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UniProtKB - P06213 (INSR_HUMAN)

Protein

Insulin receptor

Gene

INSR

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -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 phosphotyrosine 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

Activity 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

View the complete GO annotation on QuickGO ...

GO - Biological processi

View the complete GO annotation on QuickGO ...

Keywordsi

Molecular functionKinase, Receptor, Transferase, Tyrosine-protein kinase
Biological processCarbohydrate metabolism
LigandATP-binding, Nucleotide-binding

Enzyme and pathway databases

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-RKiP06213
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:
Insulin receptor subunit alpha
Insulin receptor subunit beta
Gene namesi
Name:INSR
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo
Proteomesi
  • UP000005640 Componenti: Chromosome 19

Organism-specific databases

EuPathDBiHostDB:ENSG00000171105.13
HGNCiHGNC:6091 INSR
MIMi147670 gene
neXtProtiNX_P06213

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Topology

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

Keywords - Cellular componenti

Cell membrane, Membrane

Pathology & Biotechi

Involvement in diseasei

Rabson-Mendenhall syndrome (RMS)7 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 dbSNP:rs121913143EnsemblClinVar.1
Natural variantiVAR_079536256R → C in RMS. 1 PublicationCorresponds to variant dbSNP:rs781007453EnsemblClinVar.1
Natural variantiVAR_031520386G → S in RMS; may impair receptor processing. 1 PublicationCorresponds to variant dbSNP:rs764221583Ensembl.1
Natural variantiVAR_079539635S → L in RMS; decreases post-translational processing. 1 Publication1
Natural variantiVAR_079543835S → I in RMS; impairs post-translational processing. 1 PublicationCorresponds to variant dbSNP:rs1135401739Ensembl.1
Natural variantiVAR_079544842A → V in RMS; decreases post-translational processing. 1 PublicationCorresponds to variant dbSNP:rs1135401738Ensembl.1
Natural variantiVAR_079545874P → L in RMS; impairs post-translational processing. 1 Publication1
Natural variantiVAR_079546878N → S in RMS; impairs post-translational processing. 1 PublicationCorresponds to variant dbSNP:rs887190835Ensembl.1
Natural variantiVAR_015921997P → T in RMS; reduces insulin binding. 1 Publication1
Natural variantiVAR_079548999 – 1382Missing in RMS. 1 PublicationAdd BLAST384
Natural variantiVAR_0159261143I → T in RMS; reduces insulin binding. 2 Publications1
Natural variantiVAR_0159281158R → W in RMS; abolishes insulin binding. 2 PublicationsCorresponds to variant dbSNP:rs111993466Ensembl.1
Leprechaunism (LEPRCH)20 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 dbSNP:rs121913152EnsemblClinVar.1
Natural variantiVAR_07953556I → T in LEPRCH; abolishes post-translational processing. 1 Publication1
Natural variantiVAR_00408158G → R in LEPRCH; Helmond; inhibits processing and transport. 1 PublicationCorresponds to variant dbSNP:rs52836744EnsemblClinVar.1
Natural variantiVAR_004082113R → P in LEPRCH; Atlanta-1; abolishes insulin binding. 2 PublicationsCorresponds to variant dbSNP:rs121913153EnsemblClinVar.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 dbSNP:rs121913159EnsemblClinVar.1
Natural variantiVAR_004085260L → P in LEPRCH; Geldeimalsen. 1 PublicationCorresponds to variant dbSNP:rs121913141EnsemblClinVar.1
Natural variantiVAR_079537286C → Y in LEPRCH; abolishes post-translational processing. 1 Publication1
Natural variantiVAR_015912301C → Y in LEPRCH. 1 Publication1
Natural variantiVAR_015913308Missing in LEPRCH; abolishes insulin binding. 3 Publications1
Natural variantiVAR_015541362Missing in LEPRCH. 1 Publication1
Natural variantiVAR_004086393G → R in LEPRCH; Verona-1. 1 PublicationCorresponds to variant dbSNP:rs267607184EnsemblClinVar.1
Natural variantiVAR_015542439W → S in LEPRCH; impairs transport of the receptor to the cell surface. 1 PublicationCorresponds to variant dbSNP:rs121913158EnsemblClinVar.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 dbSNP:rs121913160EnsemblClinVar.1
Natural variantiVAR_004088487K → E in LEPRCH; ARK-1. 1 PublicationCorresponds to variant dbSNP:rs121913136EnsemblClinVar.1
Natural variantiVAR_079540657V → F in LEPRCH; impairs post-translational processing. 1 Publication1
Natural variantiVAR_079541659W → R in LEPRCH; impairs post-translational processing. 1 Publication1
Natural variantiVAR_079542818Y → C in LEPRCH; abolishes post-translational processing. 2 Publications1
Natural variantiVAR_079547890 – 1382Missing in LEPRCH. 1 PublicationAdd BLAST493
Natural variantiVAR_015918925I → T in LEPRCH; abolishes post-translational processing; abolishes insulin binding. 2 Publications1
Natural variantiVAR_015919926R → W in LEPRCH; markedly impairs insulin binding;impairs post-translational processing. 2 PublicationsCorresponds to variant dbSNP:rs911929963Ensembl.1
Natural variantiVAR_015920937T → M in LEPRCH; impaired receptor processing; impairs post-translational processing. 2 Publications1
Natural variantiVAR_0159251119R → W in LEPRCH. 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 dbSNP:rs182552223EnsemblClinVar.1
Natural variantiVAR_0159271158R → Q in NIDDM. 1 Publication1
Natural variantiVAR_0040981191R → Q in NIDDM. 1 PublicationCorresponds to variant dbSNP:rs121913150EnsemblClinVar.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
Insulin-resistant diabetes mellitus with acanthosis nigricans type A (IRAN type A)17 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 dbSNP:rs121913142EnsemblClinVar.1
Natural variantiVAR_079538489N → D in IRAN type A; unknown pathological significance. 1 Publication1
Natural variantiVAR_004089489N → S in IRAN type A. 1 PublicationCorresponds to variant dbSNP:rs121913147EnsemblClinVar.1
Natural variantiVAR_004090762R → S in IRAN type A. 1 PublicationCorresponds to variant dbSNP:rs121913138EnsemblClinVar.1
Natural variantiVAR_0040921020R → Q in IRAN type A. 1 PublicationCorresponds to variant dbSNP:rs121913148EnsemblClinVar.1
Natural variantiVAR_0040931035G → V in IRAN type A. 1 PublicationCorresponds to variant dbSNP:rs121913135EnsemblClinVar.1
Natural variantiVAR_0795491054V → M in IRAN type A; unknown pathological significance. 1 Publication1
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 dbSNP:rs121913139EnsemblClinVar.1
Natural variantiVAR_0040961162A → E in IRAN type A; impairs proteolytic processing. 1 PublicationCorresponds to variant dbSNP:rs121913154EnsemblClinVar.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 dbSNP:rs52800171Ensembl.1
Natural variantiVAR_0041011227W → S in IRAN type A. 1 PublicationCorresponds to variant dbSNP:rs121913140EnsemblClinVar.1
Natural variantiVAR_0159341378R → Q in IRAN type A. 1 PublicationCorresponds to variant dbSNP:rs52826008Ensembl.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
DrugBankiDB08513 [4-({5-(AMINOCARBONYL)-4-[(3-METHYLPHENYL)AMINO]PYRIMIDIN-2-YL}AMINO)PHENYL]ACETIC ACID
DB05120 AT1391
DB09129 Chromic chloride
DB01306 Insulin Aspart
DB09564 Insulin Degludec
DB01307 Insulin Detemir
DB00047 Insulin Glargine
DB01309 Insulin Glulisine
DB00030 Insulin Human
DB00046 Insulin Lispro
DB00071 Insulin Pork
DB01277 Mecasermin
DB05115 NN344
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...) asparagine3 Publications1
Glycosylationi52N-linked (GlcNAc...) asparagine2 Publications1
Glycosylationi105N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi138N-linked (GlcNAc...) asparagine2 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...) asparagine3 Publications1
Disulfide bondi255 ↔ 264
Disulfide bondi268 ↔ 280
Glycosylationi282N-linked (GlcNAc...) asparagine2 Publications1
Disulfide bondi286 ↔ 311
Disulfide bondi293 ↔ 301
Disulfide bondi315 ↔ 328
Glycosylationi322N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi331 ↔ 335
Disulfide bondi339 ↔ 360
Glycosylationi364N-linked (GlcNAc...) asparagine1 Publication1
Modified residuei400PhosphoserineCombined sources1
Modified residuei401PhosphotyrosineCombined sources1
Modified residuei407PhosphoserineCombined sources1
Glycosylationi424N-linked (GlcNAc...) asparagine1 Publication1
Glycosylationi445N-linked (GlcNAc...) asparagine2 Publications1
Disulfide bondi462 ↔ 4951 Publication
Glycosylationi541N-linked (GlcNAc...) asparagine2 Publications1
Disulfide bondi551Interchain1 Publication
Glycosylationi633N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi651N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi674 ↔ 899
Glycosylationi698N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi769N-linked (GlcNAc...) asparagine1 Publication1
Glycosylationi782N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi825 ↔ 834
Glycosylationi920N-linked (GlcNAc...) asparagine1 Publication1
Glycosylationi933N-linked (GlcNAc...) asparagineSequence 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
ProteomicsDBi51872
51873 [P06213-2]

PTM databases

GlyConnecti1402
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 Expressed in 239 organ(s), highest expression level in oviduct epithelium
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). Interacts with the cone snail venom insulin Con-Ins G1 (PubMed:27617429).By similarity27 Publications

Binary interactionsi

GO - Molecular functioni

View the complete GO annotation on QuickGO ...

Protein-protein interaction databases

BioGridi109854, 101 interactors
CORUMiP06213
DIPiDIP-480N
ELMiP06213
IntActiP06213, 59 interactors
MINTiP06213
STRINGi9606.ENSP00000303830

Chemistry databases

BindingDBiP06213

Structurei

Secondary structure

11382
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

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

Keywords - Domaini

Repeat, Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG4258 Eukaryota
COG0515 LUCA
GeneTreeiENSGT00760000118818
HOGENOMiHOG000038045
HOVERGENiHBG006134
InParanoidiP06213
KOiK04527
OMAiRHFTSYQ
OrthoDBiEOG091G00GE
PhylomeDBiP06213
TreeFamiTF351636

Family and domain databases

CDDicd00063 FN3, 2 hits
cd00064 FU, 1 hit
Gene3Di2.60.40.10, 4 hits
3.80.20.20, 2 hits
InterProiView protein in InterPro
IPR003961 FN3_dom
IPR036116 FN3_sf
IPR006211 Furin-like_Cys-rich_dom
IPR006212 Furin_repeat
IPR009030 Growth_fac_rcpt_cys_sf
IPR013783 Ig-like_fold
IPR011009 Kinase-like_dom_sf
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
IPR000494 Rcpt_L-dom
IPR036941 Rcpt_L-dom_sf
IPR001245 Ser-Thr/Tyr_kinase_cat_dom
IPR008266 Tyr_kinase_AS
IPR020635 Tyr_kinase_cat_dom
IPR016246 Tyr_kinase_insulin-like_rcpt
IPR002011 Tyr_kinase_rcpt_2_CS
PfamiView protein in Pfam
PF00757 Furin-like, 1 hit
PF07714 Pkinase_Tyr, 1 hit
PF01030 Recep_L_domain, 2 hits
PIRSFiPIRSF000620 Insulin_receptor, 1 hit
PRINTSiPR00109 TYRKINASE
SMARTiView protein in SMART
SM00060 FN3, 3 hits
SM00261 FU, 2 hits
SM00219 TyrKc, 1 hit
SUPFAMiSSF49265 SSF49265, 3 hits
SSF56112 SSF56112, 1 hit
SSF57184 SSF57184, 1 hit
PROSITEiView protein in PROSITE
PS50853 FN3, 2 hits
PS00107 PROTEIN_KINASE_ATP, 1 hit
PS50011 PROTEIN_KINASE_DOM, 1 hit
PS00109 PROTEIN_KINASE_TYR, 1 hit
PS00239 RECEPTOR_TYR_KIN_II, 1 hit

Sequences (2+)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

This entry has 2 described isoforms and 1 potential isoform that is computationally mapped.Show allAlign All

Isoform Long (identifier: P06213-1) [UniParc]FASTAAdd to basket
Also known as: HIR-B

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide
        10         20         30         40         50
MATGGRRGAA AAPLLVAVAA LLLGAAGHLY PGEVCPGMDI RNNLTRLHEL 
        60         70         80         90        100
ENCSVIEGHL QILLMFKTRP EDFRDLSFPK LIMITDYLLL FRVYGLESLK 
       110        120        130        140        150
DLFPNLTVIR GSRLFFNYAL VIFEMVHLKE LGLYNLMNIT RGSVRIEKNN 
       160        170        180        190        200
ELCYLATIDW SRILDSVEDN YIVLNKDDNE ECGDICPGTA KGKTNCPATV 
       210        220        230        240        250
INGQFVERCW THSHCQKVCP TICKSHGCTA EGLCCHSECL GNCSQPDDPT 
       260        270        280        290        300
KCVACRNFYL DGRCVETCPP PYYHFQDWRC VNFSFCQDLH HKCKNSRRQG 
       310        320        330        340        350
CHQYVIHNNK CIPECPSGYT MNSSNLLCTP CLGPCPKVCH LLEGEKTIDS 
       360        370        380        390        400
VTSAQELRGC TVINGSLIIN IRGGNNLAAE LEANLGLIEE ISGYLKIRRS 
       410        420        430        440        450
YALVSLSFFR KLRLIRGETL EIGNYSFYAL DNQNLRQLWD WSKHNLTITQ 
       460        470        480        490        500
GKLFFHYNPK LCLSEIHKME EVSGTKGRQE RNDIALKTNG DQASCENELL 
       510        520        530        540        550
KFSYIRTSFD KILLRWEPYW PPDFRDLLGF MLFYKEAPYQ NVTEFDGQDA 
       560        570        580        590        600
CGSNSWTVVD IDPPLRSNDP KSQNHPGWLM RGLKPWTQYA IFVKTLVTFS 
       610        620        630        640        650
DERRTYGAKS DIIYVQTDAT NPSVPLDPIS VSNSSSQIIL KWKPPSDPNG 
       660        670        680        690        700
NITHYLVFWE RQAEDSELFE LDYCLKGLKL PSRTWSPPFE SEDSQKHNQS 
       710        720        730        740        750
EYEDSAGECC SCPKTDSQIL KELEESSFRK TFEDYLHNVV FVPRKTSSGT 
       760        770        780        790        800
GAEDPRPSRK RRSLGDVGNV TVAVPTVAAF PNTSSTSVPT SPEEHRPFEK 
       810        820        830        840        850
VVNKESLVIS GLRHFTGYRI ELQACNQDTP EERCSVAAYV SARTMPEAKA 
       860        870        880        890        900
DDIVGPVTHE IFENNVVHLM WQEPKEPNGL IVLYEVSYRR YGDEELHLCV 
       910        920        930        940        950
SRKHFALERG CRLRGLSPGN YSVRIRATSL AGNGSWTEPT YFYVTDYLDV 
       960        970        980        990       1000
PSNIAKIIIG PLIFVFLFSV VIGSIYLFLR KRQPDGPLGP LYASSNPEYL 
      1010       1020       1030       1040       1050
SASDVFPCSV YVPDEWEVSR EKITLLRELG QGSFGMVYEG NARDIIKGEA 
      1060       1070       1080       1090       1100
ETRVAVKTVN ESASLRERIE FLNEASVMKG FTCHHVVRLL GVVSKGQPTL 
      1110       1120       1130       1140       1150
VVMELMAHGD LKSYLRSLRP EAENNPGRPP PTLQEMIQMA AEIADGMAYL 
      1160       1170       1180       1190       1200
NAKKFVHRDL AARNCMVAHD FTVKIGDFGM TRDIYETDYY RKGGKGLLPV 
      1210       1220       1230       1240       1250
RWMAPESLKD GVFTTSSDMW SFGVVLWEIT SLAEQPYQGL SNEQVLKFVM 
      1260       1270       1280       1290       1300
DGGYLDQPDN CPERVTDLMR MCWQFNPKMR PTFLEIVNLL KDDLHPSFPE 
      1310       1320       1330       1340       1350
VSFFHSEENK APESEELEME FEDMENVPLD RSSHCQREEA GGRDGGSSLG 
      1360       1370       1380 
FKRSYEEHIP YTHMNGGKKN GRILTLPRSN PS
Length:1,382
Mass (Da):156,333
Last modified:October 5, 2010 - v4
Checksum:i709A955660739066
GO
Isoform Short (identifier: P06213-2) [UniParc]FASTAAdd to basket
Also known as: HIR-A

The sequence of this isoform differs from the canonical sequence as follows:
     745-756: Missing.

Show »
Length:1,370
Mass (Da):155,146
Checksum:iA396F39279C2764D
GO

Computationally mapped potential isoform sequencesi

There is 1 potential isoform mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
M0R3E6M0R3E6_HUMAN
Insulin receptor
INSR
152Annotation score:

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti601D → N AA sequence (PubMed:3447155).Curated1
Sequence conflicti830P → E AA sequence (PubMed:3447155).Curated1
Sequence conflicti1278K → N in CAA26096 (PubMed:2983222).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_0583952A → G8 PublicationsCorresponds to variant dbSNP:rs7508518EnsemblClinVar.1
Natural variantiVAR_00407942N → K in RMS; impairs transport to the plasma membrane and reduces the affinity to bind insulin. 2 PublicationsCorresponds to variant dbSNP:rs121913143EnsemblClinVar.1
Natural variantiVAR_00408055V → A in LEPRCH; Verona-1. 1 Publication