Insulin receptor

Uniprot/Swiss-prot ID INSR_HUMAN
Protein name Insulin receptor
Gene name Name: INSR
Organism Homo sapiens (Human).
Taxonomic lineage Eukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo.
Function 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.
PTM N-linked (Glc...)
N-linked (GlcNAc...)
Phosphoserine
Phosphotyrosine
DePhosphotyrosine
S-nitrosocysteine
Topology Preview
Localization Cell membrane; Single-pass type I membrane protein.
Gene Ontology(GO) C:caveola
C:endosome membrane
C:insulin receptor complex
F:ATP binding
F:GTP binding
F:insulin binding
F:insulin-activated receptor activity
F:insulin-like growth factor receptor binding
F:receptor signaling protein tyrosine kinase activity
P:activation of MAPK activity
P:activation of protein kinase B activity
P:carbohydrate metabolic process
P:cellular response to growth factor stimulus
P:exocrine pancreas development
P:G-protein coupled receptor signaling pathway
P:glucose homeostasis
P:heart morphogenesis
P:male sex determination
P:peptidyl-tyrosine phosphorylation
P:positive regulation of cell migration
P:positive regulation of cell proliferation
P:positive regulation of developmental growth
P:positive regulation of DNA replication
P:positive regulation of glucose import
P:positive regulation of glycogen biosynthetic process
P:positive regulation of glycolysis
P:positive regulation of mitosis
P:positive regulation of nitric oxide biosynthetic process
P:positive regulation of protein kinase B signaling cascade
P:positive regulation of respiratory burst
P:protein autophosphorylation
P:protein heterotetramerization
P:regulation of embryonic development
P:regulation of transcription, DNA-dependent
P:transformation of host cell by virus
InterPro IPR000494: 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_cat_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
PDB
EntryMethodÅChainPositions3D
1GAGX-ray2.70A1005-1310
1I44X-ray2.40A1005-1310
1IR3X-ray1.90A1005-1310
1IRKX-ray2.10A1005-1310
1P14X-ray1.90A1005-1298
1RQQX-ray2.60A/B1005-1310
2AUHX-ray3.20A1005-1310
2B4SX-ray2.30B/D1005-1310
2DTGX-ray3.80E28-943
2HR7X-ray2.32A/B28-512
2Z8CX-ray3.25A1009-1310
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, F
3W12X-ray4.30E28-337, F
3W13X-ray4.30E28-337, F
3W14X-ray4.40E28-620, F
Sequence
Length: 1382
MATGGRRGAA AAPLLVAVAA LLLGAAGHLY PGEVCPGMDI RNNLTRLHEL ENCSVIEGHL QILLMFKTRP EDFRDLSFPK LIMITDYLLL FRVYGLESLK DLFPNLTVIR GSRLFFNYAL VIFEMVHLKE LGLYNLMNIT RGSVRIEKNN ELCYLATIDW SRILDSVEDN YIVLNKDDNE ECGDICPGTA KGKTNCPATV INGQFVERCW THSHCQKVCP TICKSHGCTA EGLCCHSECL GNCSQPDDPT KCVACRNFYL DGRCVETCPP PYYHFQDWRC VNFSFCQDLH HKCKNSRRQG CHQYVIHNNK CIPECPSGYT MNSSNLLCTP CLGPCPKVCH LLEGEKTIDS VTSAQELRGC TVINGSLIIN IRGGNNLAAE LEANLGLIEE ISGYLKIRRS YALVSLSFFR KLRLIRGETL EIGNYSFYAL DNQNLRQLWD WSKHNLTITQ GKLFFHYNPK LCLSEIHKME EVSGTKGRQE RNDIALKTNG DQASCENELL KFSYIRTSFD KILLRWEPYW PPDFRDLLGF MLFYKEAPYQ NVTEFDGQDA CGSNSWTVVD IDPPLRSNDP KSQNHPGWLM RGLKPWTQYA IFVKTLVTFS DERRTYGAKS DIIYVQTDAT NPSVPLDPIS VSNSSSQIIL KWKPPSDPNG NITHYLVFWE RQAEDSELFE LDYCLKGLKL PSRTWSPPFE SEDSQKHNQS EYEDSAGECC SCPKTDSQIL KELEESSFRK TFEDYLHNVV FVPRKTSSGT GAEDPRPSRK RRSLGDVGNV TVAVPTVAAF PNTSSTSVPT SPEEHRPFEK VVNKESLVIS GLRHFTGYRI ELQACNQDTP EERCSVAAYV SARTMPEAKA DDIVGPVTHE IFENNVVHLM WQEPKEPNGL IVLYEVSYRR YGDEELHLCV SRKHFALERG CRLRGLSPGN YSVRIRATSL AGNGSWTEPT YFYVTDYLDV PSNIAKIIIG PLIFVFLFSV VIGSIYLFLR KRQPDGPLGP LYASSNPEYL SASDVFPCSV YVPDEWEVSR EKITLLRELG QGSFGMVYEG NARDIIKGEA ETRVAVKTVN ESASLRERIE FLNEASVMKG FTCHHVVRLL GVVSKGQPTL VVMELMAHGD LKSYLRSLRP EAENNPGRPP PTLQEMIQMA AEIADGMAYL NAKKFVHRDL AARNCMVAHD FTVKIGDFGM TRDIYETDYY RKGGKGLLPV RWMAPESLKD GVFTTSSDMW SFGVVLWEIT SLAEQPYQGL SNEQVLKFVM DGGYLDQPDN CPERVTDLMR MCWQFNPKMR PTFLEIVNLL KDDLHPSFPE VSFFHSEENK APESEELEME FEDMENVPLD RSSHCQREEA GGRDGGSSLG FKRSYEEHIP YTHMNGGKKN GRILTLPRSN PS
Kegg Pathway hsa04066:HIF-1 signaling pathway - Homo sapiens (human)
hsa04151:PI3K-Akt signaling pathway - Homo sapiens (human)
hsa04520:Adherens junction - Homo sapiens (human)
hsa04910:Insulin signaling pathway - Homo sapiens (human)
hsa04913:Ovarian steroidogenesis - Homo sapiens (human)
hsa04930:Type II diabetes mellitus - Homo sapiens (human)
hsa04960:Aldosterone-regulated sodium reabsorption - Homo sapiens (human)
Disease Reference
KEGG disease H00719: Leprechaunism; Donohue syndrome
H00942: Rabson-Mendenhall syndrome
H01228: Insulin-resistant diabetes mellitus with acanthosis nigricans (IRAN); Type A insulin resistance
H01267: Familial hyperinsulinemic hypoglycemia (HHF)
Omim 147670: INSULIN RECEPTOR; INSR
246200: DONOHUE SYNDROME ;;LEPRECHAUNISM INSULIN RECEPTOR, DEFECT IN, INCLUDED
262190: PINEAL HYPERPLASIA, INSULIN-RESISTANT DIABETES MELLITUS, AND SOMATIC ABNORMALITIES ;;MENDENH
609968: HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 5; HHF5
610549: DIABETES MELLITUS, INSULIN-RESISTANT, WITH ACANTHOSIS NIGRICANS ;;INSULIN RECEPTOR, DEFECT I
Drug Reference
Kegg drug D00085: Insulin (JAN/USP)
D03230: Insulin human (genetical recombination) (JP16); Insulin human (biosynthesis) (JAN); Insulin human (s
D03250: Insulin glargine (genetical recombination) (JAN); Insulin glargine (USAN/INN); Lantus (TN)
D04475: Insulin aspart (genetical recombination) (JAN); Insulin aspart (USAN/INN); Insulin X 14; NovoRapid (
D04477: Insulin lispro (genetical recombination) (JAN); Insulin lispro (USP/INN); Humalog (TN)
D04539: Insulin detemir (genetical recombination) (JAN); Insulin detemir (USAN/INN); Levemir (TN)
D04540: Insulin glulisine (genetical recombination) (JAN); Insulin glulisine (USAN/INN); Apidra (TN)
D04541: Insulin human, isophane (USP)
D04542: Insulin human zinc (USP)
D04543: Insulin human zinc, extended (USP)
D04544: Insulin I 125 (USAN); Imusay-125 (TN)
D04545: Insulin I 131 (USAN); Imusay-131 (TN)
D04546: Insulin, dalanated (USAN)
D04547: Isophane insulin injection (aqueous suspension) (JAN); Insulin, isophane (USP); Humalog PEN (TN)
D04548: Insulin, neutral (USAN); Neutral insulin injection (INN)
D04549: Insulin zinc, extended (USP); Ultralente iletin (TN)
D04550: Insulin zinc, prompt (USP); Semilente iletin (TN)
D04551: Insulin zinc (USP); Lente iletin (TN)
D05622: Proinsulin human (USAN)
D08080: Insulin injection, biphasic isophane (BAN); Insulin Humacart (TN)
D09727: Insulin degludec (genetical recombination) (JAN); Insulin degludec (USAN/INN); Tresiba (TN)
DrugBank DB00047: Insulin Glargine recombinant
DB00030: Insulin recombinant
DB00071: Insulin, porcine