ID IRS1_RAT Reviewed; 1235 AA. AC P35570; DT 01-JUN-1994, integrated into UniProtKB/Swiss-Prot. DT 01-JUN-1994, sequence version 1. DT 10-JUN-2026, entry version 193. DE RecName: Full=Insulin receptor substrate 1; DE Short=IRS-1; DE AltName: Full=pp185; GN Name=Irs1; Synonyms=Irs-1; OS Rattus norvegicus (Rat). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; OC Murinae; Rattus. OX NCBI_TaxID=10116; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], AND PARTIAL PROTEIN SEQUENCE. RC STRAIN=Sprague-Dawley; TISSUE=Liver; RX PubMed=1648180; DOI=10.1038/352073a0; RA Sun X.-J., Rothenberg P.L., Kahn C.R., Backer J.M., Araki E., Wilden P.A., RA Cahill D.A., Goldstein B.J., White M.F.; RT "Structure of the insulin receptor substrate IRS-1 defines a unique signal RT transduction protein."; RL Nature 352:73-77(1991). RN [2] RP PROTEIN SEQUENCE OF 44-51; 173-178; 223-243; 489-506; 635-646; 932-947 AND RP 1098-1106. RX PubMed=2022647; DOI=10.1016/s0021-9258(18)92976-5; RA Rothenberg P.L., Lane W.S., Karasik A., Backer J.M., White M.F., Kahn C.R.; RT "Purification and partial sequence analysis of pp185, the major cellular RT substrate of the insulin receptor tyrosine kinase."; RL J. Biol. Chem. 266:8302-8311(1991). RN [3] RP FUNCTION, PHOSPHORYLATION, AND INTERACTION WITH PIK3R1. RX PubMed=1380456; DOI=10.1002/j.1460-2075.1992.tb05426.x; RA Backer J.M., Myers M.G. Jr., Shoelson S.E., Chin D.J., Sun X.-J., RA Miralpeix M., Hu P., Margolis B., Skolnik E.Y., Schlessinger J., RA White M.F.; RT "Phosphatidylinositol 3'-kinase is activated by association with IRS-1 RT during insulin stimulation."; RL EMBO J. 11:3469-3479(1992). RN [4] RP INTERACTION WITH GRB2, AND FUNCTION. RX PubMed=8491186; DOI=10.1002/j.1460-2075.1993.tb05842.x; RA Skolnik E.Y., Lee C.-H., Batzer A.G., Vicentini L.M., Zhou M., Daly R.J., RA Myers M.J. Jr., Backer J.M., Ullrich A., White M.F., Schlessinger J.; RT "The SH2/SH3 domain-containing protein GRB2 interacts with tyrosine- RT phosphorylated IRS1 and Shc: implications for insulin control of ras RT signalling."; RL EMBO J. 12:1929-1936(1993). RN [5] RP PHOSPHORYLATION AT TYR-460; TYR-608; TYR-628; TYR-895; TYR-939; TYR-987; RP TYR-1172 AND TYR-1222. RX PubMed=7504175; DOI=10.1128/mcb.13.12.7418-7428.1993; RA Sun X.-J., Crimmins D.L., Myers M.G. Jr., Miralpeix M., White M.F.; RT "Pleiotropic insulin signals are engaged by multisite phosphorylation of RT IRS-1."; RL Mol. Cell. Biol. 13:7418-7428(1993). RN [6] RP PHOSPHORYLATION AT SER-99 AND THR-502. RX PubMed=8349691; DOI=10.1016/s0021-9258(17)46824-4; RA Tanasijevic M.J., Myers M.G. Jr., Thoma R.S., Crimmins D.L., White M.F., RA Sacks D.B.; RT "Phosphorylation of the insulin receptor substrate IRS-1 by casein kinase RT II."; RL J. Biol. Chem. 268:18157-18166(1993). RN [7] RP INTERACTION WITH PHIP, AND MUTAGENESIS OF TRP-106. RX PubMed=11018022; DOI=10.1074/jbc.c000611200; RA Farhang-Fallah J., Yin X., Trentin G., Cheng A.M., Rozakis-Adcock M.; RT "Cloning and characterization of PHIP, a novel insulin receptor substrate-1 RT pleckstrin homology domain interacting protein."; RL J. Biol. Chem. 275:40492-40497(2000). RN [8] RP PHOSPHORYLATION AT SER-307. RX PubMed=11606564; DOI=10.1074/jbc.m101521200; RA Aguirre V., Werner E.D., Giraud J., Lee Y.H., Shoelson S.E., White M.F.; RT "Phosphorylation of Ser307 in insulin receptor substrate-1 blocks RT interactions with the insulin receptor and inhibits insulin action."; RL J. Biol. Chem. 277:1531-1537(2002). RN [9] RP PHOSPHORYLATION AT SER-789. RX PubMed=12006586; DOI=10.1074/jbc.m201494200; RA Qiao L.Y., Zhande R., Jetton T.L., Zhou G., Sun X.-J.; RT "In vivo phosphorylation of insulin receptor substrate 1 at serine 789 by a RT novel serine kinase in insulin-resistant rodents."; RL J. Biol. Chem. 277:26530-26539(2002). RN [10] RP INTERACTION WITH ROCK1, AND PHOSPHORYLATION. RX PubMed=11739394; DOI=10.1074/jbc.m110508200; RA Begum N., Sandu O.A., Ito M., Lohmann S.M., Smolenski A.; RT "Active Rho kinase (ROK-alpha) associates with insulin receptor substrate-1 RT and inhibits insulin signaling in vascular smooth muscle cells."; RL J. Biol. Chem. 277:6214-6222(2002). RN [11] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=12399410; DOI=10.1210/en.2002-220321; RA Boylan J.M., Gruppuso P.A.; RT "Insulin receptor substrate-1 is present in hepatocyte nuclei from intact RT rats."; RL Endocrinology 143:4178-4183(2002). RN [12] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-3; SER-343; THR-441; THR-448 RP AND SER-891, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE RP ANALYSIS]. RX PubMed=22673903; DOI=10.1038/ncomms1871; RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C., RA Olsen J.V.; RT "Quantitative maps of protein phosphorylation sites across 14 different rat RT organs and tissues."; RL Nat. Commun. 3:876-876(2012). RN [13] RP PHOSPHORYLATION AT SER-612. RX PubMed=24187137; DOI=10.1074/jbc.m113.500736; RA Seldin M.M., Lei X., Tan S.Y., Stanson K.P., Wei Z., Wong G.W.; RT "Skeletal muscle-derived myonectin activates the mammalian target of RT rapamycin (mTOR) pathway to suppress autophagy in liver."; RL J. Biol. Chem. 288:36073-36082(2013). RN [14] RP INTERACTION WITH GKAP1. RX PubMed=25586176; DOI=10.1074/jbc.m114.624759; RA Ando Y., Shinozawa Y., Iijima Y., Yu B.C., Sone M., Ooi Y., Watanaka Y., RA Chida K., Hakuno F., Takahashi S.; RT "Tumor necrosis factor (TNF)-alpha-induced repression of GKAP42 protein RT levels through cGMP-dependent kinase (cGK)-Ialpha causes insulin resistance RT in 3T3-L1 adipocytes."; RL J. Biol. Chem. 290:5881-5892(2015). RN [15] RP INTERACTION WITH DGKZ. RX PubMed=27739494; DOI=10.1038/srep35438; RA Liu T., Yu B., Kakino M., Fujimoto H., Ando Y., Hakuno F., Takahashi S.I.; RT "A novel IRS-1-associated protein, DGKzeta regulates GLUT4 translocation in RT 3T3-L1 adipocytes."; RL Sci. Rep. 6:35438-35438(2016). CC -!- FUNCTION: Signaling adapter protein that participates in the signal CC transduction from two prominent receptor tyrosine kinases, insulin CC receptor/INSR and insulin-like growth factor I receptor/IGF1R CC (PubMed:12399410). Plays therefore an important role in development, CC growth, glucose homeostasis as well as lipid metabolism. Upon CC phosphorylation by the insulin receptor, functions as a signaling CC scaffold that propagates insulin action through binding to SH2 domain- CC containing proteins including the p85 regulatory subunit of PI3K, NCK1, CC NCK2, GRB2 or SHP2 (PubMed:1380456). Recruitment of GRB2 leads to the CC activation of the guanine nucleotide exchange factor SOS1 which in turn CC triggers the Ras/Raf/MEK/MAPK signaling cascade (PubMed:8491186). CC Activation of the PI3K/AKT pathway is responsible for most of insulin CC metabolic effects in the cell, and the Ras/Raf/MEK/MAPK is involved in CC the regulation of gene expression and in cooperation with the PI3K CC pathway regulates cell growth and differentiation (By similarity). Acts CC a positive regulator of the Wnt/beta-catenin signaling pathway through CC suppression of DVL2 autophagy-mediated degradation leading to cell CC proliferation (By similarity). {ECO:0000250|UniProtKB:P35568, CC ECO:0000269|PubMed:12399410, ECO:0000269|PubMed:1380456, CC ECO:0000269|PubMed:8491186}. CC -!- SUBUNIT: Interacts with SOCS7 (By similarity). Interacts (via IRS-type CC PTB domain) with IGF1R and INSR (via the tyrosine-phosphorylated NPXY CC motif) (By similarity). Interacts with UBTF, FER and PIK3CA (By CC similarity). Interacts (via phosphorylated YXXM motifs) with PIK3R1 CC (PubMed:1380456). Interacts with ROCK1 (PubMed:11739394). Interacts CC (via PH domain) with PHIP (PubMed:11018022). Interacts with GRB2 CC (PubMed:8491186). Interacts with ALK (By similarity). Interacts with CC EIF2AK2/PKR (By similarity). Interacts with GKAP1 (PubMed:25586176). CC Interacts with DGKZ in the absence of insulin; insulin stimulation CC decreases this interaction (PubMed:27739494). Found in a ternary CC complex with DGKZ and PIP5K1A in the absence of insulin stimulation (By CC similarity). Interacts with SQSTM1; the interaction is disrupted by the CC presence of tensin TNS2 (By similarity). Interacts with NCK1 (via SH2 CC domain). Interacts with NCK2 (via SH3 domain) (By similarity). CC Interacts with SH2B1; this interaction enhances leptin-induced CC activation of the PI3-kinase pathway (By similarity). Interacts with CC DVL2; this interaction promotes the Wnt/beta-catenin signaling pathway CC (By similarity). Interacts with JAK1 (By similarity). CC {ECO:0000250|UniProtKB:P35568, ECO:0000250|UniProtKB:P35569, CC ECO:0000269|PubMed:11018022, ECO:0000269|PubMed:11739394, CC ECO:0000269|PubMed:1380456, ECO:0000269|PubMed:25586176, CC ECO:0000269|PubMed:27739494, ECO:0000269|PubMed:8491186}. CC -!- INTERACTION: CC P35570; Q9EPH8: Pabpc1; NbExp=2; IntAct=EBI-520230, EBI-919825; CC P35570; Q63787: Pik3r1; NbExp=2; IntAct=EBI-520230, EBI-518443; CC P35570; P39688: Fyn; Xeno; NbExp=4; IntAct=EBI-520230, EBI-524514; CC P35570; P62993: GRB2; Xeno; NbExp=5; IntAct=EBI-520230, EBI-401755; CC P35570; P06213: INSR; Xeno; NbExp=6; IntAct=EBI-520230, EBI-475899; CC P35570; Q8VDD9: Phip; Xeno; NbExp=2; IntAct=EBI-520230, EBI-1369766; CC P35570; P27986: PIK3R1; Xeno; NbExp=2; IntAct=EBI-520230, EBI-79464; CC P35570; Q04759: PRKCQ; Xeno; NbExp=2; IntAct=EBI-520230, EBI-374762; CC P35570; P18031: PTPN1; Xeno; NbExp=3; IntAct=EBI-520230, EBI-968788; CC P35570; Q06124: PTPN11; Xeno; NbExp=3; IntAct=EBI-520230, EBI-297779; CC P35570; Q13625-2: TP53BP2; Xeno; NbExp=4; IntAct=EBI-520230, EBI-287091; CC P35570; P62258: YWHAE; Xeno; NbExp=4; IntAct=EBI-520230, EBI-356498; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:P35568}. Nucleus CC {ECO:0000250|UniProtKB:P35568}. Note=Nuclear or cytoplasmic CC localization of IRS1 correlates with the transition from proliferation CC to chondrogenic differentiation. {ECO:0000250|UniProtKB:P35568}. CC -!- PTM: Serine phosphorylation of IRS1 is a mechanism for insulin CC resistance. Ser-307 phosphorylation inhibits insulin action through CC disruption of IRS1 interaction with the insulin receptor, and Ser-789 CC phosphorylation is increased in the liver of insulin-resistant rats CC (PubMed:11606564, PubMed:12006586, PubMed:7504175). Phosphorylation of CC Tyr-895 is required for GRB2-binding. Phosphorylated by ALK. CC Phosphorylated at Ser-265, Ser-302, Ser-632 and Ser-1100 by RPS6KB1; CC phosphorylation induces accelerated degradation of IRS1 (By CC similarity). Phosphorylated on tyrosine residues in response to insulin CC (By similarity). In skeletal muscles, dephosphorylated on Tyr-608 by CC TNS2 under anabolic conditions; dephosphorylation results in the CC proteasomal degradation of IRS1 (By similarity). CC {ECO:0000250|UniProtKB:P35568, ECO:0000250|UniProtKB:P35569, CC ECO:0000269|PubMed:11606564, ECO:0000269|PubMed:12006586, CC ECO:0000269|PubMed:7504175}. CC -!- PTM: Ubiquitinated by the Cul7-RING(FBXW8) complex in a mTOR-dependent CC manner, leading to its degradation: the Cul7-RING(FBXW8) complex CC recognizes and binds IRS1 previously phosphorylated by S6 kinase CC (RPS6KB1 or RPS6KB2). Ubiquitinated by TRAF4 through 'Lys-29' linkage; CC this ubiquitination regulates the interaction of IRS1 with IGFR and CC IRS1 tyrosine phosphorylation upon IGF1 stimulation (By similarity). CC {ECO:0000250|UniProtKB:P35568}. CC -!- PTM: S-nitrosylation at by BLVRB inhibits its activity. CC {ECO:0000250|UniProtKB:P35568}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; X58375; CAA41264.1; -; mRNA. DR PIR; S16948; S16948. DR RefSeq; NP_037101.2; NM_012969.2. DR PDB; 5WRK; X-ray; 2.62 A; P=607-614. DR PDB; 5WRL; X-ray; 3.10 A; P=627-634. DR PDB; 5WRM; X-ray; 2.60 A; P=657-664. DR AlphaFoldDB; P35570; -. DR BMRB; P35570; -. DR SMR; P35570; -. DR BioGRID; 247500; 14. DR CORUM; P35570; -. DR DIP; DIP-664N; -. DR ELM; P35570; -. DR FunCoup; P35570; 683. DR IntAct; P35570; 23. DR MINT; P35570; -. DR STRING; 10116.ENSRNOP00000019579; -. DR BindingDB; P35570; -. DR ChEMBL; CHEMBL1163110; -. DR GlyGen; P35570; 4 sites, 1 O-linked glycan (4 sites). DR iPTMnet; P35570; -. DR PhosphoSitePlus; P35570; -. DR PaxDb; 10116-ENSRNOP00000019579; -. DR GeneID; 25467; -. DR KEGG; rno:25467; -. DR UCSC; RGD:2922; rat. DR AGR; RGD:2922; -. DR CTD; 3667; -. DR RGD; 2922; Irs1. DR eggNOG; ENOG502QUNU; Eukaryota. DR InParanoid; P35570; -. DR PhylomeDB; P35570; -. DR Reactome; R-RNO-109704; PI3K Cascade. DR Reactome; R-RNO-112399; IRS-mediated signalling. DR Reactome; R-RNO-112412; SOS-mediated signalling. DR Reactome; R-RNO-1257604; PIP3 activates AKT signaling. DR Reactome; R-RNO-1266695; Interleukin-7 signaling. DR Reactome; R-RNO-198203; PI3K/AKT activation. DR Reactome; R-RNO-201556; Signaling by ALK. DR Reactome; R-RNO-2428928; IRS-related events triggered by IGF1R. DR Reactome; R-RNO-5673001; RAF/MAP kinase cascade. DR Reactome; R-RNO-6811558; PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling. DR Reactome; R-RNO-74713; IRS activation. DR Reactome; R-RNO-74749; Signal attenuation. DR Reactome; R-RNO-9842663; Signaling by LTK. DR PRO; PR:P35570; -. DR Proteomes; UP000002494; Unplaced. DR GO; GO:0005901; C:caveola; ISO:RGD. DR GO; GO:0036064; C:ciliary basal body; ISO:RGD. DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB. DR GO; GO:0005829; C:cytosol; IBA:GO_Central. DR GO; GO:0005899; C:insulin receptor complex; IMP:BHF-UCL. DR GO; GO:0043231; C:intracellular membrane-bounded organelle; ISS:UniProtKB. DR GO; GO:0005634; C:nucleus; ISS:UniProtKB. DR GO; GO:0005886; C:plasma membrane; ISO:RGD. DR GO; GO:0005158; F:insulin receptor binding; IMP:RGD. DR GO; GO:0005159; F:insulin-like growth factor receptor binding; IPI:RGD. DR GO; GO:0141038; F:phosphatidylinositol 3-kinase activator activity; ISO:RGD. DR GO; GO:0043548; F:phosphatidylinositol 3-kinase binding; IDA:UniProtKB. DR GO; GO:0001784; F:phosphotyrosine residue binding; ISO:RGD. DR GO; GO:0019904; F:protein domain specific binding; IPI:RGD. DR GO; GO:0019901; F:protein kinase binding; IPI:RGD. DR GO; GO:0005080; F:protein kinase C binding; IPI:BHF-UCL. DR GO; GO:0044877; F:protein-containing complex binding; IDA:RGD. DR GO; GO:0030674; F:protein-macromolecule adaptor activity; ISO:RGD. DR GO; GO:0042169; F:SH2 domain binding; IPI:UniProtKB. DR GO; GO:0035591; F:signaling adaptor activity; ISO:RGD. DR GO; GO:0030159; F:signaling receptor complex adaptor activity; ISO:RGD. DR GO; GO:0005068; F:transmembrane receptor protein tyrosine kinase adaptor activity; IMP:BHF-UCL. DR GO; GO:1904385; P:cellular response to angiotensin; IEP:RGD. DR GO; GO:1990416; P:cellular response to brain-derived neurotrophic factor stimulus; IEP:RGD. DR GO; GO:0071398; P:cellular response to fatty acid; ISO:RGD. DR GO; GO:0032869; P:cellular response to insulin stimulus; ISO:RGD. DR GO; GO:0071478; P:cellular response to radiation; IEP:RGD. DR GO; GO:0019221; P:cytokine-mediated signaling pathway; ISO:RGD. DR GO; GO:0008286; P:insulin receptor signaling pathway; IDA:BHF-UCL. DR GO; GO:0048009; P:insulin-like growth factor receptor signaling pathway; ISS:UniProtKB. DR GO; GO:0016042; P:lipid catabolic process; ISO:RGD. DR GO; GO:0030879; P:mammary gland development; ISO:RGD. DR GO; GO:0046627; P:negative regulation of insulin receptor signaling pathway; IMP:BHF-UCL. DR GO; GO:0046676; P:negative regulation of insulin secretion; IMP:BHF-UCL. DR GO; GO:0090275; P:negative regulation of somatostatin secretion; IMP:BHF-UCL. DR GO; GO:0043491; P:phosphatidylinositol 3-kinase/protein kinase B signal transduction; ISO:RGD. DR GO; GO:0030335; P:positive regulation of cell migration; ISO:RGD. DR GO; GO:0046326; P:positive regulation of D-glucose import across plasma membrane; ISO:RGD. DR GO; GO:0032000; P:positive regulation of fatty acid beta-oxidation; ISO:RGD. DR GO; GO:0070094; P:positive regulation of glucagon secretion; IMP:BHF-UCL. DR GO; GO:0010907; P:positive regulation of glucose metabolic process; ISO:RGD. DR GO; GO:0045725; P:positive regulation of glycogen biosynthetic process; ISO:RGD. DR GO; GO:0046628; P:positive regulation of insulin receptor signaling pathway; IMP:BHF-UCL. DR GO; GO:0002053; P:positive regulation of mesenchymal cell proliferation; ISO:RGD. DR GO; GO:0051897; P:positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction; IDA:UniProtKB. DR GO; GO:0042327; P:positive regulation of phosphorylation; IDA:BHF-UCL. DR GO; GO:0034504; P:protein localization to nucleus; ISO:RGD. DR GO; GO:0010468; P:regulation of gene expression; ISO:RGD. DR GO; GO:0014823; P:response to activity; IEP:RGD. DR GO; GO:0031000; P:response to caffeine; IDA:RGD. DR GO; GO:0045471; P:response to ethanol; IDA:RGD. DR GO; GO:0032868; P:response to insulin; ISO:RGD. DR CDD; cd01257; PH_IRS; 1. DR CDD; cd01204; PTB_IRS; 1. DR FunFam; 2.30.29.30:FF:000029; Insulin receptor substrate 1; 1. DR FunFam; 2.30.29.30:FF:000129; Insulin receptor substrate 1; 1. DR Gene3D; 2.30.29.30; Pleckstrin-homology domain (PH domain)/Phosphotyrosine-binding domain (PTB); 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; INSULIN RECEPTOR SUBSTRATE; 1. DR PANTHER; PTHR10614:SF11; INSULIN RECEPTOR SUBSTRATE 1; 1. DR Pfam; PF02174; IRS; 1. DR Pfam; PF00169; PH; 1. DR PRINTS; PR00628; INSULINRSI. DR SMART; SM01244; IRS; 1. DR SMART; SM00233; PH; 1. DR SMART; SM00310; PTBI; 1. DR SUPFAM; SSF50729; PH domain-like; 2. DR PROSITE; PS51064; IRS_PTB; 1. DR PROSITE; PS50003; PH_DOMAIN; 1. DR PDBsum; 5WRK; -. DR PDBsum; 5WRL; -. DR PDBsum; 5WRM; -. PE 1: Evidence at protein level; KW 3D-structure; Cytoplasm; Direct protein sequencing; Isopeptide bond; KW Nucleus; Phosphoprotein; Reference proteome; Repeat; S-nitrosylation; KW Transducer; Ubl conjugation. FT CHAIN 1..1235 FT /note="Insulin receptor substrate 1" FT /id="PRO_0000084238" FT DOMAIN 12..115 FT /note="PH" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00145" FT DOMAIN 155..259 FT /note="IRS-type PTB" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00389" FT REGION 3..133 FT /note="Mediates interaction with PHIP" FT /evidence="ECO:0000269|PubMed:11018022" FT REGION 258..425 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 520..539 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 669..720 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 766..921 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 895..897 FT /note="GRB2-binding" FT REGION 1024..1165 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1177..1235 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOTIF 460..463 FT /note="YXXM motif 1" FT MOTIF 546..549 FT /note="YXXM motif 2" FT MOTIF 608..611 FT /note="YXXM motif 3" FT MOTIF 628..631 FT /note="YXXM motif 4" FT MOTIF 658..661 FT /note="YXXM motif 5" FT MOTIF 727..730 FT /note="YXXM motif 6" FT MOTIF 939..942 FT /note="YXXM motif 7" FT MOTIF 987..990 FT /note="YXXM motif 8" FT MOTIF 1010..1013 FT /note="YXXM motif 9" FT COMPBIAS 265..276 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 349..358 FT /note="Basic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 378..399 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 407..419 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 522..539 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 669..689 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 771..780 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 785..794 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 801..810 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 872..881 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1025..1046 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1072..1084 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1101..1114 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1118..1128 FT /note="Gly residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1204..1229 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 3 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:22673903" FT MOD_RES 99 FT /note="Phosphoserine; by CK2" FT /evidence="ECO:0000269|PubMed:8349691" FT MOD_RES 265 FT /note="Phosphoserine; by RPS6KB1" FT /evidence="ECO:0000250|UniProtKB:P35568" FT MOD_RES 302 FT /note="Phosphoserine; by RPS6KB1" FT /evidence="ECO:0000250|UniProtKB:P35568" FT MOD_RES 307 FT /note="Phosphoserine; by IKKB, MAPK8 and RPS6KB1" FT /evidence="ECO:0000250|UniProtKB:P35568" FT MOD_RES 318 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P35568" FT MOD_RES 325 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P35569" FT MOD_RES 340 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P35569" FT MOD_RES 343 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:22673903" FT MOD_RES 414 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P35569" FT MOD_RES 441 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:22673903" FT MOD_RES 448 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:22673903" FT MOD_RES 460 FT /note="Phosphotyrosine; by INSR" FT /evidence="ECO:0000269|PubMed:7504175" FT MOD_RES 502 FT /note="Phosphothreonine; by CK2" FT /evidence="ECO:0000269|PubMed:8349691" FT MOD_RES 522 FT /note="Phosphoserine; by RPS6KB1" FT /evidence="ECO:0000250|UniProtKB:P35568" FT MOD_RES 608 FT /note="Phosphotyrosine; by INSR" FT /evidence="ECO:0000269|PubMed:7504175" FT MOD_RES 612 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:24187137" FT MOD_RES 628 FT /note="Phosphotyrosine; by INSR" FT /evidence="ECO:0000269|PubMed:7504175" FT MOD_RES 632 FT /note="Phosphoserine; by RPS6KB1 and ROCK2" FT /evidence="ECO:0000250|UniProtKB:P35569" FT MOD_RES 658 FT /note="Phosphotyrosine" FT /evidence="ECO:0000250|UniProtKB:P35568" FT MOD_RES 789 FT /note="Phosphoserine; by AMPK and SIK2" FT /evidence="ECO:0000269|PubMed:12006586" FT MOD_RES 891 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:22673903" FT MOD_RES 895 FT /note="Phosphotyrosine; by INSR" FT /evidence="ECO:0000269|PubMed:7504175" FT MOD_RES 939 FT /note="Phosphotyrosine; by INSR" FT /evidence="ECO:0000269|PubMed:7504175" FT MOD_RES 987 FT /note="Phosphotyrosine; by INSR" FT /evidence="ECO:0000269|PubMed:7504175" FT MOD_RES 1099 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P35569" FT MOD_RES 1100 FT /note="Phosphoserine; by RPS6KB1" FT /evidence="ECO:0000250|UniProtKB:P35568" FT MOD_RES 1172 FT /note="Phosphotyrosine; by INSR" FT /evidence="ECO:0000269|PubMed:7504175" FT MOD_RES 1222 FT /note="Phosphotyrosine; by INSR" FT /evidence="ECO:0000269|PubMed:7504175" FT CROSSLNK 1179 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000250|UniProtKB:P35568" FT MUTAGEN 106 FT /note="W->A: Loss of interaction with PHIP." FT /evidence="ECO:0000269|PubMed:11018022" FT CONFLICT 1098 FT /note="H -> L (in Ref. 2; AA sequence)" FT /evidence="ECO:0000305" SQ SEQUENCE 1235 AA; 131178 MW; A274BC7540CA85C5 CRC64; MASPPDTDGF SDVRKVGYLR KPKSMHKRFF VLRAASEAGG PARLEYYENE KKWRHKSSAP KRSIPLESCF NINKRADSKN KHLVALYTRD EHFAIAADSE AEQDSWYQAL LQLHNRAKAH HDGAGGGCGG SCSGSSGVGE AGEDLSYDTG PGPAFKEVWQ VILKPKGLGQ TKNLIGIYRL CLTSKTISFV KLNSEAAAVV LQLMNIRRCG HSENFFFIEV GRSAVTGPGE FWMQVDDSVV AQNMHETILE AMRAMSDEFR PRTKSQSSSS CSNPISVPLR RHHLNNPPPS QVGLTRRSRT ESITATSPAS MVGGKPGSFR VRASSDGEGT MSRPASVDGS PVSPSTNRTH AHRHRGSSRL HPPLNHSRSI PMPSSRCSPS ATSPVSLSSS STSGHGSTSD CLFPRRSSAS VSGSPSDGGF ISSDEYGSSP CDFRSSFRSV TPDSLGHTPP ARGEEELSNY ICMGGKGAST LTAPNGHYIL SRGGNGHRYI PGATMGTSPA LTGDEAAGAA DLDNRFRKRT HSAGTSPTIS HQKTPSQSSV VSIEEYTEMM PAAYPPGGGS GGRLPGYRHS AFVPTHSYPE EGLEMHHLER RGGHHRPDSS NLHTDDGYMP MSPGVAPVPS NRKGNGDYMP MSPKSVSAPQ QIINPIRRHP QRVDPNGYMM MSPSGSCSPD IGGGSCSSSS ISAAPSGSSY GKPWTNGVGG HHTHALPHAK PPVESGGGKL LPCTGDYMNM SPVGDSNTSS PSECYYGPED PQHKPVLSYY SLPRSFKHTQ RPGEPEEGAR HQHLRLSSSS GRLRYTATAE DSSSSTSSDS LGGGYCGARP ESSVTHPHHH ALQPHLPRKV DTAAQTNSRL ARPTRLSLGD PKASTLPRVR EQQQQQQQQQ QSSLHPPEPK SPGEYVNIEF GSGQPGYLAG PATSRSSPSV RCLPQLHPAP REETGSEEYM NMDLGPGRRA TWQESGGVEL GRVGPAPPGA ASICRPTRSV PNSRGDYMTM QIGCPRQSYV DTSPVAPVSY ADMRTGIAAE KVSLPRTTGA APPPSSTASA SASVTPQGAA EQAAHSSLLG GPQGPGGMSA FTRVNLSPNH NQSAKVIRAD TQGCRRRHSS ETFSAPTRAA NTVSFGAGAA GGGSGGGSED VKRHSSASFE NVWLRPGDLG GASKESAPGC GAAGGLEKSL NYIDLDLVKD VKQHPQDCPS QQQSLPPPPP HQPLGSNEGS SPRRSSEDLS TYASINFQKQ PEDRQ //