Names & Taxonomy

Uniprot ID:
P06213
Entry Name:
INSR_HUMAN
Status:
reviewed
Protein Names:
Insulin receptor (IR) (EC 2.7.10.1) (CD antigen CD220) [Cleaved into: Insulin receptor subunit alpha; Insulin receptor subunit beta]
Gene Names:
INSR
Gene Names Primary:
INSR
Organism:
Homo sapiens (Human)

Structure

Length:
1382
Sequence:
MATGGRRGAAAAPLLVAVAALLLGAAGHLYPGEVCPGMDIRNNLTRLHELENCSVIEGHLQILLMFKTRPEDFRDLSFPKLIMITDYLLLFRVYGLESLKDLFPNLTVIRGSRLFFNYALVIFEMVHLKELGLYNLMNITRGSVRIEKNNELCYLATIDWSRILDSVEDNYIVLNKDDNEECGDICPGTAKGKTNCPATVINGQFVERCWTHSHCQKVCPTICKSHGCTAEGLCCHSECLGNCSQPDDPTKCVACRNFYLDGRCVETCPPPYYHFQDWRCVNFSFCQDLHHKCKNSRRQGCHQYVIHNNKCIPECPSGYTMNSSNLLCTPCLGPCPKVCHLLEGEKTIDSVTSAQELRGCTVINGSLIINIRGGNNLAAELEANLGLIEEISGYLKIRRSYALVSLSFFRKLRLIRGETLEIGNYSFYALDNQNLRQLWDWSKHNLTITQGKLFFHYNPKLCLSEIHKMEEVSGTKGRQERNDIALKTNGDQASCENELLKFSYIRTSFDKILLRWEPYWPPDFRDLLGFMLFYKEAPYQNVTEFDGQDACGSNSWTVVDIDPPLRSNDPKSQNHPGWLMRGLKPWTQYAIFVKTLVTFSDERRTYGAKSDIIYVQTDATNPSVPLDPISVSNSSSQIILKWKPPSDPNGNITHYLVFWERQAEDSELFELDYCLKGLKLPSRTWSPPFESEDSQKHNQSEYEDSAGECCSCPKTDSQILKELEESSFRKTFEDYLHNVVFVPRKTSSGTGAEDPRPSRKRRSLGDVGNVTVAVPTVAAFPNTSSTSVPTSPEEHRPFEKVVNKESLVISGLRHFTGYRIELQACNQDTPEERCSVAAYVSARTMPEAKADDIVGPVTHEIFENNVVHLMWQEPKEPNGLIVLYEVSYRRYGDEELHLCVSRKHFALERGCRLRGLSPGNYSVRIRATSLAGNGSWTEPTYFYVTDYLDVPSNIAKIIIGPLIFVFLFSVVIGSIYLFLRKRQPDGPLGPLYASSNPEYLSASDVFPCSVYVPDEWEVSREKITLLRELGQGSFGMVYEGNARDIIKGEAETRVAVKTVNESASLRERIEFLNEASVMKGFTCHHVVRLLGVVSKGQPTLVVMELMAHGDLKSYLRSLRPEAENNPGRPPPTLQEMIQMAAEIADGMAYLNAKKFVHRDLAARNCMVAHDFTVKIGDFGMTRDIYETDYYRKGGKGLLPVRWMAPESLKDGVFTTSSDMWSFGVVLWEITSLAEQPYQGLSNEQVLKFVMDGGYLDQPDNCPERVTDLMRMCWQFNPKMRPTFLEIVNLLKDDLHPSFPEVSFFHSEENKAPESEELEMEFEDMENVPLDRSSHCQREEAGGRDGGSSLGFKRSYEEHIPYTHMNGGKKNGRILTLPRSNPS
Proteomes:
UP000005640

Subcellular location

Subcellular Location:
Cell membrane; Single-pass type I membrane protein.

Function

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.
Catalytic Activity:
ATP + a -L-tyrosine = ADP + a -L-tyrosine phosphate.
Enzyme Regulation:
ENZYME REGULATION: 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.
Active Site:
ACT_SITE 1159 1159 Proton donor/acceptor.
Cross Reference Drug Bank:
DB01306 DB01307 DB00047 DB01309 DB00046 DB00030 DB01277
Gene Ontology Go:
caveola
cytosol
endosome membrane
extracellular exosome
insulin receptor complex
integral component of plasma membrane
intracellular membrane-bounded organelle
membrane
nucleus
plasma membrane
receptor complex
synapse
ATP binding
GTP binding
insulin binding
insulin receptor substrate binding
insulin-activated receptor activity
insulin-like growth factor I binding
insulin-like growth factor II binding
insulin-like growth factor receptor binding
lipoic acid binding
phosphatidylinositol 3-kinase binding
protein tyrosine kinase activity
PTB domain binding
receptor signaling protein tyrosine kinase activity
activation of MAPK activity
activation of protein kinase activity
activation of protein kinase B activity
adrenal gland development
carbohydrate metabolic process
cellular response to growth factor stimulus
cellular response to insulin stimulus
epidermis development
exocrine pancreas development
fat cell differentiation
G-protein coupled receptor signaling pathway
glucose homeostasis
heart morphogenesis
insulin receptor signaling pathway
male gonad development
male sex determination
negative regulation of gene expression
negative regulation of protein phosphorylation
negative regulation of transporter activity
peptidyl-tyrosine autophosphorylation
peptidyl-tyrosine phosphorylation
positive regulation of cell migration
positive regulation of cell proliferation
positive regulation of developmental growth
positive regulation of DNA replication
positive regulation of glucose import
positive regulation of glycogen biosynthetic process
positive regulation of glycolytic process
positive regulation of glycoprotein biosynthetic process
positive regulation of MAPK cascade
positive regulation of meiotic cell cycle
positive regulation of mitotic nuclear division
positive regulation of nitric oxide biosynthetic process
positive regulation of protein kinase B signaling
positive regulation of protein phosphorylation
positive regulation of respiratory burst
positive regulation of transcription, DNA-templated
protein autophosphorylation
protein heterotetramerization
regulation of embryonic development
regulation of female gonad development
regulation of hydrogen peroxide metabolic process
regulation of transcription, DNA-templated
response to activity
response to estradiol
response to ethanol
response to glucocorticoid
response to manganese ion
response to testosterone
response to tumor necrosis factor
response to vitamin D
signal transduction by protein phosphorylation
transformation of host cell by virus
Gene Ontology Biological Process:
activation of MAPK activity
activation of protein kinase activity
activation of protein kinase B activity
adrenal gland development
carbohydrate metabolic process
cellular response to growth factor stimulus
cellular response to insulin stimulus
epidermis development
exocrine pancreas development
fat cell differentiation
glucose homeostasis
G-protein coupled receptor signaling pathway
heart morphogenesis
insulin receptor signaling pathway
male gonad development
male sex determination
negative regulation of gene expression
negative regulation of protein phosphorylation
negative regulation of transporter activity
peptidyl-tyrosine autophosphorylation
peptidyl-tyrosine phosphorylation
positive regulation of cell migration
positive regulation of cell proliferation
positive regulation of developmental growth
positive regulation of DNA replication
positive regulation of glucose import
positive regulation of glycogen biosynthetic process
positive regulation of glycolytic process
positive regulation of glycoprotein biosynthetic process
positive regulation of MAPK cascade
positive regulation of meiotic cell cycle
positive regulation of mitotic nuclear division
positive regulation of nitric oxide biosynthetic process
positive regulation of protein kinase B signaling
positive regulation of protein phosphorylation
positive regulation of respiratory burst
positive regulation of transcription, DNA-templated
protein autophosphorylation
protein heterotetramerization
regulation of embryonic development
regulation of female gonad development
regulation of hydrogen peroxide metabolic process
regulation of transcription, DNA-templated
response to activity
response to estradiol
response to ethanol
response to glucocorticoid
response to manganese ion
response to testosterone
response to tumor necrosis factor
response to vitamin D
signal transduction by protein phosphorylation
transformation of host cell by virus
Gene Ontology Molecular Function:
ATP binding
GTP binding
insulin-activated receptor activity
insulin binding
insulin-like growth factor I binding
insulin-like growth factor II binding
insulin-like growth factor receptor binding
insulin receptor substrate binding
lipoic acid binding
phosphatidylinositol 3-kinase binding
protein tyrosine kinase activity
PTB domain binding
receptor signaling protein tyrosine kinase activity
Gene Ontology Cellular Component:
caveola
cytosol
endosome membrane
extracellular exosome
insulin receptor complex
integral component of plasma membrane
intracellular membrane-bounded organelle
membrane
nucleus
plasma membrane
receptor complex
synapse
Keywords:
3D-structure
ATP-binding
Alternative splicing
Carbohydrate metabolism
Cell membrane
Cleavage on pair of basic residues
Complete proteome
Diabetes mellitus
Direct protein sequencing
Disease mutation
Disulfide bond
Glycoprotein
Kinase
Membrane
Nucleotide-binding
Phosphoprotein
Polymorphism
Receptor
Reference proteome
Repeat
Signal
Transferase
Transmembrane
Transmembrane helix
Tyrosine-protein kinase
Interacts With:
Q99490; P22413; Q13322; P05019; P01317; P35568; P35570; Q15323; P27986; P19174; P18031; Q06124; Q9NRF2; P29353

Publication

PubMed ID:
2859121 2983222 2210055 15057824 15489334 3680248 2806055 2777789 2280779 2211730 8257688 2538124 2369896 2566545 3166375 2544997 3447155 3101064 2842060 1321605 1472036 8452530 8276809 7559478 7537849 9355755 9428692 8995282 8999839 9202395 10207053 10615944 10734133 10803466 11374898 11598120 11726652 12138094 12493740 12612081 16127460 16314505 15738637 16831875 16493415 17347799 18669648 19459609 19159218 19369195 19349973 24275569 7997262 9312016 11124964 12707268 14690593 16246733 16271887 16957736 16894147 18278056 18767165 19071018 19056263 19394223 20348418 23302862 3283938 2834824 2479553 2544998 2168397 2121734 2365819 1963473 2040394 2002058 1890161 1607067 1607076 1563582 1730625 1470163 8432414 8243830 8458533 8390949 8242067 8096518 8388389 8326490 8419945 8288049 8314008 8082780 8188715 7983039 7815442 7657032 7538143 8890729 8636294 9199575 9175790 9299395 9249867 9703342 10443650 10733238 11260230 12107746 12023989 12538626 12970295 15161766 17201797 17344846