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P06213

- INSR_HUMAN

UniProt

P06213 - INSR_HUMAN

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Protein

Insulin receptor

Gene

INSR

Organism
Homo sapiens (Human)
Status
Reviewed - 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.8 PublicationsPROSITE-ProRule annotation

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)LengthDescriptionGraphical viewFeature identifierActions
Sitei66 – 661Insulin-bindingCurated
Binding sitei1033 – 10331ATP1 PublicationPROSITE-ProRule annotation
Binding sitei1057 – 10571ATP1 PublicationPROSITE-ProRule annotation
Active sitei1159 – 11591Proton donor/acceptor1 Publication
Binding sitei1177 – 11771ATP1 PublicationPROSITE-ProRule annotation

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi1104 – 11107ATP1 PublicationPROSITE-ProRule annotation
Nucleotide bindingi1163 – 11642ATP1 PublicationPROSITE-ProRule annotation

GO - Molecular functioni

  1. ATP binding Source: BHF-UCL
  2. GTP binding Source: BHF-UCL
  3. insulin-activated receptor activity Source: UniProtKB
  4. insulin binding Source: UniProtKB
  5. insulin-like growth factor I binding Source: BHF-UCL
  6. insulin-like growth factor II binding Source: BHF-UCL
  7. insulin-like growth factor receptor binding Source: BHF-UCL
  8. insulin receptor substrate binding Source: UniProtKB
  9. phosphatidylinositol 3-kinase binding Source: UniProtKB
  10. protein tyrosine kinase activity Source: UniProtKB
  11. PTB domain binding Source: UniProtKB
  12. receptor signaling protein tyrosine kinase activity Source: BHF-UCL

GO - Biological processi

  1. activation of MAPK activity Source: BHF-UCL
  2. activation of protein kinase activity Source: BHF-UCL
  3. activation of protein kinase B activity Source: BHF-UCL
  4. carbohydrate metabolic process Source: UniProtKB-KW
  5. cellular response to growth factor stimulus Source: Ensembl
  6. cellular response to insulin stimulus Source: BHF-UCL
  7. epidermis development Source: Ensembl
  8. exocrine pancreas development Source: Ensembl
  9. glucose homeostasis Source: BHF-UCL
  10. G-protein coupled receptor signaling pathway Source: BHF-UCL
  11. heart morphogenesis Source: BHF-UCL
  12. insulin receptor signaling pathway Source: UniProtKB
  13. male sex determination Source: Ensembl
  14. peptidyl-tyrosine autophosphorylation Source: Ensembl
  15. peptidyl-tyrosine phosphorylation Source: BHF-UCL
  16. positive regulation of cell migration Source: BHF-UCL
  17. positive regulation of cell proliferation Source: BHF-UCL
  18. positive regulation of developmental growth Source: BHF-UCL
  19. positive regulation of DNA replication Source: BHF-UCL
  20. positive regulation of glucose import Source: BHF-UCL
  21. positive regulation of glycogen biosynthetic process Source: BHF-UCL
  22. positive regulation of glycolytic process Source: BHF-UCL
  23. positive regulation of MAPK cascade Source: BHF-UCL
  24. positive regulation of mitosis Source: BHF-UCL
  25. positive regulation of nitric oxide biosynthetic process Source: BHF-UCL
  26. positive regulation of protein kinase B signaling Source: BHF-UCL
  27. positive regulation of protein phosphorylation Source: BHF-UCL
  28. positive regulation of respiratory burst Source: BHF-UCL
  29. protein autophosphorylation Source: UniProtKB
  30. protein heterotetramerization Source: UniProtKB
  31. regulation of embryonic development Source: BHF-UCL
  32. regulation of transcription, DNA-templated Source: BHF-UCL
  33. signal transduction by phosphorylation Source: GOC
  34. 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

BRENDAi2.7.10.1. 2681.
ReactomeiREACT_1109. Insulin receptor recycling.
REACT_1661. SHC activation.
REACT_498. Signaling by Insulin receptor.
REACT_508. Signal attenuation.
REACT_570. IRS activation.
SABIO-RKP06213.
SignaLinkiP06213.

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
ProteomesiUP000005640: Chromosome 19

Organism-specific databases

HGNCiHGNC:6091. INSR.

Subcellular locationi

GO - Cellular componenti

  1. caveola Source: BHF-UCL
  2. endosome membrane Source: Reactome
  3. extracellular vesicular exosome Source: UniProt
  4. insulin receptor complex Source: BHF-UCL
  5. integral component of plasma membrane Source: BHF-UCL
  6. membrane Source: BHF-UCL
  7. plasma membrane Source: BHF-UCL
  8. receptor complex Source: MGI
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Membrane

Pathology & Biotechi

Involvement in diseasei

Rabson-Mendenhall syndrome (RMS) [MIM:262190]: Severe 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.5 Publications
Note: The disease is caused by mutations affecting the gene represented in this entry.
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti42 – 421N → K in RMS; impairs transport to the plasma membrane and reduces the affinity to bind insulin. 1 Publication
VAR_004079
Natural varianti236 – 2361H → R in LEPRCH; Winnipeg; in one patient with in RMS heterozygous compound with S-386; may impair receptor processing. 2 Publications
VAR_004084
Natural varianti350 – 3501S → L in RMS and LEPRCH. 2 Publications
VAR_015914
Natural varianti386 – 3861G → S in RMS; may impair receptor processing. 1 Publication
VAR_031520
Natural varianti997 – 9971P → T in RMS; reduces insulin binding. 1 Publication
VAR_015921
Natural varianti1143 – 11431I → T in RMS; reduces insulin binding. 2 Publications
VAR_015926
Natural varianti1158 – 11581R → W in RMS; abolishes insulin binding. 2 Publications
VAR_015928
Natural varianti1201 – 12011R → W in LEPRCH and RMS; reduces insulin binding possibly due to reduced receptor levels on the cell surface. 2 Publications
VAR_015930
Leprechaunism (LEPRCH) [MIM:246200]: Represents the most severe form of insulin resistance syndrome, characterized by intrauterine and postnatal growth retardation and death in early infancy. Inheritance is autosomal recessive.15 Publications
Note: The disease is caused by mutations affecting the gene represented in this entry.
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti55 – 551V → A in LEPRCH; Verona-1. 1 Publication
VAR_004080
Natural varianti58 – 581G → R in LEPRCH; Helmond; inhibits processing and transport. 1 Publication
Corresponds to variant rs52836744 [ dbSNP | Ensembl ].
VAR_004081
Natural varianti113 – 1131R → P in LEPRCH; Atlanta-1; abolishes insulin binding. 1 Publication
VAR_004082
Natural varianti119 – 1191A → V in LEPRCH; markedly impairs insulin binding.
VAR_015909
Natural varianti120 – 1201L → Q in LEPRCH; inhibits receptor processing. 1 Publication
VAR_031518
Natural varianti146 – 1461I → M in LEPRCH; mild. 2 Publications
VAR_015539
Natural varianti236 – 2361H → R in LEPRCH; Winnipeg; in one patient with in RMS heterozygous compound with S-386; may impair receptor processing. 2 Publications
VAR_004084
Natural varianti260 – 2601L → P in LEPRCH; Geldeimalsen. 1 Publication
VAR_004085
Natural varianti301 – 3011C → Y in LEPRCH. 1 Publication
VAR_015912
Natural varianti308 – 3081Missing in LEPRCH; abolishes insulin binding. 2 Publications
VAR_015913
Natural varianti350 – 3501S → L in RMS and LEPRCH. 2 Publications
VAR_015914
Natural varianti362 – 3621Missing in LEPRCH. 1 Publication
VAR_015541
Natural varianti393 – 3931G → R in LEPRCH; Verona-1. 1 Publication
VAR_004086
Natural varianti439 – 4391W → S in LEPRCH; impairs transport of the receptor to the cell surface. 1 Publication
VAR_015542
Natural varianti458 – 4581N → D in LEPRCH; partially inhibits receptor processing and autophosphorylation; strongly impairs ERK phosphorylation; induces wild-type levels of IRS-1 phosphorylation. 1 Publication
VAR_031521
Natural varianti487 – 4871K → E in LEPRCH; ARK-1. 1 Publication
Corresponds to variant rs28933083 [ dbSNP | Ensembl ].
VAR_004088
Natural varianti925 – 9251I → T in LEPRCH; abolishes insulin binding.
VAR_015918
Natural varianti926 – 9261R → W in LEPRCH; markedly impairs insulin binding.
VAR_015919
Natural varianti937 – 9371T → M in LEPRCH; impaired receptor processing.
VAR_015920
Natural varianti1119 – 11191R → W in LEPRCH. 2 Publications
VAR_015925
Natural varianti1201 – 12011R → W in LEPRCH and RMS; reduces insulin binding possibly due to reduced receptor levels on the cell surface. 2 Publications
VAR_015930
Natural varianti1206 – 12061E → K in LEPRCH. 1 Publication
VAR_015932
Diabetes mellitus, non-insulin-dependent (NIDDM) [MIM:125853]: A 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.3 Publications
Note: The gene represented in this entry may be involved in disease pathogenesis.
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti858 – 8581T → A in NIDDM. 1 Publication
Corresponds to variant rs182552223 [ dbSNP | Ensembl ].
VAR_015917
Natural varianti1095 – 10951K → E in a NIDDM subject. 1 Publication
VAR_015924
Natural varianti1158 – 11581R → Q in NIDDM. 1 Publication
VAR_015927
Natural varianti1191 – 11911R → Q in NIDDM. 1 Publication
VAR_004098
Familial hyperinsulinemic hypoglycemia 5 (HHF5) [MIM:609968]: Familial 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.1 Publication
Note: The disease is caused by mutations affecting the gene represented in this entry.
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti1201 – 12011R → Q in HHF5 and IRAN type A; interferes with kinase activation by insulin. 2 Publications
Corresponds to variant rs28933086 [ dbSNP | Ensembl ].
VAR_015929
Insulin-resistant diabetes mellitus with acanthosis nigricans type A (IRAN type A) [MIM:610549]: Characterized 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.16 Publications
Note: The disease is caused by mutations affecting the gene represented in this entry.
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti86 – 861D → G in IRAN type A. 1 Publication
VAR_015907
Natural varianti89 – 891L → P in IRAN type A. 1 Publication
VAR_015908
Natural varianti167 – 1671V → L in IRAN type A. 1 Publication
VAR_015910
Natural varianti279 – 2791R → C in IRAN type A; inhibits receptor internalization. 1 Publication
VAR_015540
Natural varianti279 – 2791R → H in IRAN type A; interferes with receptor processing. 1 Publication
VAR_031519
Natural varianti280 – 2801C → Y in IRAN type A. 1 Publication
VAR_015911
Natural varianti409 – 4091F → V in IRAN type A. 1 Publication
VAR_004087
Natural varianti489 – 4891N → S in IRAN type A. 1 Publication
Corresponds to variant rs28933085 [ dbSNP | Ensembl ].
VAR_004089
Natural varianti762 – 7621R → S in IRAN type A. 1 Publication
VAR_004090
Natural varianti1020 – 10201R → Q in IRAN type A. 1 Publication
VAR_004092
Natural varianti1035 – 10351G → V in IRAN type A. 1 Publication
VAR_004093
Natural varianti1055 – 10551A → V in IRAN type A. 1 Publication
VAR_015923
Natural varianti1075 – 10751A → D in IRAN type A. 1 Publication
VAR_004094
Natural varianti1161 – 11611A → T in IRAN type A. 1 Publication
Corresponds to variant rs28933084 [ dbSNP | Ensembl ].
VAR_004095
Natural varianti1162 – 11621A → E in IRAN type A; impairs proteolytic processing.
VAR_004096
Natural varianti1201 – 12011R → Q in HHF5 and IRAN type A; interferes with kinase activation by insulin. 2 Publications
Corresponds to variant rs28933086 [ dbSNP | Ensembl ].
VAR_015929
Natural varianti1205 – 12051P → L in IRAN type A; moderate. 2 Publications
VAR_004099
Natural varianti1206 – 12061E → D in IRAN type A; accelerates degradation of the protein and impairs kinase activity.
VAR_015931
Natural varianti1220 – 12201W → L in IRAN type A; accelerates degradation of the protein and impairs kinase activity. 1 Publication
Corresponds to variant rs52800171 [ dbSNP | Ensembl ].
VAR_004100
Natural varianti1227 – 12271W → S in IRAN type A. 1 Publication
VAR_004101
Natural varianti1378 – 13781R → Q in IRAN type A. 1 Publication
Corresponds to variant rs52826008 [ dbSNP | Ensembl ].
VAR_015934

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi991 – 9911L → A: Reduces interaction with IRS1 but has no effect on interaction with SHC1. 1 Publication
Mutagenesisi992 – 9921Y → A: Reduces interaction with IRS1 but has no effect on interaction with SHC1. 1 Publication
Mutagenesisi996 – 9972NP → AA: Abolishes interaction with IRS1. Severely disrupts, but does not abolish interaction with SHC1. 1 Publication
Mutagenesisi996 – 9961N → A: Abolishes interaction with IRS1 and significantly reduces interaction with SHC1. Has no effect on interaction with PIK3R1. 2 Publications
Mutagenesisi997 – 9971P → A: Abolishes interaction with IRS1 and significantly reduces interaction with SHC1. Has no effect on interaction with PIK3R1. 2 Publications
Mutagenesisi998 – 9981E → A: Does not affect interaction with IRS1, SHC1 or PIK3R1. 1 Publication
Mutagenesisi999 – 9991Y → E: Abolishes interaction with IRS1 and SHC1. 4 Publications
Mutagenesisi999 – 9991Y → 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 Publications
Mutagenesisi1000 – 10001L → A or R: Severely reduces interaction with SHC1. Has no effect on interaction with IRS1. 1 Publication
Mutagenesisi1002 – 10021A → D: Reduces interaction with IRS1 but has no effect on interaction with SHC1. 1 Publication
Mutagenesisi1011 – 10111Y → A: Increases kinase activity. 1 Publication
Mutagenesisi1057 – 10571K → A: Abolishes the kinase activity and abolishes interaction with IRS1, SHC1, GRB7 and PIK3R1. 3 Publications
Mutagenesisi1057 – 10571K → M or R: Abolishes the kinase activity. 3 Publications
Mutagenesisi1159 – 11591D → N: Loss of kinase activity. 1 Publication
Mutagenesisi1163 – 11631R → Q: Loss of kinase activity. 1 Publication
Mutagenesisi1189 – 11891Y → F: Reduced interaction with GRB7. 1 Publication
Mutagenesisi1190 – 11901Y → F: Strongly reduced interaction with GRB7. 1 Publication

Keywords - Diseasei

Diabetes mellitus, Disease mutation

Organism-specific databases

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

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Signal peptidei1 – 27273 PublicationsAdd
BLAST
Chaini28 – 758731Insulin receptor subunit alphaPRO_0000016687Add
BLAST
Chaini763 – 1382620Insulin receptor subunit betaPRO_0000016689Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Disulfide bondi35 ↔ 53
Glycosylationi43 – 431N-linked (GlcNAc...)3 Publications
Glycosylationi52 – 521N-linked (GlcNAc...)2 Publications
Glycosylationi105 – 1051N-linked (GlcNAc...)Sequence Analysis
Glycosylationi138 – 1381N-linked (GlcNAc...)2 Publications
Disulfide bondi153 ↔ 182
Disulfide bondi186 ↔ 209
Disulfide bondi196 ↔ 215
Disulfide bondi219 ↔ 228
Disulfide bondi223 ↔ 234
Disulfide bondi235 ↔ 243
Disulfide bondi239 ↔ 252
Glycosylationi242 – 2421N-linked (GlcNAc...)3 Publications
Disulfide bondi255 ↔ 264
Disulfide bondi268 ↔ 280
Glycosylationi282 – 2821N-linked (GlcNAc...)2 Publications
Disulfide bondi286 ↔ 311
Disulfide bondi293 ↔ 301
Disulfide bondi315 ↔ 328
Glycosylationi322 – 3221N-linked (GlcNAc...)Sequence Analysis
Disulfide bondi331 ↔ 335
Disulfide bondi339 ↔ 360
Glycosylationi364 – 3641N-linked (GlcNAc...)1 Publication
Modified residuei400 – 4001Phosphoserine1 Publication
Modified residuei401 – 4011Phosphotyrosine1 Publication
Modified residuei407 – 4071Phosphoserine1 Publication
Glycosylationi424 – 4241N-linked (GlcNAc...)1 Publication
Glycosylationi445 – 4451N-linked (GlcNAc...)2 Publications
Disulfide bondi462 ↔ 4951 Publication
Glycosylationi541 – 5411N-linked (GlcNAc...)2 Publications
Disulfide bondi551 – 551Interchain1 Publication
Glycosylationi633 – 6331N-linked (GlcNAc...)Sequence Analysis
Glycosylationi651 – 6511N-linked (GlcNAc...)Sequence Analysis
Disulfide bondi674 ↔ 899
Glycosylationi698 – 6981N-linked (GlcNAc...)Sequence Analysis
Glycosylationi769 – 7691N-linked (GlcNAc...)1 Publication
Glycosylationi782 – 7821N-linked (GlcNAc...)Sequence Analysis
Disulfide bondi825 ↔ 834
Glycosylationi920 – 9201N-linked (GlcNAc...)1 Publication
Glycosylationi933 – 9331N-linked (GlcNAc...)Sequence Analysis
Modified residuei992 – 9921Phosphotyrosine; by autocatalysisCurated
Modified residuei999 – 9991Phosphotyrosine; by autocatalysis1 Publication
Modified residuei1011 – 10111Phosphotyrosine; by autocatalysisCurated
Modified residuei1185 – 11851Phosphotyrosine; by autocatalysis7 Publications
Modified residuei1189 – 11891Phosphotyrosine; by autocatalysis7 Publications
Modified residuei1190 – 11901Phosphotyrosine; by autocatalysis7 Publications
Modified residuei1355 – 13551Phosphotyrosine; by autocatalysis1 Publication
Modified residuei1361 – 13611Phosphotyrosine; by autocatalysis1 Publication

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.10 Publications

Keywords - PTMi

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

Proteomic databases

MaxQBiP06213.
PaxDbiP06213.
PRIDEiP06213.

PTM databases

PhosphoSiteiP06213.

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

BgeeiP06213.
CleanExiHS_INSR.
ExpressionAtlasiP06213. baseline and differential.
GenevestigatoriP06213.

Organism-specific databases

HPAiHPA036302.

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.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.
PIK3R1P279863EBI-475899,EBI-79464
PLCG1P191749EBI-475899,EBI-79387
PTPN1P1803133EBI-475899,EBI-968788
PTPN11Q061242EBI-475899,EBI-297779
SH2B1Q9NRF26EBI-475899,EBI-310491
SHC1P293532EBI-475899,EBI-78835

Protein-protein interaction databases

BioGridi109854. 60 interactions.
DIPiDIP-480N.
IntActiP06213. 43 interactions.
MINTiMINT-1516246.
STRINGi9606.ENSP00000303830.

Structurei

Secondary structure

1
1382
Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Beta strandi33 – 4210
Helixi45 – 506
Beta strandi53 – 6513
Helixi70 – 723
Turni73 – 753
Beta strandi83 – 864
Beta strandi88 – 936
Turni100 – 1023
Beta strandi118 – 1247
Beta strandi141 – 1499
Helixi160 – 1623
Beta strandi171 – 1755
Helixi176 – 1783
Turni187 – 1926
Beta strandi199 – 2013
Beta strandi204 – 2063
Beta strandi209 – 2113
Helixi221 – 2233
Beta strandi243 – 2475
Beta strandi251 – 26010
Beta strandi263 – 2675
Beta strandi273 – 2753
Turni276 – 2783
Beta strandi279 – 2813
Helixi283 – 29513
Beta strandi298 – 3003
Beta strandi305 – 3073
Beta strandi310 – 3145
Beta strandi319 – 3213
Beta strandi327 – 3304
Beta strandi332 – 3343
Beta strandi338 – 34811
Helixi351 – 3555
Turni356 – 3594
Beta strandi361 – 3699
Helixi377 – 3859
Beta strandi390 – 3934
Beta strandi395 – 3995
Beta strandi404 – 4063
Turni422 – 4243
Beta strandi425 – 4306
Turni441 – 4433
Beta strandi452 – 4587
Helixi463 – 47210
Turni476 – 4783
Turni481 – 4833
Beta strandi486 – 4905
Helixi941 – 9466
Helixi953 – 97927
Helixi1009 – 10113
Helixi1014 – 10163
Helixi1020 – 10223
Beta strandi1023 – 10319
Beta strandi1033 – 104311
Beta strandi1046 – 10483
Beta strandi1050 – 10578
Helixi1065 – 107814
Beta strandi1089 – 10935
Beta strandi1095 – 10984
Beta strandi1100 – 11045
Helixi1111 – 11177
Beta strandi1119 – 11213
Helixi1133 – 115220
Beta strandi1154 – 11563
Helixi1162 – 11643
Beta strandi1165 – 11673
Beta strandi1173 – 11753
Beta strandi1181 – 11833
Turni1185 – 11873
Beta strandi1190 – 11923
Beta strandi1194 – 11985
Helixi1200 – 12023
Helixi1205 – 12106
Helixi1215 – 123016
Turni1236 – 12394
Helixi1242 – 12509
Helixi1263 – 127210
Helixi1277 – 12793
Helixi1283 – 12908
Helixi1291 – 12933
Helixi1298 – 13014
Turni1303 – 13053
Helixi1307 – 13093

3D structure databases

Select the link destinations:
PDBe
RCSB PDB
PDBj
Links Updated
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[»]
2DTGX-ray3.80E28-955[»]
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[»]
3LOHX-ray3.80E28-956[»]
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[»]
ProteinModelPortaliP06213.
SMRiP06213. Positions 31-988, 1009-1339.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP06213.

Topological domain

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Topological domaini28 – 758731ExtracellularCuratedAdd
BLAST
Topological domaini763 – 956194ExtracellularCuratedAdd
BLAST
Topological domaini980 – 1382403CytoplasmicCuratedAdd
BLAST

Transmembrane

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Transmembranei957 – 97923HelicalSequence AnalysisAdd
BLAST

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini624 – 726103Fibronectin type-III 1PROSITE-ProRule annotationAdd
BLAST
Domaini757 – 84286Fibronectin type-III 2PROSITE-ProRule annotationAdd
BLAST
Domaini853 – 94795Fibronectin type-III 3PROSITE-ProRule annotationAdd
BLAST
Domaini1023 – 1298276Protein kinasePROSITE-ProRule annotationAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni733 – 7419Insulin-binding
Regioni999 – 9991Important for interaction with IRS1, SHC1 and STAT5B
Regioni1361 – 13644PIK3R1-binding

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi28 – 174147Leu-richAdd
BLAST
Compositional biasi182 – 339158Cys-richAdd
BLAST

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

eggNOGiCOG0515.
GeneTreeiENSGT00760000118818.
HOGENOMiHOG000038045.
HOVERGENiHBG006134.
InParanoidiP06213.
KOiK04527.
OMAiCPERVTD.
OrthoDBiEOG73RB9N.
PhylomeDBiP06213.
TreeFamiTF351636.

Family and domain databases

Gene3Di2.60.40.10. 4 hits.
3.80.20.20. 2 hits.
InterProiIPR000494. EGF_rcpt_L.
IPR003961. Fibronectin_type3.
IPR006211. Furin-like_Cys-rich_dom.
IPR006212. Furin_repeat.
IPR009030. Growth_fac_rcpt_N_dom.
IPR013783. Ig-like_fold.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
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.
[Graphical view]
PfamiPF00041. fn3. 1 hit.
PF00757. Furin-like. 1 hit.
PF07714. Pkinase_Tyr. 1 hit.
PF01030. Recep_L_domain. 2 hits.
[Graphical view]
PIRSFiPIRSF000620. Insulin_receptor. 1 hit.
PRINTSiPR00109. TYRKINASE.
SMARTiSM00060. FN3. 3 hits.
SM00261. FU. 2 hits.
SM00219. TyrKc. 1 hit.
[Graphical view]
SUPFAMiSSF49265. SSF49265. 4 hits.
SSF56112. SSF56112. 1 hit.
SSF57184. SSF57184. 1 hit.
PROSITEiPS50853. 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.
[Graphical view]

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. Align

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

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti601 – 6011D → N AA sequence (PubMed:3447155)Curated
Sequence conflicti830 – 8301P → E AA sequence (PubMed:3447155)Curated
Sequence conflicti1278 – 12781K → N in CAA26096. (PubMed:2983222)Curated

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti2 – 21A → G.8 Publications
Corresponds to variant rs7508518 [ dbSNP | Ensembl ].
VAR_058395
Natural varianti42 – 421N → K in RMS; impairs transport to the plasma membrane and reduces the affinity to bind insulin. 1 Publication
VAR_004079
Natural varianti55 – 551V → A in LEPRCH; Verona-1. 1 Publication
VAR_004080
Natural varianti58 – 581G → R in LEPRCH; Helmond; inhibits processing and transport. 1 Publication
Corresponds to variant rs52836744 [ dbSNP | Ensembl ].
VAR_004081
Natural varianti86 – 861D → G in IRAN type A. 1 Publication
VAR_015907
Natural varianti89 – 891L → P in IRAN type A. 1 Publication
VAR_015908
Natural varianti113 – 1131R → P in LEPRCH; Atlanta-1; abolishes insulin binding. 1 Publication
VAR_004082
Natural varianti119 – 1191A → V in LEPRCH; markedly impairs insulin binding.
VAR_015909
Natural varianti120 – 1201L → Q in LEPRCH; inhibits receptor processing. 1 Publication
VAR_031518
Natural varianti146 – 1461I → M in LEPRCH; mild. 2 Publications
VAR_015539
Natural varianti167 – 1671V → L in IRAN type A. 1 Publication
VAR_015910
Natural varianti171 – 1711Y → H.1 Publication
Corresponds to variant rs1051692 [ dbSNP | Ensembl ].
VAR_058396
Natural varianti220 – 2201P → L in Ins resistance; severe. 1 Publication
VAR_004083
Natural varianti228 – 2281C → R in a gastric adenocarcinoma sample; somatic mutation. 1 Publication
VAR_041429
Natural varianti236 – 2361H → R in LEPRCH; Winnipeg; in one patient with in RMS heterozygous compound with S-386; may impair receptor processing. 2 Publications
VAR_004084
Natural varianti260 – 2601L → P in LEPRCH; Geldeimalsen. 1 Publication
VAR_004085
Natural varianti279 – 2791R → C in IRAN type A; inhibits receptor internalization. 1 Publication
VAR_015540
Natural varianti279 – 2791R → H in IRAN type A; interferes with receptor processing. 1 Publication
VAR_031519
Natural varianti280 – 2801C → Y in IRAN type A. 1 Publication
VAR_015911
Natural varianti301 – 3011C → Y in LEPRCH. 1 Publication
VAR_015912
Natural varianti308 – 3081Missing in LEPRCH; abolishes insulin binding. 2 Publications
VAR_015913
Natural varianti350 – 3501S → L in RMS and LEPRCH. 2 Publications
VAR_015914
Natural varianti362 – 3621Missing in LEPRCH. 1 Publication
VAR_015541
Natural varianti386 – 3861G → S in RMS; may impair receptor processing. 1 Publication
VAR_031520
Natural varianti393 – 3931G → R in LEPRCH; Verona-1. 1 Publication
VAR_004086
Natural varianti409 – 4091F → V in IRAN type A. 1 Publication
VAR_004087
Natural varianti439 – 4391W → S in LEPRCH; impairs transport of the receptor to the cell surface. 1 Publication
VAR_015542
Natural varianti448 – 4481I → T.1 Publication
Corresponds to variant rs1051691 [ dbSNP | Ensembl ].
VAR_015915
Natural varianti458 – 4581N → D in LEPRCH; partially inhibits receptor processing and autophosphorylation; strongly impairs ERK phosphorylation; induces wild-type levels of IRS-1 phosphorylation. 1 Publication
VAR_031521
Natural varianti487 – 4871K → E in LEPRCH; ARK-1. 1 Publication
Corresponds to variant rs28933083 [ dbSNP | Ensembl ].
VAR_004088
Natural varianti489 – 4891N → S in IRAN type A. 1 Publication
Corresponds to variant rs28933085 [ dbSNP | Ensembl ].
VAR_004089
Natural varianti492 – 4921Q → K.1 Publication
Corresponds to variant rs1131851 [ dbSNP | Ensembl ].
VAR_015916
Natural varianti695 – 6951Q → R.1 Publication
Corresponds to variant rs55906835 [ dbSNP | Ensembl ].
VAR_041430
Natural varianti762 – 7621R → S in IRAN type A. 1 Publication