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Protein

Insulin receptor

Gene

INSR

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Receptor tyrosine kinase which mediates the pleiotropic actions of insulin. Binding of insulin leads to phosphorylation of several intracellular substrates, including, insulin receptor substrates (IRS1, 2, 3, 4), SHC, GAB1, CBL and other signaling intermediates. Each of these phosphorylated proteins serve as docking proteins for other signaling proteins that contain Src-homology-2 domains (SH2 domain) that specifically recognize different phosphotyrosines residues, including the p85 regulatory subunit of PI3K and SHP2. Phosphorylation of IRSs proteins lead to the activation of two main signaling pathways: the PI3K-AKT/PKB pathway, which is responsible for most of the metabolic actions of insulin, and the Ras-MAPK pathway, which regulates expression of some genes and cooperates with the PI3K pathway to control cell growth and differentiation. Binding of the SH2 domains of PI3K to phosphotyrosines on IRS1 leads to the activation of PI3K and the generation of phosphatidylinositol-(3, 4, 5)-triphosphate (PIP3), a lipid second messenger, which activates several PIP3-dependent serine/threonine kinases, such as PDPK1 and subsequently AKT/PKB. The net effect of this pathway is to produce a translocation of the glucose transporter SLC2A4/GLUT4 from cytoplasmic vesicles to the cell membrane to facilitate glucose transport. Moreover, upon insulin stimulation, activated AKT/PKB is responsible for: anti-apoptotic effect of insulin by inducing phosphorylation of BAD; regulates the expression of gluconeogenic and lipogenic enzymes by controlling the activity of the winged helix or forkhead (FOX) class of transcription factors. Another pathway regulated by PI3K-AKT/PKB activation is mTORC1 signaling pathway which regulates cell growth and metabolism and integrates signals from insulin. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 thereby activating mTORC1 pathway. The Ras/RAF/MAP2K/MAPK pathway is mainly involved in mediating cell growth, survival and cellular differentiation of insulin. Phosphorylated IRS1 recruits GRB2/SOS complex, which triggers the activation of the Ras/RAF/MAP2K/MAPK pathway. In addition to binding insulin, the insulin receptor can bind insulin-like growth factors (IGFI and IGFII). Isoform Short has a higher affinity for IGFII binding. When present in a hybrid receptor with IGF1R, binds IGF1. PubMed:12138094 shows that hybrid receptors composed of IGF1R and INSR isoform Long are activated with a high affinity by IGF1, with low affinity by IGF2 and not significantly activated by insulin, and that hybrid receptors composed of IGF1R and INSR isoform Short are activated by IGF1, IGF2 and insulin. In contrast, PubMed:16831875 shows that hybrid receptors composed of IGF1R and INSR isoform Long and hybrid receptors composed of IGF1R and INSR isoform Short have similar binding characteristics, both bind IGF1 and have a low affinity for insulin.7 Publications

Catalytic activityi

ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.PROSITE-ProRule annotation8 Publications

Enzyme regulationi

Activated in response to insulin. Autophosphorylation activates the kinase activity. PTPN1, PTPRE and PTPRF dephosphorylate important tyrosine residues, thereby reducing INSR activity. Inhibited by ENPP1. GRB10 and GRB14 inhibit the catalytic activity of the INSR, they block access of substrates to the activated receptor. SOCS1 and SOCS3 act as negative regulators of INSR activity, they bind to the activated INRS and interfere with the phosphorylation of INSR substrates.5 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei66Insulin-bindingCurated1
Binding sitei1033ATPPROSITE-ProRule annotation1 Publication1
Binding sitei1057ATPPROSITE-ProRule annotation1 Publication1
Active sitei1159Proton donor/acceptor1 Publication1
Binding sitei1177ATPPROSITE-ProRule annotation1 Publication1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi1104 – 1110ATPPROSITE-ProRule annotation1 Publication7
Nucleotide bindingi1163 – 1164ATPPROSITE-ProRule annotation1 Publication2

GO - Molecular functioni

  • ATP binding Source: BHF-UCL
  • GTP binding Source: BHF-UCL
  • insulin-activated receptor activity Source: UniProtKB
  • insulin binding Source: UniProtKB
  • insulin-like growth factor I binding Source: BHF-UCL
  • insulin-like growth factor II binding Source: BHF-UCL
  • insulin-like growth factor receptor binding Source: BHF-UCL
  • insulin receptor substrate binding Source: UniProtKB
  • phosphatidylinositol 3-kinase binding Source: UniProtKB
  • protein tyrosine kinase activity Source: UniProtKB
  • PTB domain binding Source: UniProtKB
  • receptor signaling protein tyrosine kinase activity Source: BHF-UCL

GO - Biological processi

  • activation of MAPK activity Source: BHF-UCL
  • activation of protein kinase activity Source: BHF-UCL
  • activation of protein kinase B activity Source: BHF-UCL
  • adrenal gland development Source: Ensembl
  • carbohydrate metabolic process Source: UniProtKB-KW
  • cellular response to growth factor stimulus Source: Ensembl
  • cellular response to insulin stimulus Source: BHF-UCL
  • epidermis development Source: Ensembl
  • exocrine pancreas development Source: Ensembl
  • glucose homeostasis Source: BHF-UCL
  • G-protein coupled receptor signaling pathway Source: BHF-UCL
  • heart morphogenesis Source: BHF-UCL
  • insulin receptor signaling pathway Source: UniProtKB
  • male gonad development Source: Ensembl
  • male sex determination Source: Ensembl
  • peptidyl-tyrosine autophosphorylation Source: Ensembl
  • peptidyl-tyrosine phosphorylation Source: BHF-UCL
  • positive regulation of cell migration Source: BHF-UCL
  • positive regulation of cell proliferation Source: BHF-UCL
  • positive regulation of developmental growth Source: BHF-UCL
  • positive regulation of DNA replication Source: BHF-UCL
  • positive regulation of glucose import Source: BHF-UCL
  • positive regulation of glycogen biosynthetic process Source: BHF-UCL
  • positive regulation of glycolytic process Source: BHF-UCL
  • positive regulation of MAPK cascade Source: BHF-UCL
  • positive regulation of meiotic cell cycle Source: Ensembl
  • positive regulation of mitotic nuclear division Source: BHF-UCL
  • positive regulation of nitric oxide biosynthetic process Source: BHF-UCL
  • positive regulation of protein kinase B signaling Source: BHF-UCL
  • positive regulation of protein phosphorylation Source: BHF-UCL
  • positive regulation of respiratory burst Source: BHF-UCL
  • positive regulation of transcription, DNA-templated Source: Ensembl
  • protein autophosphorylation Source: UniProtKB
  • protein heterotetramerization Source: UniProtKB
  • regulation of embryonic development Source: BHF-UCL
  • regulation of female gonad development Source: Ensembl
  • regulation of transcription, DNA-templated Source: BHF-UCL
  • transformation of host cell by virus Source: BHF-UCL
Complete GO annotation...

Keywords - Molecular functioni

Kinase, Receptor, Transferase, Tyrosine-protein kinase

Keywords - Biological processi

Carbohydrate metabolism

Keywords - Ligandi

ATP-binding, Nucleotide-binding

Enzyme and pathway databases

BioCyciZFISH:HS10244-MONOMER.
BRENDAi2.7.10.1. 2681.
ReactomeiR-HSA-6811558. PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling.
R-HSA-74713. IRS activation.
R-HSA-74749. Signal attenuation.
R-HSA-74751. Insulin receptor signalling cascade.
R-HSA-74752. Signaling by Insulin receptor.
R-HSA-77387. Insulin receptor recycling.
SABIO-RKP06213.
SignaLinkiP06213.
SIGNORiP06213.

Names & Taxonomyi

Protein namesi
Recommended name:
Insulin receptor (EC:2.7.10.1)
Short name:
IR
Alternative name(s):
CD_antigen: CD220
Cleaved into the following 2 chains:
Gene namesi
Name:INSR
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 19

Organism-specific databases

HGNCiHGNC:6091. INSR.

Subcellular locationi

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini28 – 758ExtracellularCuratedAdd BLAST731
Topological domaini763 – 956ExtracellularCuratedAdd BLAST194
Transmembranei957 – 979HelicalSequence analysisAdd BLAST23
Topological domaini980 – 1382CytoplasmicCuratedAdd BLAST403

GO - Cellular componenti

  • caveola Source: BHF-UCL
  • endosome membrane Source: Reactome
  • extracellular exosome Source: UniProtKB
  • insulin receptor complex Source: BHF-UCL
  • integral component of plasma membrane Source: BHF-UCL
  • intracellular membrane-bounded organelle Source: HPA
  • membrane Source: BHF-UCL
  • plasma membrane Source: BHF-UCL
  • receptor complex Source: MGI
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Membrane

Pathology & Biotechi

Involvement in diseasei

Rabson-Mendenhall syndrome (RMS)5 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionSevere insulin resistance syndrome characterized by insulin-resistant diabetes mellitus with pineal hyperplasia and somatic abnormalities. Typical features include coarse, senile-appearing facies, dental and skin abnormalities, abdominal distension, and phallic enlargement. Inheritance is autosomal recessive.
See also OMIM:262190
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_00407942N → K in RMS; impairs transport to the plasma membrane and reduces the affinity to bind insulin. 2 PublicationsCorresponds to variant rs121913143dbSNPEnsembl.1
Natural variantiVAR_004084236H → R in RMS and LEPRCH; Winnipeg; may impair receptor processing. 2 PublicationsCorresponds to variant rs121913145dbSNPEnsembl.1
Natural variantiVAR_015914350S → L in RMS and LEPRCH. 2 Publications1
Natural variantiVAR_031520386G → S in RMS; may impair receptor processing. 1 PublicationCorresponds to variant rs764221583dbSNPEnsembl.1
Natural variantiVAR_015921997P → T in RMS; reduces insulin binding. 1 Publication1
Natural variantiVAR_0159261143I → T in RMS; reduces insulin binding. 2 Publications1
Natural variantiVAR_0159281158R → W in RMS; abolishes insulin binding. 2 PublicationsCorresponds to variant rs111993466dbSNPEnsembl.1
Natural variantiVAR_0159301201R → W in LEPRCH and RMS; reduces insulin binding possibly due to reduced receptor levels on the cell surface. 2 Publications1
Leprechaunism (LEPRCH)15 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionRepresents the most severe form of insulin resistance syndrome, characterized by intrauterine and postnatal growth retardation and death in early infancy. Inheritance is autosomal recessive.
See also OMIM:246200
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_00408055V → A in LEPRCH; Verona-1. 1 PublicationCorresponds to variant rs121913152dbSNPEnsembl.1
Natural variantiVAR_00408158G → R in LEPRCH; Helmond; inhibits processing and transport. 1 PublicationCorresponds to variant rs52836744dbSNPEnsembl.1
Natural variantiVAR_004082113R → P in LEPRCH; Atlanta-1; abolishes insulin binding. 2 PublicationsCorresponds to variant rs121913153dbSNPEnsembl.1
Natural variantiVAR_015909119A → V in LEPRCH; markedly impairs insulin binding. 1 Publication1
Natural variantiVAR_031518120L → Q in LEPRCH; inhibits receptor processing. 1 Publication1
Natural variantiVAR_015539146I → M in LEPRCH; mild. 2 PublicationsCorresponds to variant rs121913159dbSNPEnsembl.1
Natural variantiVAR_004084236H → R in RMS and LEPRCH; Winnipeg; may impair receptor processing. 2 PublicationsCorresponds to variant rs121913145dbSNPEnsembl.1
Natural variantiVAR_004085260L → P in LEPRCH; Geldeimalsen. 1 PublicationCorresponds to variant rs121913141dbSNPEnsembl.1
Natural variantiVAR_015912301C → Y in LEPRCH. 1 Publication1
Natural variantiVAR_015913308Missing in LEPRCH; abolishes insulin binding. 3 Publications1
Natural variantiVAR_015914350S → L in RMS and LEPRCH. 2 Publications1
Natural variantiVAR_015541362Missing in LEPRCH. 1 Publication1
Natural variantiVAR_004086393G → R in LEPRCH; Verona-1. 1 PublicationCorresponds to variant rs267607184dbSNPEnsembl.1
Natural variantiVAR_015542439W → S in LEPRCH; impairs transport of the receptor to the cell surface. 1 PublicationCorresponds to variant rs121913158dbSNPEnsembl.1
Natural variantiVAR_031521458N → D in LEPRCH; partially inhibits receptor processing and autophosphorylation; strongly impairs ERK phosphorylation; induces wild-type levels of IRS-1 phosphorylation. 1 PublicationCorresponds to variant rs121913160dbSNPEnsembl.1
Natural variantiVAR_004088487K → E in LEPRCH; ARK-1. 1 PublicationCorresponds to variant rs28933083dbSNPEnsembl.1
Natural variantiVAR_015918925I → T in LEPRCH; abolishes insulin binding. 1 Publication1
Natural variantiVAR_015919926R → W in LEPRCH; markedly impairs insulin binding. 1 Publication1
Natural variantiVAR_015920937T → M in LEPRCH; impaired receptor processing. 1 Publication1
Natural variantiVAR_0159251119R → W in LEPRCH. 2 Publications1
Natural variantiVAR_0159301201R → W in LEPRCH and RMS; reduces insulin binding possibly due to reduced receptor levels on the cell surface. 2 Publications1
Natural variantiVAR_0159321206E → K in LEPRCH. 1 Publication1
Diabetes mellitus, non-insulin-dependent (NIDDM)3 Publications
The gene represented in this entry may be involved in disease pathogenesis.
Disease descriptionA multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to the body's own insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels.
See also OMIM:125853
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_015917858T → A in NIDDM. 1 PublicationCorresponds to variant rs182552223dbSNPEnsembl.1
Natural variantiVAR_0159241095K → E in a NIDDM subject. 1 Publication1
Natural variantiVAR_0159271158R → Q in NIDDM. 1 Publication1
Natural variantiVAR_0040981191R → Q in NIDDM. 1 PublicationCorresponds to variant rs121913150dbSNPEnsembl.1
Familial hyperinsulinemic hypoglycemia 5 (HHF5)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionFamilial hyperinsulinemic hypoglycemia [MIM:256450], also referred to as congenital hyperinsulinism, nesidioblastosis, or persistent hyperinsulinemic hypoglycemia of infancy (PPHI), is the most common cause of persistent hypoglycemia in infancy and is due to defective negative feedback regulation of insulin secretion by low glucose levels.
See also OMIM:609968
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_0159291201R → Q in HHF5 and IRAN type A; interferes with kinase activation by insulin. 3 PublicationsCorresponds to variant rs28933086dbSNPEnsembl.1
Insulin-resistant diabetes mellitus with acanthosis nigricans type A (IRAN type A)16 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionCharacterized by the association of severe insulin resistance (manifested by marked hyperinsulinemia and a failure to respond to exogenous insulin) with the skin lesion acanthosis nigricans and ovarian hyperandrogenism in adolescent female subjects. Women frequently present with hirsutism, acne, amenorrhea or oligomenorrhea, and virilization. This syndrome is different from the type B that has been demonstrated to be secondary to the presence of circulating autoantibodies against the insulin receptor.
See also OMIM:610549
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_01590786D → G in IRAN type A. 1 Publication1
Natural variantiVAR_01590889L → P in IRAN type A. 1 Publication1
Natural variantiVAR_015910167V → L in IRAN type A. 1 Publication1
Natural variantiVAR_015540279R → C in IRAN type A; inhibits receptor internalization. 1 Publication1
Natural variantiVAR_031519279R → H in IRAN type A; interferes with receptor processing. 1 Publication1
Natural variantiVAR_015911280C → Y in IRAN type A. 1 Publication1
Natural variantiVAR_004087409F → V in IRAN type A. 1 PublicationCorresponds to variant rs121913142dbSNPEnsembl.1
Natural variantiVAR_004089489N → S in IRAN type A. 1 PublicationCorresponds to variant rs28933085dbSNPEnsembl.1
Natural variantiVAR_004090762R → S in IRAN type A. 1 PublicationCorresponds to variant rs121913138dbSNPEnsembl.1
Natural variantiVAR_0040921020R → Q in IRAN type A. 1 PublicationCorresponds to variant rs121913148dbSNPEnsembl.1
Natural variantiVAR_0040931035G → V in IRAN type A. 1 PublicationCorresponds to variant rs121913135dbSNPEnsembl.1
Natural variantiVAR_0159231055A → V in IRAN type A. 1 Publication1
Natural variantiVAR_0040941075A → D in IRAN type A. 1 Publication1
Natural variantiVAR_0040951161A → T in IRAN type A. 1 PublicationCorresponds to variant rs28933084dbSNPEnsembl.1
Natural variantiVAR_0040961162A → E in IRAN type A; impairs proteolytic processing. 1 PublicationCorresponds to variant rs121913154dbSNPEnsembl.1
Natural variantiVAR_0159291201R → Q in HHF5 and IRAN type A; interferes with kinase activation by insulin. 3 PublicationsCorresponds to variant rs28933086dbSNPEnsembl.1
Natural variantiVAR_0040991205P → L in IRAN type A; moderate. 2 Publications1
Natural variantiVAR_0159311206E → D in IRAN type A; accelerates degradation of the protein and impairs kinase activity. 1 Publication1
Natural variantiVAR_0041001220W → L in IRAN type A; accelerates degradation of the protein and impairs kinase activity. 2 PublicationsCorresponds to variant rs52800171dbSNPEnsembl.1
Natural variantiVAR_0041011227W → S in IRAN type A. 1 PublicationCorresponds to variant rs121913140dbSNPEnsembl.1
Natural variantiVAR_0159341378R → Q in IRAN type A. 1 PublicationCorresponds to variant rs52826008dbSNPEnsembl.1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi991L → A: Reduces interaction with IRS1 but has no effect on interaction with SHC1. 1 Publication1
Mutagenesisi992Y → A: Reduces interaction with IRS1 but has no effect on interaction with SHC1. 1 Publication1
Mutagenesisi996 – 997NP → AA: Abolishes interaction with IRS1. Severely disrupts, but does not abolish interaction with SHC1. 1 Publication2
Mutagenesisi996N → A: Abolishes interaction with IRS1 and significantly reduces interaction with SHC1. Has no effect on interaction with PIK3R1. 2 Publications1
Mutagenesisi997P → A: Abolishes interaction with IRS1 and significantly reduces interaction with SHC1. Has no effect on interaction with PIK3R1. 2 Publications1
Mutagenesisi998E → A: Does not affect interaction with IRS1, SHC1 or PIK3R1. 1 Publication1
Mutagenesisi999Y → E: Abolishes interaction with IRS1 and SHC1. 4 Publications1
Mutagenesisi999Y → F: Has no effect on insulin-stimulated autophosphorylation, but inhibits the biological activity of the receptor. Abolishes interaction with IRS1 and almost completely prevents interaction with SHC1. Has no effect on interaction with PIK3R1. Abolishes interaction with STAT5B. 4 Publications1
Mutagenesisi1000L → A or R: Severely reduces interaction with SHC1. Has no effect on interaction with IRS1. 1 Publication1
Mutagenesisi1002A → D: Reduces interaction with IRS1 but has no effect on interaction with SHC1. 1 Publication1
Mutagenesisi1011Y → A: Increases kinase activity. 1 Publication1
Mutagenesisi1057K → A: Abolishes the kinase activity and abolishes interaction with IRS1, SHC1, GRB7 and PIK3R1. 3 Publications1
Mutagenesisi1057K → M or R: Abolishes the kinase activity. 3 Publications1
Mutagenesisi1159D → N: Loss of kinase activity. 1 Publication1
Mutagenesisi1163R → Q: Loss of kinase activity. 1 Publication1
Mutagenesisi1189Y → F: Reduced interaction with GRB7. 1 Publication1
Mutagenesisi1190Y → F: Strongly reduced interaction with GRB7. 1 Publication1

Keywords - Diseasei

Diabetes mellitus, Disease mutation

Organism-specific databases

DisGeNETi3643.
MalaCardsiINSR.
MIMi125853. phenotype.
246200. phenotype.
262190. phenotype.
609968. phenotype.
610549. phenotype.
OpenTargetsiENSG00000171105.
Orphaneti263458. Hyperinsulinism due to INSR deficiency.
2297. Insulin-resistance syndrome type A.
508. Leprechaunism.
769. Rabson-Mendenhall syndrome.
PharmGKBiPA202.

Chemistry databases

ChEMBLiCHEMBL1981.
DrugBankiDB01306. Insulin Aspart.
DB01307. Insulin Detemir.
DB00047. Insulin Glargine.
DB01309. Insulin Glulisine.
DB00046. Insulin Lispro.
DB00030. Insulin Regular.
DB01277. Mecasermin.
GuidetoPHARMACOLOGYi1800.

Polymorphism and mutation databases

BioMutaiINSR.
DMDMi308153655.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 273 PublicationsAdd BLAST27
ChainiPRO_000001668728 – 758Insulin receptor subunit alphaAdd BLAST731
ChainiPRO_0000016689763 – 1382Insulin receptor subunit betaAdd BLAST620

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi35 ↔ 53
Glycosylationi43N-linked (GlcNAc...)3 Publications1
Glycosylationi52N-linked (GlcNAc...)2 Publications1
Glycosylationi105N-linked (GlcNAc...)Sequence analysis1
Glycosylationi138N-linked (GlcNAc...)2 Publications1
Disulfide bondi153 ↔ 182
Disulfide bondi186 ↔ 209
Disulfide bondi196 ↔ 215
Disulfide bondi219 ↔ 228
Disulfide bondi223 ↔ 234
Disulfide bondi235 ↔ 243
Disulfide bondi239 ↔ 252
Glycosylationi242N-linked (GlcNAc...)3 Publications1
Disulfide bondi255 ↔ 264
Disulfide bondi268 ↔ 280
Glycosylationi282N-linked (GlcNAc...)2 Publications1
Disulfide bondi286 ↔ 311
Disulfide bondi293 ↔ 301
Disulfide bondi315 ↔ 328
Glycosylationi322N-linked (GlcNAc...)Sequence analysis1
Disulfide bondi331 ↔ 335
Disulfide bondi339 ↔ 360
Glycosylationi364N-linked (GlcNAc...)1 Publication1
Modified residuei400PhosphoserineCombined sources1
Modified residuei401PhosphotyrosineCombined sources1
Modified residuei407PhosphoserineCombined sources1
Glycosylationi424N-linked (GlcNAc...)1 Publication1
Glycosylationi445N-linked (GlcNAc...)2 Publications1
Disulfide bondi462 ↔ 4951 Publication
Glycosylationi541N-linked (GlcNAc...)2 Publications1
Disulfide bondi551Interchain1 Publication
Glycosylationi633N-linked (GlcNAc...)Sequence analysis1
Glycosylationi651N-linked (GlcNAc...)Sequence analysis1
Disulfide bondi674 ↔ 899
Glycosylationi698N-linked (GlcNAc...)Sequence analysis1
Glycosylationi769N-linked (GlcNAc...)1 Publication1
Glycosylationi782N-linked (GlcNAc...)Sequence analysis1
Disulfide bondi825 ↔ 834
Glycosylationi920N-linked (GlcNAc...)1 Publication1
Glycosylationi933N-linked (GlcNAc...)Sequence analysis1
Modified residuei992Phosphotyrosine; by autocatalysisCurated1
Modified residuei999Phosphotyrosine; by autocatalysis1 Publication1
Modified residuei1011Phosphotyrosine; by autocatalysisCurated1
Modified residuei1185Phosphotyrosine; by autocatalysis7 Publications1
Modified residuei1189Phosphotyrosine; by autocatalysis7 Publications1
Modified residuei1190Phosphotyrosine; by autocatalysis7 Publications1
Modified residuei1355Phosphotyrosine; by autocatalysis1 Publication1
Modified residuei1361Phosphotyrosine; by autocatalysis1 Publication1

Post-translational modificationi

After being transported from the endoplasmic reticulum to the Golgi apparatus, the single glycosylated precursor is further glycosylated and then cleaved, followed by its transport to the plasma membrane.6 Publications
Autophosphorylated on tyrosine residues in response to insulin. Phosphorylation of Tyr-999 is required for binding to IRS1, SHC1 and STAT5B. Dephosphorylated by PTPRE at Tyr-999, Tyr-1185, Tyr-1189 and Tyr-1190. Dephosphorylated by PTPRF and PTPN1. Dephosphorylated by PTPN2; down-regulates insulin-induced signaling.9 Publications

Keywords - PTMi

Cleavage on pair of basic residues, Disulfide bond, Glycoprotein, Phosphoprotein

Proteomic databases

EPDiP06213.
MaxQBiP06213.
PaxDbiP06213.
PeptideAtlasiP06213.
PRIDEiP06213.

PTM databases

iPTMnetiP06213.
PhosphoSitePlusiP06213.

Expressioni

Tissue specificityi

Isoform Long and isoform Short are predominantly expressed in tissue targets of insulin metabolic effects: liver, adipose tissue and skeletal muscle but are also expressed in the peripheral nerve, kidney, pulmonary alveoli, pancreatic acini, placenta vascular endothelium, fibroblasts, monocytes, granulocytes, erythrocytes and skin. Isoform Short is preferentially expressed in fetal cells such as fetal fibroblasts, muscle, liver and kidney. Found as a hybrid receptor with IGF1R in muscle, heart, kidney, adipose tissue, skeletal muscle, hepatoma, fibroblasts, spleen and placenta (at protein level). Overexpressed in several tumors, including breast, colon, lung, ovary, and thyroid carcinomas.4 Publications

Gene expression databases

BgeeiENSG00000171105.
CleanExiHS_INSR.
ExpressionAtlasiP06213. baseline and differential.
GenevisibleiP06213. HS.

Organism-specific databases

HPAiHPA036302.
HPA036303.

Interactioni

Subunit structurei

Tetramer of 2 alpha and 2 beta chains linked by disulfide bonds. The alpha chains carry the insulin-binding regions, while the beta chains carry the kinase domain. Forms a hybrid receptor with IGF1R, the hybrid is a tetramer consisting of 1 alpha chain and 1 beta chain of INSR and 1 alpha chain and 1 beta chain of IGF1R. Interacts with SORBS1 but dissociates from it following insulin stimulation. Binds SH2B2. Activated form of INSR interacts (via Tyr-999) with the PTB/PID domains of IRS1 and SHC1. The sequences surrounding the phosphorylated NPXY motif contribute differentially to either IRS1 or SHC1 recognition. Interacts (via tyrosines in the C-terminus) with IRS2 (via PTB domain and 591-786 AA); the 591-786 would be the primary anchor of IRS2 to INSR while the PTB domain would have a stabilizing action on the interaction with INSR. Interacts with the SH2 domains of the 85 kDa regulatory subunit of PI3K (PIK3R1) in vitro, when autophosphorylated on tyrosine residues. Interacts with SOCS7. Interacts (via the phosphorylated Tyr-999), with SOCS3. Interacts (via the phosphorylated Tyr-1185, Tyr-1189, Tyr-1190) with SOCS1. Interacts with CAV2 (tyrosine-phosphorylated form); the interaction is increased with 'Tyr-27'phosphorylation of CAV2 (By similarity). Interacts with ARRB2 (By similarity). Interacts with GRB10; this interaction blocks the association between IRS1/IRS2 and INSR, significantly reduces insulin-stimulated tyrosine phosphorylation of IRS1 and IRS2 and thus decreases insulin signaling. Interacts with GRB7. Interacts with PDPK1. Interacts (via Tyr-1190) with GRB14 (via BPS domain); this interaction protects the tyrosines in the activation loop from dephosphorylation, but promotes dephosphorylation of Tyr-999, this results in decreased interaction with, and phosphorylation of, IRS1. Interacts (via subunit alpha) with ENPP1 (via 485-599 AA); this interaction blocks autophosphorylation. Interacts with PTPRE; this interaction is dependent of Tyr-1185, Tyr-1189 and Tyr-1190 of the INSR. Interacts with STAT5B (via SH2 domain). Interacts with PTPRF. Interacts with ATIC; ATIC together with PRKAA2/AMPK2 and HACD3/PTPLAD1 is proposed to be part of a signaling netwok regulating INSR autophosphorylation and endocytosis (By similarity).By similarity26 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
AGAP2Q994902EBI-475899,EBI-2361824
ENPP1P224132EBI-475899,EBI-3197846
GRB10Q133223EBI-475899,EBI-80275
IGF1P050194EBI-475899,EBI-7902275
INSP013175EBI-475899,EBI-3989070From a different organism.
IRS1P355683EBI-475899,EBI-517592
Irs1P355705EBI-475899,EBI-520230From a different organism.
KRT31Q153233EBI-475899,EBI-948001
PIK3R1P279863EBI-475899,EBI-79464
PLCG1P191749EBI-475899,EBI-79387
PTPN1P1803133EBI-475899,EBI-968788
PTPN11Q061242EBI-475899,EBI-297779
SH2B1Q9NRF26EBI-475899,EBI-310491
SHC1P293532EBI-475899,EBI-78835

GO - Molecular functioni

  • insulin binding Source: UniProtKB
  • insulin-like growth factor I binding Source: BHF-UCL
  • insulin-like growth factor II binding Source: BHF-UCL
  • insulin-like growth factor receptor binding Source: BHF-UCL
  • insulin receptor substrate binding Source: UniProtKB
  • phosphatidylinositol 3-kinase binding Source: UniProtKB
  • PTB domain binding Source: UniProtKB

Protein-protein interaction databases

BioGridi109854. 77 interactors.
DIPiDIP-480N.
IntActiP06213. 50 interactors.
MINTiMINT-1516246.
STRINGi9606.ENSP00000303830.

Chemistry databases

BindingDBiP06213.

Structurei

Secondary structure

11382
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi33 – 42Combined sources10
Helixi45 – 50Combined sources6
Beta strandi53 – 65Combined sources13
Helixi70 – 72Combined sources3
Turni73 – 75Combined sources3
Beta strandi83 – 86Combined sources4
Beta strandi88 – 93Combined sources6
Turni100 – 102Combined sources3
Beta strandi118 – 124Combined sources7
Beta strandi141 – 149Combined sources9
Helixi160 – 162Combined sources3
Beta strandi171 – 175Combined sources5
Helixi176 – 178Combined sources3
Turni187 – 192Combined sources6
Beta strandi199 – 201Combined sources3
Beta strandi204 – 206Combined sources3
Beta strandi209 – 211Combined sources3
Helixi221 – 223Combined sources3
Beta strandi243 – 247Combined sources5
Beta strandi251 – 260Combined sources10
Beta strandi263 – 267Combined sources5
Beta strandi273 – 275Combined sources3
Turni276 – 278Combined sources3
Beta strandi279 – 281Combined sources3
Helixi283 – 295Combined sources13
Beta strandi298 – 300Combined sources3
Beta strandi305 – 307Combined sources3
Beta strandi310 – 314Combined sources5
Beta strandi319 – 321Combined sources3
Turni323 – 325Combined sources3
Beta strandi327 – 330Combined sources4
Beta strandi332 – 334Combined sources3
Beta strandi338 – 348Combined sources11
Helixi351 – 355Combined sources5
Turni356 – 359Combined sources4
Beta strandi361 – 369Combined sources9
Helixi377 – 385Combined sources9
Beta strandi390 – 393Combined sources4
Beta strandi395 – 399Combined sources5
Beta strandi404 – 406Combined sources3
Turni422 – 424Combined sources3
Beta strandi425 – 430Combined sources6
Beta strandi437 – 439Combined sources3
Turni441 – 443Combined sources3
Beta strandi452 – 458Combined sources7
Helixi463 – 472Combined sources10
Turni476 – 478Combined sources3
Turni481 – 483Combined sources3
Beta strandi486 – 490Combined sources5
Beta strandi498 – 500Combined sources3
Beta strandi502 – 507Combined sources6
Beta strandi512 – 516Combined sources5
Helixi524 – 526Combined sources3
Beta strandi527 – 536Combined sources10
Beta strandi538 – 540Combined sources3
Beta strandi559 – 561Combined sources3
Beta strandi577 – 580Combined sources4
Beta strandi588 – 597Combined sources10
Beta strandi601 – 603Combined sources3
Beta strandi608 – 610Combined sources3
Beta strandi613 – 616Combined sources4
Beta strandi626 – 631Combined sources6
Beta strandi633 – 636Combined sources4
Beta strandi638 – 643Combined sources6
Beta strandi654 – 658Combined sources5
Helixi666 – 669Combined sources4
Helixi722 – 735Combined sources14
Beta strandi798 – 803Combined sources6
Beta strandi805 – 809Combined sources5
Beta strandi817 – 827Combined sources11
Beta strandi838 – 843Combined sources6
Beta strandi858 – 861Combined sources4
Beta strandi867 – 870Combined sources4
Beta strandi881 – 890Combined sources10
Beta strandi896 – 901Combined sources6
Helixi902 – 908Combined sources7
Beta strandi910 – 913Combined sources4
Beta strandi918 – 931Combined sources14
Beta strandi940 – 944Combined sources5
Helixi953 – 979Combined sources27
Turni1003 – 1005Combined sources3
Helixi1009 – 1011Combined sources3
Helixi1014 – 1016Combined sources3
Helixi1020 – 1022Combined sources3
Beta strandi1023 – 1031Combined sources9
Beta strandi1033 – 1043Combined sources11
Beta strandi1046 – 1048Combined sources3
Beta strandi1050 – 1057Combined sources8
Helixi1065 – 1078Combined sources14
Beta strandi1089 – 1093Combined sources5
Beta strandi1095 – 1098Combined sources4
Beta strandi1100 – 1104Combined sources5
Helixi1111 – 1117Combined sources7
Beta strandi1119 – 1121Combined sources3
Helixi1133 – 1152Combined sources20
Beta strandi1154 – 1156Combined sources3
Helixi1162 – 1164Combined sources3
Beta strandi1165 – 1167Combined sources3
Beta strandi1173 – 1175Combined sources3
Beta strandi1181 – 1183Combined sources3
Turni1185 – 1187Combined sources3
Beta strandi1190 – 1192Combined sources3
Beta strandi1194 – 1198Combined sources5
Helixi1200 – 1202Combined sources3
Helixi1205 – 1210Combined sources6
Helixi1215 – 1230Combined sources16
Turni1236 – 1239Combined sources4
Helixi1242 – 1250Combined sources9
Helixi1263 – 1272Combined sources10
Helixi1277 – 1279Combined sources3
Helixi1283 – 1290Combined sources8
Helixi1291 – 1293Combined sources3
Helixi1298 – 1301Combined sources4
Turni1303 – 1305Combined sources3
Helixi1307 – 1309Combined sources3

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1GAGX-ray2.70A1005-1310[»]
1I44X-ray2.40A1005-1310[»]
1IR3X-ray1.90A1005-1310[»]
1IRKX-ray2.10A1005-1310[»]
1P14X-ray1.90A1005-1310[»]
1RQQX-ray2.60A/B1005-1310[»]
2AUHX-ray3.20A1005-1310[»]
2B4SX-ray2.30B/D1005-1310[»]
2HR7X-ray2.32A/B28-512[»]
2MFRNMR-A940-988[»]
2Z8CX-ray3.25A1008-1310[»]
3BU3X-ray1.65A1005-1310[»]
3BU5X-ray2.10A1005-1310[»]
3BU6X-ray1.95A1005-1310[»]
3EKKX-ray2.10A1005-1310[»]
3EKNX-ray2.20A1005-1310[»]
3ETAX-ray2.60A/B1017-1322[»]
3W11X-ray3.90E28-337[»]
F731-744[»]
3W12X-ray4.30E28-337[»]
F731-744[»]
3W13X-ray4.30E28-337[»]
F724-744[»]
3W14X-ray4.40E/F28-746[»]
4IBMX-ray1.80A/B1005-1310[»]
4OGAX-ray3.50E28-337[»]
F731-744[»]
4XLVX-ray2.30A983-1310[»]
4XSSX-ray3.00E28-337[»]
4XSTX-ray3.00E28-337[»]
4ZXBX-ray3.30E28-956[»]
5E1SX-ray2.26A1005-1310[»]
5HHWX-ray1.79A1005-1310[»]
5J3HX-ray3.27E28-337[»]
ProteinModelPortaliP06213.
SMRiP06213.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP06213.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini624 – 726Fibronectin type-III 1PROSITE-ProRule annotationAdd BLAST103
Domaini757 – 842Fibronectin type-III 2PROSITE-ProRule annotationAdd BLAST86
Domaini853 – 947Fibronectin type-III 3PROSITE-ProRule annotationAdd BLAST95
Domaini1023 – 1298Protein kinasePROSITE-ProRule annotationAdd BLAST276

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni733 – 741Insulin-binding9
Regioni999Important for interaction with IRS1, SHC1 and STAT5B1 Publication1
Regioni1361 – 1364PIK3R1-binding4

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi28 – 174Leu-richAdd BLAST147
Compositional biasi182 – 339Cys-richAdd BLAST158

Domaini

The tetrameric insulin receptor binds insulin via non-identical regions from two alpha chains, primarily via the C-terminal region of the first INSR alpha chain. Residues from the leucine-rich N-terminus of the other INSR alpha chain also contribute to this insulin binding site. A secondary insulin-binding site is formed by residues at the junction of fibronectin type-III domain 1 and 2.3 Publications

Sequence similaritiesi

Belongs to the protein kinase superfamily. Tyr protein kinase family. Insulin receptor subfamily.PROSITE-ProRule annotation
Contains 3 fibronectin type-III domains.PROSITE-ProRule annotation
Contains 1 protein kinase domain.PROSITE-ProRule annotation

Keywords - Domaini

Repeat, Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG4258. Eukaryota.
COG0515. LUCA.
GeneTreeiENSGT00760000118818.
HOGENOMi