INSR_RAT
ID INSR_RAT Reviewed; 1383 AA.
AC P15127; P97681;
DT 01-APR-1990, integrated into UniProtKB/Swiss-Prot.
DT 01-APR-1990, sequence version 1.
DT 03-AUG-2022, entry version 207.
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 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] (ISOFORM LONG), AND ALTERNATIVE SPLICING
RP (ISOFORM SHORT).
RX PubMed=2330003; DOI=10.1210/mend-4-2-235;
RA Goldstein B.J., Dudley A.L.;
RT "The rat insulin receptor: primary structure and conservation of tissue-
RT specific alternative messenger RNA splicing.";
RL Mol. Endocrinol. 4:235-244(1990).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 731-756; 758-819; 969-994 AND
RP 1119-1177.
RC STRAIN=Sprague-Dawley;
RA Liu Y., Tam J.W.O.;
RL Submitted (MAY-1997) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP INTERACTION WITH GRB7.
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 [4]
RP FUNCTION, AND FORMATION OF A HYBRID RECEPTOR WITH IGF1R.
RX PubMed=16803852; DOI=10.1152/ajpendo.00565.2005;
RA Johansson G.S., Arnqvist H.J.;
RT "Insulin and IGF-I action on insulin receptors, IGF-I receptors, and hybrid
RT insulin/IGF-I receptors in vascular smooth muscle cells.";
RL Am. J. Physiol. 291:E1124-E1130(2006).
RN [5]
RP INTERACTION WITH CAV2.
RX PubMed=19778377; DOI=10.1111/j.1582-4934.2009.00391.x;
RA Kwon H., Jeong K., Pak Y.;
RT "Identification of pY19-caveolin-2 as a positive regulator of insulin-
RT stimulated actin cytoskeleton-dependent mitogenesis.";
RL J. Cell. Mol. Med. 13:1549-1564(2009).
RN [6]
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 [7]
RP INTERACTION WITH ATIC.
RX PubMed=25687571; DOI=10.1074/mcp.m114.047159;
RA Boutchueng-Djidjou M., Collard-Simard G., Fortier S., Hebert S.S.,
RA Kelly I., Landry C.R., Faure R.L.;
RT "The last enzyme of the de novo purine synthesis pathway 5-aminoimidazole-
RT 4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase (ATIC)
RT plays a central role in insulin signaling and the Golgi/endosomes protein
RT network.";
RL Mol. Cell. Proteomics 14:1079-1092(2015).
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 (By
CC similarity). {ECO:0000250, ECO:0000250|UniProtKB:P15208,
CC ECO:0000269|PubMed:16803852}.
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). {ECO:0000250}.
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-1000) 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-1000), with SOCS3. Interacts (via
CC the phosphorylated Tyr-1186, Tyr-1190, Tyr-1191) with SOCS1. Interacts
CC with ARRB2 (By similarity). Interacts with GRB10; this interaction
CC blocks the association between IRS1/IRS2 and INSR, significantly
CC reduces insulin-stimulated tyrosine phosphorylation of IRS1 and IRS2
CC and thus decreases insulin signaling. Interacts with PDPK1. Interacts
CC (via Tyr-1191) with GRB14 (via BPS domain); this interaction protects
CC the tyrosines in the activation loop from dephosphorylation, but
CC promotes dephosphorylation of Tyr-1000, 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-1186, Tyr-1190 and Tyr-1191 of the INSR. Interacts
CC with STAT5B (via SH2 domain). Interacts with PTPRF (By similarity).
CC Interacts with GRB7. Interacts with CAV2 (tyrosine-phosphorylated
CC form); the interaction is increased with 'Tyr-27'phosphorylation of
CC CAV2. Interacts with ATIC; ATIC together with PRKAA2/AMPK2 and
CC HACD3/PTPLAD1 is proposed to be part of a signaling netwok regulating
CC INSR autophosphorylation and endocytosis (PubMed:25687571). Interacts
CC with the insulin receptor SORL1; this interaction strongly increases
CC its surface exposure, hence strengthens insulin signal reception (By
CC similarity). Interacts (tyrosine phosphorylated) with CCDC88A/GIV (via
CC SH2-like region); binding requires autophosphorylation of the INSR C-
CC terminal region (PubMed:25187647). Interacts with GNAI3; the
CC interaction is probably mediated by CCDC88A/GIV (PubMed:25187647).
CC Interacts with LMBRD1 (By similarity). {ECO:0000250,
CC ECO:0000250|UniProtKB:P15208, ECO:0000269|PubMed:10803466,
CC ECO:0000269|PubMed:19778377, ECO:0000269|PubMed:25187647,
CC ECO:0000269|PubMed:25687571}.
CC -!- INTERACTION:
CC P15127; Q62689: Jak2; NbExp=2; IntAct=EBI-7472166, EBI-8656708;
CC PRO_0000016698; O35567: Atic; NbExp=3; IntAct=EBI-10768746, EBI-10768817;
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=RIR-B;
CC IsoId=P15127-1; Sequence=Displayed;
CC Name=Short; Synonyms=RIR-A;
CC IsoId=P15127-2; Sequence=VSP_036680;
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.
CC Phosphorylation of Tyr-1000 is required for binding to IRS1, SHC1, and
CC STAT5B. Dephosphorylated by PTPRE on Tyr-1000, Tyr-1186, Tyr-1190 and
CC Tyr-1191 residues. Dephosphorylated by PTPRF and PTPN1.
CC Dephosphorylated by PTPN2; down-regulates insulin-induced signaling.
CC {ECO:0000250}.
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; M29014; AAA41441.1; -; mRNA.
DR EMBL; AF005776; AAB61414.1; -; Genomic_DNA.
DR EMBL; AF005777; AAB61415.1; -; Genomic_DNA.
DR EMBL; AH004882; AAB38967.1; -; Genomic_DNA.
DR EMBL; AH004883; AAB38968.1; -; Genomic_DNA.
DR EMBL; U80633; AAB38746.1; -; Genomic_DNA.
DR PIR; A36080; A36080.
DR PDB; 4XST; X-ray; 3.00 A; F=726-748.
DR PDB; 5TQ1; X-ray; 1.49 A; B=1008-1018.
DR PDBsum; 4XST; -.
DR PDBsum; 5TQ1; -.
DR AlphaFoldDB; P15127; -.
DR BMRB; P15127; -.
DR SMR; P15127; -.
DR DIP; DIP-42209N; -.
DR IntAct; P15127; 460.
DR MINT; P15127; -.
DR STRING; 10116.ENSRNOP00000060141; -.
DR BindingDB; P15127; -.
DR ChEMBL; CHEMBL5486; -.
DR DrugCentral; P15127; -.
DR GlyGen; P15127; 18 sites, 5 N-linked glycans (1 site).
DR iPTMnet; P15127; -.
DR PhosphoSitePlus; P15127; -.
DR PaxDb; P15127; -.
DR PeptideAtlas; P15127; -.
DR PRIDE; P15127; -.
DR UCSC; RGD:2917; rat. [P15127-1]
DR RGD; 2917; Insr.
DR eggNOG; KOG4258; Eukaryota.
DR InParanoid; P15127; -.
DR PhylomeDB; P15127; -.
DR BRENDA; 2.7.10.1; 5301.
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-74751; Insulin receptor signalling cascade.
DR Reactome; R-RNO-74752; Signaling by Insulin receptor.
DR Reactome; R-RNO-77387; Insulin receptor recycling.
DR PRO; PR:P15127; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0030424; C:axon; IBA:GO_Central.
DR GO; GO:0005901; C:caveola; ISO:RGD.
DR GO; GO:0031410; C:cytoplasmic vesicle; IDA:RGD.
DR GO; GO:0005829; C:cytosol; IDA:RGD.
DR GO; GO:0032590; C:dendrite membrane; IDA:ARUK-UCL.
DR GO; GO:0005768; C:endosome; IDA:RGD.
DR GO; GO:0009897; C:external side of plasma membrane; IDA:ARUK-UCL.
DR GO; GO:0005899; C:insulin receptor complex; ISO:RGD.
DR GO; GO:0005887; C:integral component of plasma membrane; ISO:RGD.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:RGD.
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; ISO:RGD.
DR GO; GO:0043025; C:neuronal cell body; IDA:RGD.
DR GO; GO:0032809; C:neuronal cell body membrane; IDA:ARUK-UCL.
DR GO; GO:0005634; C:nucleus; IDA:RGD.
DR GO; GO:0005886; C:plasma membrane; IDA:RGD.
DR GO; GO:0043235; C:receptor complex; ISO:RGD.
DR GO; GO:0045202; C:synapse; IDA:RGD.
DR GO; GO:0060417; C:yolk; IDA:RGD.
DR GO; GO:0043423; F:3-phosphoinositide-dependent protein kinase binding; IDA:RGD.
DR GO; GO:0001540; F:amyloid-beta binding; ISO:RGD.
DR GO; GO:0005524; F:ATP binding; ISO:RGD.
DR GO; GO:0038024; F:cargo receptor activity; IMP:ARUK-UCL.
DR GO; GO:0005525; F:GTP binding; ISO:RGD.
DR GO; GO:0043559; F:insulin binding; IDA:RGD.
DR GO; GO:0005009; F:insulin receptor activity; IDA:RGD.
DR GO; GO:0043560; F:insulin receptor substrate binding; IMP:RGD.
DR GO; GO:0031994; F:insulin-like growth factor I binding; ISO:RGD.
DR GO; GO:0031995; F:insulin-like growth factor II binding; ISO:RGD.
DR GO; GO:0005159; F:insulin-like growth factor receptor binding; ISO:RGD.
DR GO; GO:0031405; F:lipoic acid binding; IPI:RGD.
DR GO; GO:0043548; F:phosphatidylinositol 3-kinase binding; ISO:RGD.
DR GO; GO:0019904; F:protein domain specific binding; IPI:RGD.
DR GO; GO:0004672; F:protein kinase activity; IDA:RGD.
DR GO; GO:0019901; F:protein kinase binding; IPI:RGD.
DR GO; GO:0019903; F:protein phosphatase binding; IMP:RGD.
DR GO; GO:0004713; F:protein tyrosine kinase activity; IDA:RGD.
DR GO; GO:0044877; F:protein-containing complex binding; IPI:RGD.
DR GO; GO:0051425; F:PTB domain binding; ISO:RGD.
DR GO; GO:0005198; F:structural molecule activity; ISO:RGD.
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:RGD.
DR GO; GO:0032148; P:activation of protein kinase B activity; ISO:RGD.
DR GO; GO:0030325; P:adrenal gland development; ISO:RGD.
DR GO; GO:0000380; P:alternative mRNA splicing, via spliceosome; IEP:RGD.
DR GO; GO:0097242; P:amyloid-beta clearance; IMP:ARUK-UCL.
DR GO; GO:0009887; P:animal organ morphogenesis; ISO:RGD.
DR GO; GO:0071363; P:cellular response to growth factor stimulus; ISO:RGD.
DR GO; GO:0032869; P:cellular response to insulin stimulus; ISO:RGD.
DR GO; GO:0021549; P:cerebellum development; IEP:RGD.
DR GO; GO:0097062; P:dendritic spine maintenance; IGI:ARUK-UCL.
DR GO; GO:1990402; P:embryonic liver development; IEP:RGD.
DR GO; GO:0008544; P:epidermis development; ISO:RGD.
DR GO; GO:0031017; P:exocrine pancreas development; ISO:RGD.
DR GO; GO:0045444; P:fat cell differentiation; IEP:RGD.
DR GO; GO:0007186; P:G protein-coupled receptor signaling pathway; ISO:RGD.
DR GO; GO:0042593; P:glucose homeostasis; IDA:RGD.
DR GO; GO:0003007; P:heart morphogenesis; ISO:RGD.
DR GO; GO:0021766; P:hippocampus development; IEP:RGD.
DR GO; GO:0008286; P:insulin receptor signaling pathway; IDA:RGD.
DR GO; GO:0001889; P:liver development; IEP:RGD.
DR GO; GO:0097421; P:liver regeneration; IEP:RGD.
DR GO; GO:0008584; P:male gonad development; ISO:RGD.
DR GO; GO:0030238; P:male sex determination; ISO:RGD.
DR GO; GO:2000252; P:negative regulation of feeding behavior; IMP:RGD.
DR GO; GO:0010629; P:negative regulation of gene expression; IMP:RGD.
DR GO; GO:0045719; P:negative regulation of glycogen biosynthetic process; IEP:RGD.
DR GO; GO:0001933; P:negative regulation of protein phosphorylation; IMP:RGD.
DR GO; GO:0032410; P:negative regulation of transporter activity; IMP:RGD.
DR GO; GO:1990535; P:neuron projection maintenance; IGI:ARUK-UCL.
DR GO; GO:0038083; P:peptidyl-tyrosine autophosphorylation; ISO:RGD.
DR GO; GO:0018108; P:peptidyl-tyrosine phosphorylation; IMP:RGD.
DR GO; GO:0030335; P:positive regulation of cell migration; ISO:RGD.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; ISO:RGD.
DR GO; GO:0048639; P:positive regulation of developmental growth; ISO:RGD.
DR GO; GO:0046326; P:positive regulation of glucose import; ISO:RGD.
DR GO; GO:0045725; P:positive regulation of glycogen biosynthetic process; ISO:RGD.
DR GO; GO:0045821; P:positive regulation of glycolytic process; ISO:RGD.
DR GO; GO:0010560; P:positive regulation of glycoprotein biosynthetic process; IMP:RGD.
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:RGD.
DR GO; GO:0043410; P:positive regulation of MAPK cascade; ISO:RGD.
DR GO; GO:0051446; P:positive regulation of meiotic cell cycle; ISO:RGD.
DR GO; GO:0045840; P:positive regulation of mitotic nuclear division; ISO:RGD.
DR GO; GO:0045429; P:positive regulation of nitric oxide biosynthetic process; ISO:RGD.
DR GO; GO:0014068; P:positive regulation of phosphatidylinositol 3-kinase signaling; IBA:GO_Central.
DR GO; GO:0042327; P:positive regulation of phosphorylation; IDA:BHF-UCL.
DR GO; GO:0051897; P:positive regulation of protein kinase B signaling; ISO:RGD.
DR GO; GO:0001934; P:positive regulation of protein phosphorylation; ISO:RGD.
DR GO; GO:0043243; P:positive regulation of protein-containing complex disassembly; IGI:ARUK-UCL.
DR GO; GO:0002092; P:positive regulation of receptor internalization; ISO:RGD.
DR GO; GO:0060267; P:positive regulation of respiratory burst; ISO:RGD.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; ISO:RGD.
DR GO; GO:0046777; P:protein autophosphorylation; IDA:RGD.
DR GO; GO:0006468; P:protein phosphorylation; IDA:RGD.
DR GO; GO:0006898; P:receptor-mediated endocytosis; IMP:ARUK-UCL.
DR GO; GO:0045995; P:regulation of embryonic development; ISO:RGD.
DR GO; GO:2000194; P:regulation of female gonad development; ISO:RGD.
DR GO; GO:0006111; P:regulation of gluconeogenesis; IEP:RGD.
DR GO; GO:0010310; P:regulation of hydrogen peroxide metabolic process; IDA:RGD.
DR GO; GO:0006355; P:regulation of transcription, DNA-templated; ISO:RGD.
DR GO; GO:0014823; P:response to activity; IEP:RGD.
DR GO; GO:0032355; P:response to estradiol; IEP:RGD.
DR GO; GO:0045471; P:response to ethanol; IEP:RGD.
DR GO; GO:0032094; P:response to food; IEP:RGD.
DR GO; GO:0051384; P:response to glucocorticoid; IEP:RGD.
DR GO; GO:0009749; P:response to glucose; IEP:BHF-UCL.
DR GO; GO:0009725; P:response to hormone; IEP:RGD.
DR GO; GO:0001666; P:response to hypoxia; IEP:RGD.
DR GO; GO:0032868; P:response to insulin; IEP:BHF-UCL.
DR GO; GO:0010042; P:response to manganese ion; IEP:RGD.
DR GO; GO:0031667; P:response to nutrient levels; IDA:RGD.
DR GO; GO:0010033; P:response to organic substance; IEP:RGD.
DR GO; GO:1904638; P:response to resveratrol; IEP:RGD.
DR GO; GO:0042594; P:response to starvation; IEP:RGD.
DR GO; GO:0033574; P:response to testosterone; IEP:RGD.
DR GO; GO:0034612; P:response to tumor necrosis factor; IMP:RGD.
DR GO; GO:1902438; P:response to vanadate(3-); IEP:RGD.
DR GO; GO:0033280; P:response to vitamin D; IEP:RGD.
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:RGD.
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; 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; Alternative splicing; 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..26
FT CHAIN 27..759
FT /note="Insulin receptor subunit alpha"
FT /id="PRO_0000016696"
FT CHAIN 764..1383
FT /note="Insulin receptor subunit beta"
FT /id="PRO_0000016698"
FT TOPO_DOM 27..759
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TOPO_DOM 764..957
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 958..978
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 979..1383
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT DOMAIN 625..727
FT /note="Fibronectin type-III 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316"
FT DOMAIN 754..848
FT /note="Fibronectin type-III 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316"
FT DOMAIN 854..948
FT /note="Fibronectin type-III 3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316"
FT DOMAIN 1024..1299
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 687..709
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 734..742
FT /note="Insulin-binding"
FT /evidence="ECO:0000250"
FT REGION 747..783
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 997..1000
FT /note="Important for interaction with IRS1, SHC1 and
FT STAT5B"
FT REGION 1361..1383
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1362..1365
FT /note="PIK3R1 binding"
FT /evidence="ECO:0000250"
FT COMPBIAS 768..783
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 1160
FT /note="Proton donor/acceptor"
FT /evidence="ECO:0000250"
FT BINDING 1034
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 1058
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 1105..1111
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 1164..1165
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 1178
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT SITE 65
FT /note="Insulin-binding"
FT /evidence="ECO:0000250"
FT MOD_RES 399
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P06213"
FT MOD_RES 400
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:P06213"
FT MOD_RES 406
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P06213"
FT MOD_RES 1000
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P06213"
FT MOD_RES 1186
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P06213"
FT MOD_RES 1190
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P06213"
FT MOD_RES 1191
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P06213"
FT MOD_RES 1356
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P06213"
FT MOD_RES 1362
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P06213"
FT CARBOHYD 42
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 51
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 104
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 137
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 241
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 281
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 321
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 363
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 423
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 444
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 540
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 634
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 652
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 699
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 770
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 783
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 921
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 934
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 34..52
FT /evidence="ECO:0000250"
FT DISULFID 152..181
FT /evidence="ECO:0000250"
FT DISULFID 185..208
FT /evidence="ECO:0000250"
FT DISULFID 195..214
FT /evidence="ECO:0000250"
FT DISULFID 218..227
FT /evidence="ECO:0000250"
FT DISULFID 222..233
FT /evidence="ECO:0000250"
FT DISULFID 234..242
FT /evidence="ECO:0000250"
FT DISULFID 238..251
FT /evidence="ECO:0000250"
FT DISULFID 254..263
FT /evidence="ECO:0000250"
FT DISULFID 267..279
FT /evidence="ECO:0000250"
FT DISULFID 285..310
FT /evidence="ECO:0000250"
FT DISULFID 292..300
FT /evidence="ECO:0000250"
FT DISULFID 314..327
FT /evidence="ECO:0000250"
FT DISULFID 330..334
FT /evidence="ECO:0000250"
FT DISULFID 338..359
FT /evidence="ECO:0000250"
FT DISULFID 461..494
FT /evidence="ECO:0000250"
FT DISULFID 550
FT /note="Interchain"
FT /evidence="ECO:0000250"
FT DISULFID 675..900
FT /evidence="ECO:0000250"
FT VAR_SEQ 746..757
FT /note="Missing (in isoform Short)"
FT /evidence="ECO:0000305"
FT /id="VSP_036680"
FT HELIX 727..736
FT /evidence="ECO:0007829|PDB:4XST"
SQ SEQUENCE 1383 AA; 156757 MW; 4B919566902A944A CRC64;
MGSGRGCETT AVPLLMAVAV AGGTAGHLYP GEVCPGMDIR NNLTRLHELE NCSVIEGHLQ
ILLMFKTRPE DFRDLSFPKL IMITDYLLLF RVYGLESLKD LFPNLTVIRG SRLFFNYALV
IFEMVHLKEL GLYNLMNITR GSVRIEKNNE LCYLATIDWS RILDYVEDNY IVLNKDDNEE
CGDVCPGTAK GKTNCPATVI NGQFVERCWT HSHCQKVCPT ICKSHGCTAE GLCCHKECLG
NCSEPDDPTK CVACRNFYLD GQCVETCPPP YYHFQDWRCV NFSFCQDLHY KCRNSRKPGC
HQYVIHNNKC IPECPSGYTM NSSNLMCTPC LGPCPKVCQI LEGEKTIDSV TSAQELRGCT
VINGSLIINI RGGNNLAAEL EANLGLIEEI SGFLKIRRSY ALVSLSFFRK LHLIRGETLE
IGNYSFYALD NQNLRQLWDW NKHNLTITQG KLFFHYNPKL CLSEIHKMEE VSGTKGRQER
NDIALKTNGD QASCENELLK FSFIRTSFDK ILLRWEPYWP PDFRDLLGFM LFYKEAPYQN
VTEFDGQDAC GSNSWTVVDI DPPQRSNDPK SQTPSHPGWL MRGLKPWTQY AIFVKTLVTF
SDERRTYGAK SDIIYVQTDA TNPSVPLDPI SVSNSSSQII LKWKPPSDPN GNITHYLVYW
ERQAEDSELF ELDYCLKGLK LPSRTWSPPF ESDDSQKHNQ SEYDDSASEC CSCPKTDSQI
LKELEESSFR KTFEDYLHNV VFVPRKTSSG NGAEDTRPSR KRRSLEEVGN VTATTPTLPD
FPNISSTIAP TSHEEHRPFE KVVNKESLVI SGLRHFTGYR IELQACNQDS PEERSGVAAY
VSARTMPEAK ADDIVGPVTH EIFENNVVHL MWQEPKEPNG LIVLYEVSYR RYGDEELHLC
VSRKHFALER GCRLRGLSPG NYSVRVRATS LAGNGSWTEP TYFYVTDYLD VPSNIAKIII
GPLIFVFLFS VVIGSIYLFL RKRQPDGPMG PLYASSNPEY LSASDVFPSS VYVPDEWEVP
REKITLLREL GQGSFGMVYE GNAKDIIKGE VETRVAVKTV NESASLRERI EFLNEASVMK
GFTCHHVVRL LGVVSKGQPT LVVMELMAHG DLKSHLRSLR PDAENNPGRP PPTLQEMIQM
TAEIADGMAY LNAKKFVHRD LAARNCMVAH DFTVKIGDFG MTRDIYETDY YRKGGKGLLP
VRWMSPESLK DGVFTASSDM WSFGVVLWEI TSLAEQPYQG LSNEQVLKFV MDGGYLDPPD
NCPERLTDLM RMCWQFNPKM RPTFLEIVNL LKDDLHPSFP EVSFFYSEEN KAPESEELEM
EFEDMENVPL DRSSHCQREE AGCREGGSSL SIKRTYDEHI PYTHMNGGKK NGRVLTLPRS
NPS
