INSR_MACMU
ID INSR_MACMU Reviewed; 210 AA.
AC Q28516;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 03-AUG-2022, entry version 148.
DE RecName: Full=Insulin receptor;
DE Short=IR;
DE EC=2.7.10.1;
DE AltName: CD_antigen=CD220;
DE Contains:
DE RecName: Full=Insulin receptor subunit alpha;
DE Contains:
DE RecName: Full=Insulin receptor subunit beta;
DE Flags: Fragment;
GN Name=INSR;
OS Macaca mulatta (Rhesus macaque).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini;
OC Cercopithecidae; Cercopithecinae; Macaca.
OX NCBI_TaxID=9544;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Liver;
RX PubMed=8083370; DOI=10.1172/jci117447;
RA Huang Z., Bodkin N.L., Ortmeyer H.K., Hansen B.C., Shuldiner A.R.;
RT "Hyperinsulinemia is associated with altered insulin receptor mRNA splicing
RT in muscle of the spontaneously obese diabetic rhesus monkey.";
RL J. Clin. Invest. 94:1289-1296(1994).
CC -!- FUNCTION: Receptor tyrosine kinase which mediates the pleiotropic
CC actions of insulin. Binding of insulin leads to phosphorylation of
CC several intracellular substrates, including, insulin receptor
CC substrates (IRS1, 2, 3, 4), SHC, GAB1, CBL and other signaling
CC intermediates. Each of these phosphorylated proteins serve as docking
CC proteins for other signaling proteins that contain Src-homology-2
CC domains (SH2 domain) that specifically recognize different
CC phosphotyrosine residues, including the p85 regulatory subunit of PI3K
CC and SHP2. Phosphorylation of IRSs proteins lead to the activation of
CC two main signaling pathways: the PI3K-AKT/PKB pathway, which is
CC responsible for most of the metabolic actions of insulin, and the Ras-
CC MAPK pathway, which regulates expression of some genes and cooperates
CC with the PI3K pathway to control cell growth and differentiation.
CC Binding of the SH2 domains of PI3K to phosphotyrosines on IRS1 leads to
CC the activation of PI3K and the generation of phosphatidylinositol-(3,
CC 4, 5)-triphosphate (PIP3), a lipid second messenger, which activates
CC several PIP3-dependent serine/threonine kinases, such as PDPK1 and
CC subsequently AKT/PKB. The net effect of this pathway is to produce a
CC translocation of the glucose transporter SLC2A4/GLUT4 from cytoplasmic
CC vesicles to the cell membrane to facilitate glucose transport.
CC Moreover, upon insulin stimulation, activated AKT/PKB is responsible
CC for: anti-apoptotic effect of insulin by inducing phosphorylation of
CC BAD; regulates the expression of gluconeogenic and lipogenic enzymes by
CC controlling the activity of the winged helix or forkhead (FOX) class of
CC transcription factors. Another pathway regulated by PI3K-AKT/PKB
CC activation is mTORC1 signaling pathway which regulates cell growth and
CC metabolism and integrates signals from insulin. AKT mediates insulin-
CC stimulated protein synthesis by phosphorylating TSC2 thereby activating
CC mTORC1 pathway. The Ras/RAF/MAP2K/MAPK pathway is mainly involved in
CC mediating cell growth, survival and cellular differentiation of
CC insulin. Phosphorylated IRS1 recruits GRB2/SOS complex, which triggers
CC the activation of the Ras/RAF/MAP2K/MAPK pathway. In addition to
CC binding insulin, the insulin receptor can bind insulin-like growth
CC factors (IGFI and IGFII). When present in a hybrid receptor with IGF1R,
CC binds IGF1 (By similarity). In adipocytes, inhibits lipolysis (By
CC similarity). {ECO:0000250, ECO:0000250|UniProtKB:P15208}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl-
CC [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA-
CC COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858,
CC ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.1;
CC Evidence={ECO:0000255|PROSITE-ProRule:PRU10028};
CC -!- ACTIVITY REGULATION: Activated in response to insulin.
CC Autophosphorylation activates the kinase activity. PTPN1, PTPRE and
CC PTPRF dephosphorylate important tyrosine residues, thereby reducing
CC INSR activity. Inhibited by ENPP1. GRB10 and GRB14 inhibit the
CC catalytic activity of the INSR, they block access of substrates to the
CC activated receptor. SOCS1 and SOCS3 act as negative regulators of INSR
CC activity, they bind to the activated INRS and interfere with the
CC phosphorylation of INSR substrates (By similarity). {ECO:0000250}.
CC -!- SUBUNIT: Tetramer of 2 alpha and 2 beta chains linked by disulfide
CC bonds. The alpha chains carry the insulin-binding regions, while the
CC beta chains carry the kinase domain. Forms a hybrid receptor with
CC IGF1R, the hybrid is a tetramer consisting of 1 alpha chain and 1 beta
CC chain of INSR and 1 alpha chain and 1 beta chain of IGF1R (By
CC similarity). Interacts with SORBS1 but dissociates from it following
CC insulin stimulation (By similarity). Binds SH2B2 (By similarity).
CC Activated form of INSR interacts (via phosphorylated Tyrosine) with the
CC PTB/PID domains of IRS1 and SHC1 (By similarity). The sequences
CC surrounding the phosphorylated NPXY motif contribute differentially to
CC either IRS1 or SHC1 recognition (By similarity). Interacts (via
CC tyrosines in the C-terminus) with IRS2 (via PTB domain and 591-786 AA);
CC the 591-786 would be the primary anchor of IRS2 to INSR while the PTB
CC domain would have a stabilizing action on the interaction with INSR (By
CC similarity). Interacts with the SH2 domains of the 85 kDa regulatory
CC subunit of PI3K (PIK3R1) in vitro, when autophosphorylated on tyrosine
CC residues (By similarity). Interacts with SOCS7. Interacts with SOCS3
CC (By similarity). Interacts with SOCS1 (By similarity). Interacts with
CC CAV2 (tyrosine-phosphorylated form); the interaction is increased with
CC 'Tyr-27'phosphorylation of CAV2 (By similarity). Interacts with ARRB2
CC (By similarity). Interacts with GRB10; this interaction blocks the
CC association between IRS1/IRS2 and INSR, significantly reduces insulin-
CC stimulated tyrosine phosphorylation of IRS1 and IRS2 and thus decreases
CC insulin signaling (By similarity). Interacts with GRB7 (By similarity).
CC Interacts with PDPK1 (By similarity). Interacts with GRB14 (via BPS
CC domain) (By similarity). Interacts (via subunit alpha) with ENPP1 (via
CC 485-599 AA); this interaction blocks autophosphorylation (By
CC similarity). Interacts with PTPRE (By similarity). Interacts with
CC STAT5B (via SH2 domain) (By similarity). Interacts with PTPRF (By
CC similarity). Interacts with ATIC; ATIC together with PRKAA2/AMPK2 and
CC HACD3/PTPLAD1 is proposed to be part of a signaling netwok regulating
CC INSR autophosphorylation and endocytosis (By similarity). Interacts
CC with the insulin receptor SORL1; this interaction strongly increases
CC its surface exposure, hence strengthens insulin signal reception (By
CC similarity). Interacts (tyrosine phosphorylated) with CCDC88A/GIV (via
CC SH2-like region); binding requires autophosphorylation of the INSR C-
CC terminal region (By similarity). Interacts with GNAI3; the interaction
CC is probably mediated by CCDC88A/GIV (By similarity). Interacts with
CC LMBRD1 (By similarity). {ECO:0000250, ECO:0000250|UniProtKB:P06213,
CC ECO:0000250|UniProtKB:P15127, ECO:0000250|UniProtKB:P15208}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:P15208};
CC Single-pass type I membrane protein {ECO:0000305}. Late endosome
CC {ECO:0000250|UniProtKB:P15208}. Lysosome
CC {ECO:0000250|UniProtKB:P15208}. Note=Binding of insulin to INSR induces
CC internalization and lysosomal degradation of the receptor, a means for
CC down-regulating this signaling pathway after stimulation. In the
CC presence of SORL1, internalized INSR molecules are redirected back to
CC the cell surface, thereby preventing their lysosomal catabolism and
CC strengthening insulin signal reception. {ECO:0000250|UniProtKB:P15208}.
CC -!- DOMAIN: The tetrameric insulin receptor binds insulin via non-identical
CC regions from two alpha chains, primarily via the C-terminal region of
CC the first INSR alpha chain. {ECO:0000250}.
CC -!- PTM: Autophosphorylated on tyrosine residues in response to insulin.
CC Dephosphorylated by PTPN1, PTPRE and PTPRF. Dephosphorylated by PTPN2;
CC down-regulates insulin-induced signaling. {ECO:0000250}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein
CC kinase family. Insulin receptor subfamily. {ECO:0000255|PROSITE-
CC ProRule:PRU00159}.
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DR EMBL; L35039; AAA62227.1; -; Genomic_DNA.
DR PIR; I55609; I55609.
DR AlphaFoldDB; Q28516; -.
DR SMR; Q28516; -.
DR STRING; 9544.ENSMMUP00000004959; -.
DR eggNOG; KOG4258; Eukaryota.
DR HOGENOM; CLU_000288_166_0_1; -.
DR Proteomes; UP000006718; Unplaced.
DR GO; GO:0005770; C:late endosome; IEA:UniProtKB-SubCell.
DR GO; GO:0005764; C:lysosome; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0043559; F:insulin binding; ISS:UniProtKB.
DR GO; GO:0005009; F:insulin receptor activity; ISS:UniProtKB.
DR GO; GO:0043560; F:insulin receptor substrate binding; ISS:UniProtKB.
DR GO; GO:0043548; F:phosphatidylinositol 3-kinase binding; ISS:UniProtKB.
DR GO; GO:0008286; P:insulin receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:0046777; P:protein autophosphorylation; ISS:UniProtKB.
DR CDD; cd00063; FN3; 1.
DR Gene3D; 2.60.40.10; -; 2.
DR InterPro; IPR003961; FN3_dom.
DR InterPro; IPR036116; FN3_sf.
DR InterPro; IPR013783; Ig-like_fold.
DR SUPFAM; SSF49265; SSF49265; 1.
DR PROSITE; PS50853; FN3; 1.
PE 3: Inferred from homology;
KW ATP-binding; Cell membrane; Cleavage on pair of basic residues;
KW Disulfide bond; Endosome; Glycoprotein; Kinase; Lysosome; Membrane;
KW Nucleotide-binding; Receptor; Reference proteome; Repeat; Transferase;
KW Tyrosine-protein kinase.
FT CHAIN <1..128
FT /note="Insulin receptor subunit alpha"
FT /id="PRO_0000016690"
FT CHAIN 133..>210
FT /note="Insulin receptor subunit beta"
FT /id="PRO_0000016692"
FT TOPO_DOM 133..>210
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT DOMAIN <1..96
FT /note="Fibronectin type-III"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316"
FT REGION 55..78
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 103..111
FT /note="Insulin-binding"
FT /evidence="ECO:0000250"
FT REGION 116..169
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 146..162
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT CARBOHYD 3
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 21
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 68
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 139
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 152
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 195..204
FT /evidence="ECO:0000250"
FT NON_TER 1
FT NON_TER 210
SQ SEQUENCE 210 AA; 23607 MW; 2D7ADDAA6A8649A4 CRC64;
VSNSSSQIIL KWKPPSDPNG NITHYLVFWE RQAEDSELFE LDYCLKGLKL PSRTWSPPFE
SEDSQKHNQS EYEDSAGECC SCPKTDSQIL KELEESSFRK TFEDYLHNVV FVPRKTSSGT
GAEDPRPSRK RRSLGDVGNV TVAVPTVAAF PNTSSTSTPT SPEEHRPFEK VVNKESLVIS
GLRHFTGYRI ELQACNQDTP EERCSVAAYV
