSGT00940000160883; -.
DR HOGENOM; CLU_290952_0_0_1; -.
DR InParanoid; Q9Z0Y7; -.
DR OMA; EDSRGYM; -.
DR OrthoDB; 298675at2759; -.
DR PhylomeDB; Q9Z0Y7; -.
DR TreeFam; TF325994; -.
DR Reactome; R-MMU-2428928; IRS-related events triggered by IGF1R.
DR BioGRID-ORCS; 16370; 1 hit in 71 CRISPR screens.
DR PRO; PR:Q9Z0Y7; -.
DR Proteomes; UP000000589; Chromosome X.
DR RNAct; Q9Z0Y7; protein.
DR Bgee; ENSMUSG00000054667; Expressed in median eminence of neurohypophysis and 83 other tissues.
DR Genevisible; Q9Z0Y7; MM.
DR GO; GO:0005829; C:cytosol; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
DR GO; GO:0005158; F:insulin receptor binding; IBA:GO_Central.
DR GO; GO:0043548; F:phosphatidylinositol 3-kinase binding; IBA:GO_Central.
DR GO; GO:0008286; P:insulin receptor signaling pathway; IBA:GO_Central.
DR CDD; cd01204; PTB_IRS; 1.
DR Gene3D; 2.30.29.30; -; 2.
DR InterPro; IPR039011; IRS.
DR InterPro; IPR002404; IRS_PTB.
DR InterPro; IPR011993; PH-like_dom_sf.
DR InterPro; IPR001849; PH_domain.
DR PANTHER; PTHR10614; PTHR10614; 1.
DR Pfam; PF02174; IRS; 1.
DR PRINTS; PR00628; INSULINRSI.
DR SMART; SM00233; PH; 1.
DR SMART; SM00310; PTBI; 1.
DR PROSITE; PS51064; IRS_PTB; 1.
DR PROSITE; PS50003; PH_DOMAIN; 1.
PE 1: Evidence at protein level;
KW Cell membrane; Membrane; Phosphoprotein; Reference proteome; Repeat;
KW Transducer.
FT CHAIN 1..1216
FT /note="Insulin receptor substrate 4"
FT /id="PRO_0000314679"
FT DOMAIN 79..200
FT /note="PH"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00145"
FT DOMAIN 232..336
FT /note="IRS-type PTB"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00389"
FT REGION 399..799
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 650..773
FT /note="CRK-binding"
FT /evidence="ECO:0000250"
FT REGION 816..888
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 868..870
FT /note="GRB2-binding"
FT /evidence="ECO:0000250"
FT REGION 1168..1204
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 480..483
FT /note="YXXM motif 1"
FT MOTIF 672..675
FT /note="YXXM motif 2"
FT MOTIF 689..692
FT /note="YXXM motif 3"
FT MOTIF 715..718
FT /note="YXXM motif 4"
FT MOTIF 752..755
FT /note="YXXM motif 5"
FT MOTIF 801..804
FT /note="YXXM motif 6"
FT MOTIF 894..897
FT /note="YXXM motif 7"
FT COMPBIAS 462..477
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 487..540
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 631..650
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 767..797
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 817..840
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 844..858
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 894
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:O14654"
FT CONFLICT 35
FT /note="L -> F (in Ref. 1; AAD17797)"
FT /evidence="ECO:0000305"
FT CONFLICT 651
FT /note="S -> P (in Ref. 1; AAD17797)"
FT /evidence="ECO:0000305"
FT CONFLICT 1162
FT /note="R -> G (in Ref. 1; AAD17797)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 1216 AA; 130147 MW; B52B01DB468AED3B CRC64;
MASCSFSGHQ ALRRLRASAA AAASAALAAV ATTPLLSSGT RTALIGTGSS CPGAMWLSTA
TGSRSDSESE EEDLPVGDEV CKRGYLRKQK HGHRRYFVLK LETADAPARL EYYRNARKFR
HSVRAAAAAA EAAASGAAVP ALIPPRRVII LYQCFSVSQR ADARYRHLIA LFTQDEYFAM
VAENESEQES WYLLLSRLIL ESKRRRCGTL GALPDGEPAA LAAAAAAEPP FYKDVWQVVV
KPRGLGHRKE LSGVFRLCLT DEEVVFVRLN TEVASVVVQL LSIRRCGHSE QYFFLEVGRS
TVIGPGELWM QVDDSVVAQN MHELFLEKMR ALCADEYRAR CRSYSISIGA HLLTLLSTRR
HLGLLPLEPG GWLRRYGLEQ FCRLRAIRER EEMLFTRRFI SPREPPPPFR RGRGHLPRAR
RSRRAASVPP SLFRRSAPSP GRIPQPEDVP NDRAREASGS SSGNTEEKDK EGEEGNRGDC
IPMNNWGSGN GRGSGGGRGS SGQGSSSQGS GGRQGSGGGQ GSGGQGAGGN QCSGNGQGTA
GGHGSGGGGH GSGGGQRPGD GHGSGGGKNS GSGKNSDDGD RGKSVKKRSY FGKFTQSKQQ
QTLPPPPPPP PAAGATGGKG KSGGRFRLYF CADRGTKERK EAKEVRDMET SGGATRGPYR
ARAFDEDEDD PYVPMRPGVA APLACSSDYM PMAPQNSSAS TKRHSRSPFE DSRGYMMMFP
RVSPPPPVPS APKAPDTNKG DDSKDNDSDS DYMFMAPGAG AIPKNPPNAQ GGSSSKSWSS
YFSLPSPFQS SPLGQSDHSE YVPMLPGKFL GSGLHKEASF SQGTKNVSSK PSTEASFSKP
EDKGSSAKPS DDVPPMNKAK EPNHLSFIAK GTQVKPKPLN PTQERREAAG SRDYINIDFI
KRERLVLPSS AQGLPDMRGV VTDPAPTAFS GYLNVEFGVP FPNPTIRLSD LLRVLPGANS
IPLAGTRWPF PGSAIGSIVE AGEYIEVIFN PAMTPAMSFA DSAICYDAQT GQIYVVDPFS
ECCMDVSLSP GRCSEPPPVA RLRREEAQER RRPQSRSQSL FASTRAAVSA FPTDSLDRDF
PAASAVIAAP AEAPLLAVSR ALAVVSALAA APSIGDVFAG FRAAAGVDSA SARGFQPVAG
AQAVREFQDL AAGWNPGALN HRARGEDLAA GAAAPPPPPR QIWVLRPQER ADSEDDDDDD
DDIYVRMDFA RRDYRK
