P15127 · INSR_RAT

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 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). When present in a hybrid receptor with IGF1R, binds IGF1 (By similarity).
In adipocytes, inhibits lipolysis (By similarity).

Catalytic activity

Activity 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 (By similarity).

Features

Showing features for site, binding site, active site.

TypeIDPosition(s)Description
Site65Insulin-binding
Binding site1034ATP (UniProtKB | ChEBI)
Binding site1058ATP (UniProtKB | ChEBI)
Binding site1105-1111ATP (UniProtKB | ChEBI)
Active site1160Proton donor/acceptor
Binding site1164-1165ATP (UniProtKB | ChEBI)
Binding site1178ATP (UniProtKB | ChEBI)

GO annotations

AspectTerm
Cellular Componentaxon
Cellular Componentcaveola
Cellular Componentdendrite membrane
Cellular Componentendosome
Cellular Componentexternal side of plasma membrane
Cellular Componentinsulin receptor complex
Cellular Componentlate endosome
Cellular Componentlysosome
Cellular Componentmembrane
Cellular Componentneuronal cell body
Cellular Componentneuronal cell body membrane
Cellular Componentnuclear envelope
Cellular Componentnuclear lumen
Cellular Componentplasma membrane
Cellular Componentreceptor complex
Cellular Componentyolk
Molecular Function3-phosphoinositide-dependent protein kinase binding
Molecular Functionamyloid-beta binding
Molecular FunctionATP binding
Molecular Functioncargo receptor activity
Molecular FunctionGTP binding
Molecular Functioninsulin binding
Molecular Functioninsulin receptor activity
Molecular Functioninsulin receptor substrate binding
Molecular Functioninsulin-like growth factor I binding
Molecular Functioninsulin-like growth factor II binding
Molecular Functioninsulin-like growth factor receptor binding
Molecular Functionlipoic acid binding
Molecular Functionphosphatidylinositol 3-kinase binding
Molecular Functionprotein domain specific binding
Molecular Functionprotein kinase activity
Molecular Functionprotein kinase binding
Molecular Functionprotein phosphatase binding
Molecular Functionprotein tyrosine kinase activity
Molecular Functionprotein-containing complex binding
Molecular FunctionPTB domain binding
Molecular Functionstructural molecule activity
Biological Processadrenal gland development
Biological Processamyloid-beta clearance
Biological Processanimal organ morphogenesis
Biological Processcellular response to growth factor stimulus
Biological Processcellular response to insulin stimulus
Biological Processcellular response to zinc ion starvation
Biological Processcerebellum development
Biological Processdendritic spine maintenance
Biological Processembryonic liver development
Biological Processepidermis development
Biological Processexocrine pancreas development
Biological Processfat cell differentiation
Biological ProcessG protein-coupled receptor signaling pathway
Biological Processglucose homeostasis
Biological Processheart morphogenesis
Biological Processhippocampus development
Biological Processinsulin receptor signaling pathway
Biological Processliver development
Biological Processliver regeneration
Biological Processmale gonad development
Biological Processmale sex determination
Biological Processnegative regulation of feeding behavior
Biological Processnegative regulation of gene expression
Biological Processnegative regulation of glycogen biosynthetic process
Biological Processnegative regulation of protein phosphorylation
Biological Processneuron projection maintenance
Biological Processpositive regulation of cell migration
Biological Processpositive regulation of cell population proliferation
Biological Processpositive regulation of developmental growth
Biological Processpositive regulation of DNA-templated transcription
Biological Processpositive regulation of glucose import
Biological Processpositive regulation of glycogen biosynthetic process
Biological Processpositive regulation of glycolytic process
Biological Processpositive regulation of glycoprotein biosynthetic process
Biological Processpositive regulation of MAPK cascade
Biological Processpositive regulation of meiotic cell cycle
Biological Processpositive regulation of mitotic nuclear division
Biological Processpositive regulation of nitric oxide biosynthetic process
Biological Processpositive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction
Biological Processpositive regulation of phosphorylation
Biological Processpositive regulation of protein phosphorylation
Biological Processpositive regulation of protein-containing complex disassembly
Biological Processpositive regulation of receptor internalization
Biological Processpositive regulation of respiratory burst
Biological Processreceptor internalization
Biological Processreceptor-mediated endocytosis
Biological Processregulation of DNA-templated transcription
Biological Processregulation of embryonic development
Biological Processregulation of female gonad development
Biological Processregulation of gluconeogenesis
Biological Processregulation of hydrogen peroxide metabolic process
Biological Processresponse to activity
Biological Processresponse to estradiol
Biological Processresponse to ethanol
Biological Processresponse to food
Biological Processresponse to glucocorticoid
Biological Processresponse to glucose
Biological Processresponse to hormone
Biological Processresponse to hypoxia
Biological Processresponse to insulin
Biological Processresponse to manganese ion
Biological Processresponse to nutrient levels
Biological Processresponse to resveratrol
Biological Processresponse to starvation
Biological Processresponse to testosterone
Biological Processresponse to tumor necrosis factor
Biological Processresponse to vanadate(3-)
Biological Processresponse to vitamin D
Biological Processsymbiont entry into host cell

Keywords

Enzyme and pathway databases

Names & Taxonomy

Protein names

Gene names

    • Name
      Insr

Organism names

  • Taxonomic identifier
  • Strain
    • Sprague-Dawley
  • Taxonomic lineage
    Eukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Glires > Rodentia > Myomorpha > Muroidea > Muridae > Murinae > Rattus

Accessions

  • Primary accession
    P15127
  • Secondary accessions
    • P97681

Proteomes

Organism-specific databases

Subcellular Location

Cell membrane
; Single-pass type I membrane protein
Late endosome
Lysosome
Note: Binding of insulin to INSR induces internalization and lysosomal degradation of the receptor, a means for down-regulating this signaling pathway after stimulation. In the presence of SORL1, internalized INSR molecules are redirected back to the cell surface, thereby preventing their lysosomal catabolism and strengthening insulin signal reception.

Features

Showing features for topological domain, transmembrane.

TypeIDPosition(s)Description
Topological domain27-759Extracellular
Topological domain764-957Extracellular
Transmembrane958-978Helical
Topological domain979-1383Cytoplasmic

Keywords

Phenotypes & Variants

PTM/Processing

Features

Showing features for signal, chain, disulfide bond, glycosylation, modified residue.

TypeIDPosition(s)Description
Signal1-26
ChainPRO_000001669627-759Insulin receptor subunit alpha
Disulfide bond34↔52
Glycosylation42N-linked (GlcNAc...) asparagine
Glycosylation51N-linked (GlcNAc...) asparagine
Glycosylation104N-linked (GlcNAc...) asparagine
Glycosylation137N-linked (GlcNAc...) asparagine
Disulfide bond152↔181
Disulfide bond185↔208
Disulfide bond195↔214
Disulfide bond218↔227
Disulfide bond222↔233
Disulfide bond234↔242
Disulfide bond238↔251
Glycosylation241N-linked (GlcNAc...) asparagine
Disulfide bond254↔263
Disulfide bond267↔279
Glycosylation281N-linked (GlcNAc...) asparagine
Disulfide bond285↔310
Disulfide bond292↔300
Disulfide bond314↔327
Glycosylation321N-linked (GlcNAc...) asparagine
Disulfide bond330↔334
Disulfide bond338↔359
Glycosylation363N-linked (GlcNAc...) asparagine
Modified residue399Phosphoserine
Modified residue400Phosphotyrosine
Modified residue406Phosphoserine
Glycosylation423N-linked (GlcNAc...) asparagine
Glycosylation444N-linked (GlcNAc...) asparagine
Disulfide bond461↔494
Glycosylation540N-linked (GlcNAc...) asparagine
Disulfide bond550Interchain
Glycosylation634N-linked (GlcNAc...) asparagine
Glycosylation652N-linked (GlcNAc...) asparagine
Disulfide bond675↔900
Glycosylation699N-linked (GlcNAc...) asparagine
ChainPRO_0000016698764-1383Insulin receptor subunit beta
Glycosylation770N-linked (GlcNAc...) asparagine
Glycosylation783N-linked (GlcNAc...) asparagine
Glycosylation921N-linked (GlcNAc...) asparagine
Glycosylation934N-linked (GlcNAc...) asparagine
Modified residue1000Phosphotyrosine; by autocatalysis
Modified residue1084S-nitrosocysteine
Modified residue1186Phosphotyrosine; by autocatalysis
Modified residue1190Phosphotyrosine; by autocatalysis
Modified residue1191Phosphotyrosine; by autocatalysis
Modified residue1356Phosphotyrosine; by autocatalysis
Modified residue1362Phosphotyrosine; by autocatalysis

Post-translational modification

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.
Autophosphorylated on tyrosine residues in response to insulin. Phosphorylation of Tyr-1000 is required for binding to IRS1, SHC1 and STAT5B. Dephosphorylated by PTPRE at Tyr-1000, Tyr-1186, Tyr-1190 and Tyr-1191. Dephosphorylated by PTPRF and PTPN1. Dephosphorylated by PTPN2; down-regulates insulin-induced signaling.
S-nitrosylation at Cys-1084 by BLVRB inhibits the receptor tyrosine kinase, thereby inhibiting insulin signaling.

Keywords

Proteomic databases

PTM databases

Interaction

Subunit

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-1000) 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-1000), with SOCS3. Interacts (via the phosphorylated Tyr-1186, Tyr-1190, Tyr-1191) with SOCS1. 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 PDPK1. Interacts (via Tyr-1191) with GRB14 (via BPS domain); this interaction protects the tyrosines in the activation loop from dephosphorylation, but promotes dephosphorylation of Tyr-1000, 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-1186, Tyr-1190 and Tyr-1191 of the INSR. Interacts with STAT5B (via SH2 domain). Interacts with PTPRF (By similarity).
Interacts with GRB7. Interacts with CAV2 (tyrosine-phosphorylated form); the interaction is increased with 'Tyr-27'phosphorylation of CAV2. 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 (PubMed:25687571).
Interacts with the insulin receptor SORL1; this interaction strongly increases its surface exposure, hence strengthens insulin signal reception (By similarity).
Interacts (tyrosine phosphorylated) with CCDC88A/GIV (via SH2-like region); binding requires autophosphorylation of the Insr C-terminal region (PubMed:25187647).
Interacts with GNAI3; the interaction is probably mediated by CCDC88A/GIV (PubMed:25187647).
Interacts with LMBRD1 (By similarity).
Interacts (in response to insulin stimulation) with NCK1; this interaction may recruit PTPN1 to mediate INSR dephosphorylation (By similarity).
Interacts with CD248; this interaction diminishes INSR autophosphorylation (By similarity).

Binary interactions

TypeEntry 1Entry 2Number of experimentsIntact
BINARY P15127Jak2 Q626892EBI-7472166, EBI-8656708
BINARY PRO_0000016698Atic O355673EBI-10768746, EBI-10768817

Protein-protein interaction databases

Chemistry

Family & Domains

Features

Showing features for domain, region, compositional bias.

TypeIDPosition(s)Description
Domain625-727Fibronectin type-III 1
Region687-709Disordered
Region734-742Insulin-binding
Region747-783Disordered
Domain754-848Fibronectin type-III 2
Compositional bias768-783Polar residues
Domain854-948Fibronectin type-III 3
Region997-1000Important for interaction with IRS1, SHC1 and STAT5B
Domain1024-1299Protein kinase
Region1361-1383Disordered
Region1362-1365PIK3R1 binding

Domain

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 (By similarity).

Sequence similarities

Keywords

Phylogenomic databases

Family and domain databases

Sequence & Isoform

Align isoforms (2)
  • Sequence status
    Complete
  • Sequence processing
    The displayed sequence is further processed into a mature form.

This entry describes 2 isoforms produced by Alternative splicing.

P15127-1

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.

  • Name
    Long
  • Synonyms
    RIR-B
  • See also
    sequence in UniParc or sequence clusters in UniRef
  • Length
    1,383
  • Mass (Da)
    156,757
  • Last updated
    1990-04-01 v1
  • Checksum
    4B919566902A944A
MGSGRGCETTAVPLLMAVAVAGGTAGHLYPGEVCPGMDIRNNLTRLHELENCSVIEGHLQILLMFKTRPEDFRDLSFPKLIMITDYLLLFRVYGLESLKDLFPNLTVIRGSRLFFNYALVIFEMVHLKELGLYNLMNITRGSVRIEKNNELCYLATIDWSRILDYVEDNYIVLNKDDNEECGDVCPGTAKGKTNCPATVINGQFVERCWTHSHCQKVCPTICKSHGCTAEGLCCHKECLGNCSEPDDPTKCVACRNFYLDGQCVETCPPPYYHFQDWRCVNFSFCQDLHYKCRNSRKPGCHQYVIHNNKCIPECPSGYTMNSSNLMCTPCLGPCPKVCQILEGEKTIDSVTSAQELRGCTVINGSLIINIRGGNNLAAELEANLGLIEEISGFLKIRRSYALVSLSFFRKLHLIRGETLEIGNYSFYALDNQNLRQLWDWNKHNLTITQGKLFFHYNPKLCLSEIHKMEEVSGTKGRQERNDIALKTNGDQASCENELLKFSFIRTSFDKILLRWEPYWPPDFRDLLGFMLFYKEAPYQNVTEFDGQDACGSNSWTVVDIDPPQRSNDPKSQTPSHPGWLMRGLKPWTQYAIFVKTLVTFSDERRTYGAKSDIIYVQTDATNPSVPLDPISVSNSSSQIILKWKPPSDPNGNITHYLVYWERQAEDSELFELDYCLKGLKLPSRTWSPPFESDDSQKHNQSEYDDSASECCSCPKTDSQILKELEESSFRKTFEDYLHNVVFVPRKTSSGNGAEDTRPSRKRRSLEEVGNVTATTPTLPDFPNISSTIAPTSHEEHRPFEKVVNKESLVISGLRHFTGYRIELQACNQDSPEERSGVAAYVSARTMPEAKADDIVGPVTHEIFENNVVHLMWQEPKEPNGLIVLYEVSYRRYGDEELHLCVSRKHFALERGCRLRGLSPGNYSVRVRATSLAGNGSWTEPTYFYVTDYLDVPSNIAKIIIGPLIFVFLFSVVIGSIYLFLRKRQPDGPMGPLYASSNPEYLSASDVFPSSVYVPDEWEVPREKITLLRELGQGSFGMVYEGNAKDIIKGEVETRVAVKTVNESASLRERIEFLNEASVMKGFTCHHVVRLLGVVSKGQPTLVVMELMAHGDLKSHLRSLRPDAENNPGRPPPTLQEMIQMTAEIADGMAYLNAKKFVHRDLAARNCMVAHDFTVKIGDFGMTRDIYETDYYRKGGKGLLPVRWMSPESLKDGVFTASSDMWSFGVVLWEITSLAEQPYQGLSNEQVLKFVMDGGYLDPPDNCPERLTDLMRMCWQFNPKMRPTFLEIVNLLKDDLHPSFPEVSFFYSEENKAPESEELEMEFEDMENVPLDRSSHCQREEAGCREGGSSLSIKRTYDEHIPYTHMNGGKKNGRVLTLPRSNPS

P15127-2

  • Name
    Short
  • Synonyms
    RIR-A
  • See also
    sequence in UniParc or sequence clusters in UniRef
  • Differences from canonical

Computationally mapped potential isoform sequences

There are 3 potential isoforms mapped to this entry

View all
EntryEntry nameGene nameLength
T2CB11T2CB11_RATInsr1384
A0A8J8Y5N6A0A8J8Y5N6_RATInsr1384
A0A8I5ZMZ8A0A8I5ZMZ8_RATInsr1372

Features

Showing features for alternative sequence, compositional bias.

TypeIDPosition(s)Description
Alternative sequenceVSP_036680746-757in isoform Short
Compositional bias768-783Polar residues

Keywords

Sequence databases

Nucleotide SequenceProtein SequenceMolecule TypeStatus
M29014
EMBL· GenBank· DDBJ
AAA41441.1
EMBL· GenBank· DDBJ
mRNA
AF005776
EMBL· GenBank· DDBJ
AAB61414.1
EMBL· GenBank· DDBJ
Genomic DNA
AF005777
EMBL· GenBank· DDBJ
AAB61415.1
EMBL· GenBank· DDBJ
Genomic DNA
AH004882
EMBL· GenBank· DDBJ
AAB38967.1
EMBL· GenBank· DDBJ
Genomic DNA
AH004883
EMBL· GenBank· DDBJ
AAB38968.1
EMBL· GenBank· DDBJ
Genomic DNA
U80633
EMBL· GenBank· DDBJ
AAB38746.1
EMBL· GenBank· DDBJ
Genomic DNA

Genome annotation databases

Similar Proteins

Disclaimer

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