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UniProtKB - P06213 (INSR_HUMAN)

Entry version 256 (13 Feb 2019)
Sequence version 4 (05 Oct 2010)
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Protein

Insulin receptor

Gene

INSR

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score:

Annotation score:5 out of 5

<p>The annotation score provides a heuristic measure of the annotation content of a UniProtKB entry or proteome. This score <strong>cannot</strong> be used as a measure of the accuracy of the annotation as we cannot define the ‘correct annotation’ for any given protein.<p><a href='/help/annotation_score' target='_top'>More...</a></p>-Experimental evidence at protein leveli <p>This indicates the type of evidence that supports the existence of the protein. Note that the ‘protein existence’ evidence does not give information on the accuracy or correctness of the sequence(s) displayed.<p><a href='/help/protein_existence' target='_top'>More...</a></p>

<p>This section provides any useful information about the protein, mostly biological knowledge.<p><a href='/help/function_section' target='_top'>More...</a></p>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 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). 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

<p>This subsection of the <a href="http://www.uniprot.org/help/function_section">Function</a> section describes the catalytic activity of an enzyme, i.e. a chemical reaction that the enzyme catalyzes.<p><a href='/help/catalytic_activity' target='_top'>More...</a></p>Catalytic activityi

<p>This subsection of the ‘Function’ section describes regulatory mechanisms for enzymes, transporters or microbial transcription factors, and reports the components which regulate (by activation or inhibition) the reaction.<p><a href='/help/activity_regulation' target='_top'>More...</a></p>Activity 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)DescriptionActionsGraphical viewLength
<p>This subsection describes interesting single amino acid sites on the sequence that are not defined in any other subsection. This subsection can be displayed in different sections (‘Function’, ‘PTM / Processing’, ‘Pathology and Biotech’) according to its content.<p><a href='/help/site' target='_top'>More...</a></p>Sitei66Insulin-bindingCurated1
<p>This subsection of the ‘Function’ section describes the interaction between a single amino acid and another chemical entity. Priority is given to the annotation of physiological ligands.<p><a href='/help/binding' target='_top'>More...</a></p>Binding sitei1033ATPPROSITE-ProRule annotation1 Publication1
Binding sitei1057ATPPROSITE-ProRule annotation1 Publication1
<p>This subsection of the ‘Function’ section is used for enzymes and indicates the residues directly involved in catalysis.<p><a href='/help/act_site' target='_top'>More...</a></p>Active sitei1159Proton donor/acceptor1 Publication1
Binding sitei1177ATPPROSITE-ProRule annotation1 Publication1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection of the ‘Function’ section describes a region in the protein which binds nucleotide phosphates. It always involves more than one amino acid and includes all residues involved in nucleotide-binding.<p><a href='/help/np_bind' target='_top'>More...</a></p>Nucleotide bindingi1104 – 1110ATPPROSITE-ProRule annotation1 Publication7
Nucleotide bindingi1163 – 1164ATPPROSITE-ProRule annotation1 Publication2

<p>The <a href="http://www.geneontology.org/">Gene Ontology (GO)</a> project provides a set of hierarchical controlled vocabulary split into 3 categories:<p><a href='/help/gene_ontology' target='_top'>More...</a></p>GO - Molecular functioni

View the complete GO annotation on QuickGO ...

GO - Biological processi

View the complete GO annotation on QuickGO ...

<p>UniProtKB Keywords constitute a <a href="http://www.uniprot.org/keywords">controlled vocabulary</a> with a hierarchical structure. Keywords summarise the content of a UniProtKB entry and facilitate the search for proteins of interest.<p><a href='/help/keywords' target='_top'>More...</a></p>Keywordsi

Molecular functionKinase, Receptor, Transferase, Tyrosine-protein kinase
Biological processCarbohydrate metabolism
LigandATP-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDA Comprehensive Enzyme Information System

More...BRENDAi		2.7.10.1 2681

Reactome - a knowledgebase of biological pathways and processes

More...Reactomei		R-HSA-6811558 PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
R-HSA-74713 IRS activation
R-HSA-74749 Signal attenuation
R-HSA-74751 Insulin receptor signalling cascade
R-HSA-74752 Signaling by Insulin receptor
R-HSA-77387 Insulin receptor recycling

SABIO-RK: Biochemical Reaction Kinetics Database

More...SABIO-RKi		P06213

SignaLink: a signaling pathway resource with multi-layered regulatory networks

More...SignaLinki		P06213

SIGNOR Signaling Network Open Resource

More...SIGNORi		P06213

<p>This section provides information about the protein and gene name(s) and synonym(s) and about the organism that is the source of the protein sequence.<p><a href='/help/names_and_taxonomy_section' target='_top'>More...</a></p>Names & Taxonomyi

<p>This subsection of the <a href="http://www.uniprot.org/help/names_and_taxonomy_section">Names and taxonomy</a> section provides an exhaustive list of all names of the protein, from commonly used to obsolete, to allow unambiguous identification of a protein.<p><a href='/help/protein_names' target='_top'>More...</a></p>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:
Insulin receptor subunit alpha
Insulin receptor subunit beta
<p>This subsection of the <a href="http://www.uniprot.org/help/names_and_taxonomy_section">Names and taxonomy</a> section indicates the name(s) of the gene(s) that code for the protein sequence(s) described in the entry. Four distinct tokens exist: ‘Name’, ‘Synonyms’, ‘Ordered locus names’ and ‘ORF names’.<p><a href='/help/gene_name' target='_top'>More...</a></p>Gene namesi
Name:INSR
<p>This subsection of the <a href="http://www.uniprot.org/help/names_and_taxonomy_section">Names and taxonomy</a> section provides information on the name(s) of the organism that is the source of the protein sequence.<p><a href='/help/organism-name' target='_top'>More...</a></p>OrganismiHomo sapiens (Human)
<p>This subsection of the <a href="http://www.uniprot.org/help/names_and_taxonomy_section">Names and taxonomy</a> section shows the unique identifier assigned by the NCBI to the source organism of the protein. This is known as the ‘taxonomic identifier’ or ‘taxid’.<p><a href='/help/taxonomic_identifier' target='_top'>More...</a></p>Taxonomic identifieri9606 [NCBI]
<p>This subsection of the <a href="http://www.uniprot.org/help/names_and_taxonomy_section">Names and taxonomy</a> section contains the taxonomic hierarchical classification lineage of the source organism. It lists the nodes as they appear top-down in the taxonomic tree, with the more general grouping listed first.<p><a href='/help/taxonomic_lineage' target='_top'>More...</a></p>Taxonomic lineageiEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo
<p>This subsection of the <a href="http://www.uniprot.org/help/names_and_taxonomy_section">Names and taxonomy</a> section is present for entries that are part of a <a href="http://www.uniprot.org/proteomes">proteome</a>, i.e. of a set of proteins thought to be expressed by organisms whose genomes have been completely sequenced.<p><a href='/help/proteomes_manual' target='_top'>More...</a></p>Proteomesi
  • UP000005640 <p>A UniProt <a href="http://www.uniprot.org/manual/proteomes_manual">proteome</a> can consist of several components. <br></br>The component name refers to the genomic component encoding a set of proteins.<p><a href='/help/proteome_component' target='_top'>More...</a></p> Componenti: Chromosome 19

Organism-specific databases

Eukaryotic Pathogen Database Resources

More...EuPathDBi		HostDB:ENSG00000171105.13

Human Gene Nomenclature Database

More...HGNCi		HGNC:6091 INSR

Online Mendelian Inheritance in Man (OMIM)

More...MIMi		147670 gene

neXtProt; the human protein knowledge platform

More...neXtProti		NX_P06213

<p>This section provides information on the location and the topology of the mature protein in the cell.<p><a href='/help/subcellular_location_section' target='_top'>More...</a></p>Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte & Seán O’Donoghue; Source: COMPARTMENTS

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection of the <a href="http://www.uniprot.org/help/subcellular_location_section">'Subcellular location'</a> section describes the subcellular compartment where each non-membrane region of a membrane-spanning protein is found.<p><a href='/help/topo_dom' target='_top'>More...</a></p>Topological domaini28 – 758ExtracellularCuratedAdd BLAST731
Topological domaini763 – 956ExtracellularCuratedAdd BLAST194
<p>This subsection of the <a href="http://www.uniprot.org/help/subcellular_location_section">'Subcellular location'</a> section describes the extent of a membrane-spanning region of the protein. It denotes the presence of both alpha-helical transmembrane regions and the membrane spanning regions of beta-barrel transmembrane proteins.<p><a href='/help/transmem' target='_top'>More...</a></p>Transmembranei957 – 979HelicalSequence analysisAdd BLAST23
Topological domaini980 – 1382CytoplasmicCuratedAdd BLAST403

Keywords - Cellular componenti

Cell membrane, Membrane

<p>This section provides information on the disease(s) and phenotype(s) associated with a protein.<p><a href='/help/pathology_and_biotech_section' target='_top'>More...</a></p>Pathology & Biotechi

<p>This subsection of the ‘Pathology and Biotech’ section provides information on the disease(s) associated with genetic variations in a given protein. The information is extracted from the scientific literature and diseases that are also described in the <a href="http://www.ncbi.nlm.nih.gov/sites/entrez?db=omim">OMIM</a> database are represented with a <a href="http://www.uniprot.org/diseases">controlled vocabulary</a> in the following way:<p><a href='/help/involvement_in_disease' target='_top'>More...</a></p>Involvement in diseasei

Rabson-Mendenhall syndrome (RMS)7 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionSevere 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.
See also OMIM:262190
Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection of the ‘Sequence’ section describes natural variant(s) of the protein sequence.<p><a href='/help/variant' target='_top'>More...</a></p>Natural variantiVAR_00407942N → K in RMS; impairs transport to the plasma membrane and reduces the affinity to bind insulin. 2 PublicationsCorresponds to variant dbSNP:rs121913143EnsemblClinVar.1
Natural variantiVAR_004084236H → R in RMS and LEPRCH; Winnipeg; may impair receptor processing. 2 PublicationsCorresponds to variant dbSNP:rs121913145EnsemblClinVar.1
Natural variantiVAR_079536256R → C in RMS. 1 PublicationCorresponds to variant dbSNP:rs781007453EnsemblClinVar.1
Natural variantiVAR_015914350S → L in RMS and LEPRCH. 2 Publications1
Natural variantiVAR_031520386G → S in RMS; may impair receptor processing. 1 PublicationCorresponds to variant dbSNP:rs764221583Ensembl.1
Natural variantiVAR_079539635S → L in RMS; decreases post-translational processing. 1 Publication1
Natural variantiVAR_079543835S → I in RMS; impairs post-translational processing. 1 PublicationCorresponds to variant dbSNP:rs1135401739EnsemblClinVar.1
Natural variantiVAR_079544842A → V in RMS; decreases post-translational processing. 1 PublicationCorresponds to variant dbSNP:rs1135401738EnsemblClinVar.1
Natural variantiVAR_079545874P → L in RMS; impairs post-translational processing. 1 Publication1
Natural variantiVAR_079546878N → S in RMS; impairs post-translational processing. 1 PublicationCorresponds to variant dbSNP:rs887190835Ensembl.1
Natural variantiVAR_015921997P → T in RMS; reduces insulin binding. 1 Publication1
Natural variantiVAR_079548999 – 1382Missing in RMS. 1 PublicationAdd BLAST384
Natural variantiVAR_0159261143I → T in RMS; reduces insulin binding. 2 Publications1
Natural variantiVAR_0159281158R → W in RMS; abolishes insulin binding. 2 PublicationsCorresponds to variant dbSNP:rs111993466Ensembl.1
Natural variantiVAR_0159301201R → W in LEPRCH and RMS; reduces insulin binding possibly due to reduced receptor levels on the cell surface. 2 Publications1
Leprechaunism (LEPRCH)20 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionRepresents the most severe form of insulin resistance syndrome, characterized by intrauterine and postnatal growth retardation and death in early infancy. Inheritance is autosomal recessive.
See also OMIM:246200
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_00408055V → A in LEPRCH; Verona-1. 1 PublicationCorresponds to variant dbSNP:rs121913152EnsemblClinVar.1
Natural variantiVAR_07953556I → T in LEPRCH; abolishes post-translational processing. 1 Publication1
Natural variantiVAR_00408158G → R in LEPRCH; Helmond; inhibits processing and transport. 1 PublicationCorresponds to variant dbSNP:rs52836744EnsemblClinVar.1
Natural variantiVAR_004082113R → P in LEPRCH; Atlanta-1; abolishes insulin binding. 2 PublicationsCorresponds to variant dbSNP:rs121913153EnsemblClinVar.1
Natural variantiVAR_015909119A → V in LEPRCH; markedly impairs insulin binding. 1 PublicationCorresponds to variant dbSNP:rs1347473020Ensembl.1
Natural variantiVAR_031518120L → Q in LEPRCH; inhibits receptor processing. 1 Publication1
Natural variantiVAR_015539146I → M in LEPRCH; mild. 2 PublicationsCorresponds to variant dbSNP:rs121913159EnsemblClinVar.1
Natural variantiVAR_004084236H → R in RMS and LEPRCH; Winnipeg; may impair receptor processing. 2 PublicationsCorresponds to variant dbSNP:rs121913145EnsemblClinVar.1
Natural variantiVAR_004085260L → P in LEPRCH; Geldeimalsen. 1 PublicationCorresponds to variant dbSNP:rs121913141EnsemblClinVar.1
Natural variantiVAR_079537286C → Y in LEPRCH; abolishes post-translational processing. 1 Publication1
Natural variantiVAR_015912301C → Y in LEPRCH. 1 Publication1
Natural variantiVAR_015913308Missing in LEPRCH; abolishes insulin binding. 3 Publications1
Natural variantiVAR_015914350S → L in RMS and LEPRCH. 2 Publications1
Natural variantiVAR_015541362Missing in LEPRCH. 1 Publication1
Natural variantiVAR_004086393G → R in LEPRCH; Verona-1. 1 PublicationCorresponds to variant dbSNP:rs267607184EnsemblClinVar.1
Natural variantiVAR_015542439W → S in LEPRCH; impairs transport of the receptor to the cell surface. 1 PublicationCorresponds to variant dbSNP:rs121913158EnsemblClinVar.1
Natural variantiVAR_031521458N → D in LEPRCH; partially inhibits receptor processing and autophosphorylation; strongly impairs ERK phosphorylation; induces wild-type levels of IRS-1 phosphorylation. 1 PublicationCorresponds to variant dbSNP:rs121913160EnsemblClinVar.1
Natural variantiVAR_004088487K → E in LEPRCH; ARK-1. 1 PublicationCorresponds to variant dbSNP:rs121913136EnsemblClinVar.1
Natural variantiVAR_079540657V → F in LEPRCH; impairs post-translational processing. 1 PublicationCorresponds to variant dbSNP:rs1135401737EnsemblClinVar.1
Natural variantiVAR_079541659W → R in LEPRCH; impairs post-translational processing. 1 Publication1
Natural variantiVAR_079542818Y → C in LEPRCH; abolishes post-translational processing. 2 Publications1
Natural variantiVAR_079547890 – 1382Missing in LEPRCH. 1 PublicationAdd BLAST493
Natural variantiVAR_015918925I → T in LEPRCH; abolishes post-translational processing; abolishes insulin binding. 2 Publications1
Natural variantiVAR_015919926R → W in LEPRCH; markedly impairs insulin binding;impairs post-translational processing. 2 PublicationsCorresponds to variant dbSNP:rs911929963Ensembl.1
Natural variantiVAR_015920937T → M in LEPRCH; impaired receptor processing; impairs post-translational processing. 2 Publications1
Natural variantiVAR_0159251119R → W in LEPRCH. 2 PublicationsCorresponds to variant dbSNP:rs1229730671Ensembl.1
Natural variantiVAR_0159301201R → W in LEPRCH and RMS; reduces insulin binding possibly due to reduced receptor levels on the cell surface. 2 Publications1
Natural variantiVAR_0159321206E → K in LEPRCH. 1 Publication1
Diabetes mellitus, non-insulin-dependent (NIDDM)3 Publications
The gene represented in this entry may be involved in disease pathogenesis.
Disease descriptionA 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.
See also OMIM:125853
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_015917858T → A in NIDDM. 1 PublicationCorresponds to variant dbSNP:rs182552223EnsemblClinVar.1
Natural variantiVAR_0159271158R → Q in NIDDM. 1 Publication1
Natural variantiVAR_0040981191R → Q in NIDDM. 1 PublicationCorresponds to variant dbSNP:rs121913150EnsemblClinVar.1
Familial hyperinsulinemic hypoglycemia 5 (HHF5)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionFamilial 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.
See also OMIM:609968
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_0159291201R → Q in HHF5 and IRAN type A; interferes with kinase activation by insulin. 3 PublicationsCorresponds to variant dbSNP:rs121913156EnsemblClinVar.1
Insulin-resistant diabetes mellitus with acanthosis nigricans type A (IRAN type A)17 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionCharacterized 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.
See also OMIM:610549
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_01590786D → G in IRAN type A. 1 Publication1
Natural variantiVAR_01590889L → P in IRAN type A. 1 Publication1
Natural variantiVAR_015910167V → L in IRAN type A. 1 PublicationCorresponds to variant dbSNP:rs938519025Ensembl.1
Natural variantiVAR_015540279R → C in IRAN type A; inhibits receptor internalization. 1 Publication1
Natural variantiVAR_031519279R → H in IRAN type A; interferes with receptor processing. 1 PublicationCorresponds to variant dbSNP:rs1329693158Ensembl.1
Natural variantiVAR_015911280C → Y in IRAN type A. 1 Publication1
Natural variantiVAR_004087409F → V in IRAN type A. 1 PublicationCorresponds to variant dbSNP:rs121913142EnsemblClinVar.1
Natural variantiVAR_079538489N → D in IRAN type A; unknown pathological significance. 1 PublicationCorresponds to variant dbSNP:rs1135401742EnsemblClinVar.1
Natural variantiVAR_004089489N → S in IRAN type A. 1 PublicationCorresponds to variant dbSNP:rs121913147EnsemblClinVar.1
Natural variantiVAR_004090762R → S in IRAN type A. 1 PublicationCorresponds to variant dbSNP:rs121913138EnsemblClinVar.1
Natural variantiVAR_0040921020R → Q in IRAN type A. 1 PublicationCorresponds to variant dbSNP:rs121913148EnsemblClinVar.1
Natural variantiVAR_0040931035G → V in IRAN type A. 1 PublicationCorresponds to variant dbSNP:rs121913135EnsemblClinVar.1
Natural variantiVAR_0795491054V → M in IRAN type A; unknown pathological significance. 1 PublicationCorresponds to variant dbSNP:rs1135401741EnsemblClinVar.1
Natural variantiVAR_0159231055A → V in IRAN type A. 1 Publication1
Natural variantiVAR_0040941075A → D in IRAN type A. 1 Publication1
Natural variantiVAR_0040951161A → T in IRAN type A. 1 PublicationCorresponds to variant dbSNP:rs121913139EnsemblClinVar.1
Natural variantiVAR_0040961162A → E in IRAN type A; impairs proteolytic processing. 1 PublicationCorresponds to variant dbSNP:rs121913154EnsemblClinVar.1
Natural variantiVAR_0159291201R → Q in HHF5 and IRAN type A; interferes with kinase activation by insulin. 3 PublicationsCorresponds to variant dbSNP:rs121913156EnsemblClinVar.1
Natural variantiVAR_0040991205P → L in IRAN type A; moderate. 2 PublicationsCorresponds to variant dbSNP:rs1295645322Ensembl.1
Natural variantiVAR_0159311206E → D in IRAN type A; accelerates degradation of the protein and impairs kinase activity. 1 Publication1
Natural variantiVAR_0041001220W → L in IRAN type A; accelerates degradation of the protein and impairs kinase activity. 2 PublicationsCorresponds to variant dbSNP:rs52800171Ensembl.1
Natural variantiVAR_0041011227W → S in IRAN type A. 1 PublicationCorresponds to variant dbSNP:rs121913140EnsemblClinVar.1
Natural variantiVAR_0159341378R → Q in IRAN type A. 1 PublicationCorresponds to variant dbSNP:rs52826008Ensembl.1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection of the <a href="http://www.uniprot.org/manual/pathology_and_biotech_section">'Pathology and Biotech'</a> section describes the effect of the experimental mutation of one or more amino acid(s) on the biological properties of the protein.<p><a href='/help/mutagen' target='_top'>More...</a></p>Mutagenesisi991L → A: Reduces interaction with IRS1 but has no effect on interaction with SHC1. 1 Publication1
Mutagenesisi992Y → A: Reduces interaction with IRS1 but has no effect on interaction with SHC1. 1 Publication1
Mutagenesisi996 – 997NP → AA: Abolishes interaction with IRS1. Severely disrupts, but does not abolish interaction with SHC1. 1 Publication2
Mutagenesisi996N → A: Abolishes interaction with IRS1 and significantly reduces interaction with SHC1. Has no effect on interaction with PIK3R1. 2 Publications1
Mutagenesisi997P → A: Abolishes interaction with IRS1 and significantly reduces interaction with SHC1. Has no effect on interaction with PIK3R1. 2 Publications1
Mutagenesisi998E → A: Does not affect interaction with IRS1, SHC1 or PIK3R1. 1 Publication1
Mutagenesisi999Y → E: Abolishes interaction with IRS1 and SHC1. 4 Publications1
Mutagenesisi999Y → 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 Publications1
Mutagenesisi1000L → A or R: Severely reduces interaction with SHC1. Has no effect on interaction with IRS1. 1 Publication1
Mutagenesisi1002A → D: Reduces interaction with IRS1 but has no effect on interaction with SHC1. 1 Publication1
Mutagenesisi1011Y → A: Increases kinase activity. 1 Publication1
Mutagenesisi1057K → A: Abolishes the kinase activity and abolishes interaction with IRS1, SHC1, GRB7 and PIK3R1. 3 Publications1
Mutagenesisi1057K → M or R: Abolishes the kinase activity. 3 Publications1
Mutagenesisi1159D → N: Loss of kinase activity. 1 Publication1
Mutagenesisi1163R → Q: Loss of kinase activity. 1 Publication1
Mutagenesisi1189Y → F: Reduced interaction with GRB7. 1 Publication1
Mutagenesisi1190Y → F: Strongly reduced interaction with GRB7. 1 Publication1

Keywords - Diseasei

Diabetes mellitus, Disease mutation

Organism-specific databases

DisGeNET

More...DisGeNETi		3643

GeneReviews a resource of expert-authored, peer-reviewed disease descriptions.

More...GeneReviewsi		INSR

MalaCards human disease database

More...MalaCardsi		INSR
MIMi125853 phenotype
246200 phenotype
262190 phenotype
609968 phenotype
610549 phenotype

Open Targets

More...OpenTargetsi		ENSG00000171105

Orphanet; a database dedicated to information on rare diseases and orphan drugs

More...Orphaneti		263458 Hyperinsulinism due to INSR deficiency
2297 Insulin-resistance syndrome type A
508 Leprechaunism
769 Rabson-Mendenhall syndrome

The Pharmacogenetics and Pharmacogenomics Knowledge Base

More...PharmGKBi		PA202

Chemistry databases

ChEMBL database of bioactive drug-like small molecules

More...ChEMBLi		CHEMBL1981

Drug and drug target database

More...DrugBanki		DB08513 [4-({5-(AMINOCARBONYL)-4-[(3-METHYLPHENYL)AMINO]PYRIMIDIN-2-YL}AMINO)PHENYL]ACETIC ACID
DB05120 AT1391
DB09129 Chromic chloride
DB01306 Insulin Aspart
DB09564 Insulin Degludec
DB01307 Insulin Detemir
DB00047 Insulin Glargine
DB01309 Insulin Glulisine
DB00030 Insulin Human
DB00046 Insulin Lispro
DB00071 Insulin Pork
DB01277 Mecasermin
DB05115 NN344

IUPHAR/BPS Guide to PHARMACOLOGY

More...GuidetoPHARMACOLOGYi		1800

Polymorphism and mutation databases

BioMuta curated single-nucleotide variation and disease association database

More...BioMutai		INSR

Domain mapping of disease mutations (DMDM)

More...DMDMi		308153655

<p>This section describes post-translational modifications (PTMs) and/or processing events.<p><a href='/help/ptm_processing_section' target='_top'>More...</a></p>PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection of the ‘PTM / Processing’ section denotes the presence of an N-terminal signal peptide.<p><a href='/help/signal' target='_top'>More...</a></p>Signal peptidei1 – 273 PublicationsAdd BLAST27
<p>This subsection of the ‘PTM / Processing’ section describes the extent of a polypeptide chain in the mature protein following processing.<p><a href='/help/chain' target='_top'>More...</a></p>ChainiPRO_000001668728 – 758Insulin receptor subunit alphaAdd BLAST731
ChainiPRO_0000016689763 – 1382Insulin receptor subunit betaAdd BLAST620

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection of the PTM / Processing":/help/ptm_processing_section section describes the positions of cysteine residues participating in disulfide bonds.<p><a href='/help/disulfid' target='_top'>More...</a></p>Disulfide bondi35 ↔ 53
<p>This subsection of the <a href="http://www.uniprot.org/help/ptm_processing_section">PTM / Processing</a> section specifies the position and type of each covalently attached glycan group (mono-, di-, or polysaccharide).<p><a href='/help/carbohyd' target='_top'>More...</a></p>Glycosylationi43N-linked (GlcNAc...) asparagine3 Publications1
Glycosylationi52N-linked (GlcNAc...) asparagine2 Publications1
Glycosylationi105N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi138N-linked (GlcNAc...) asparagine2 Publications1
Disulfide bondi153 ↔ 182
Disulfide bondi186 ↔ 209
Disulfide bondi196 ↔ 215
Disulfide bondi219 ↔ 228
Disulfide bondi223 ↔ 234
Disulfide bondi235 ↔ 243
Disulfide bondi239 ↔ 252
Glycosylationi242N-linked (GlcNAc...) asparagine3 Publications1
Disulfide bondi255 ↔ 264
Disulfide bondi268 ↔ 280
Glycosylationi282N-linked (GlcNAc...) asparagine2 Publications1
Disulfide bondi286 ↔ 311
Disulfide bondi293 ↔ 301
Disulfide bondi315 ↔ 328
Glycosylationi322N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi331 ↔ 335
Disulfide bondi339 ↔ 360
Glycosylationi364N-linked (GlcNAc...) asparagine1 Publication1
<p>This subsection of the ‘PTM / Processing’ section specifies the position and type of each modified residue excluding <a href="http://www.uniprot.org/manual/lipid">lipids</a>, <a href="http://www.uniprot.org/manual/carbohyd">glycans</a> and <a href="http://www.uniprot.org/manual/crosslnk">protein cross-links</a>.<p><a href='/help/mod_res' target='_top'>More...</a></p>Modified residuei400PhosphoserineCombined sources1
Modified residuei401PhosphotyrosineCombined sources1
Modified residuei407PhosphoserineCombined sources1
Glycosylationi424N-linked (GlcNAc...) asparagine1 Publication1
Glycosylationi445N-linked (GlcNAc...) asparagine2 Publications1
Disulfide bondi462 ↔ 4951 Publication
Glycosylationi541N-linked (GlcNAc...) asparagine2 Publications1
Disulfide bondi551Interchain1 Publication
Glycosylationi633N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi651N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi674 ↔ 899
Glycosylationi698N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi769N-linked (GlcNAc...) asparagine1 Publication1
Glycosylationi782N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi825 ↔ 834
Glycosylationi920N-linked (GlcNAc...) asparagine1 Publication1
Glycosylationi933N-linked (GlcNAc...) asparagineSequence analysis1
Modified residuei992Phosphotyrosine; by autocatalysisCurated1
Modified residuei999Phosphotyrosine; by autocatalysis1 Publication1
Modified residuei1011Phosphotyrosine; by autocatalysisCurated1
Modified residuei1185Phosphotyrosine; by autocatalysis7 Publications1
Modified residuei1189Phosphotyrosine; by autocatalysis7 Publications1
Modified residuei1190Phosphotyrosine; by autocatalysis7 Publications1
Modified residuei1355Phosphotyrosine; by autocatalysis1 Publication1
Modified residuei1361Phosphotyrosine; by autocatalysis1 Publication1

<p>This subsection of the <a href="http://www.uniprot.org/help/ptm_processing_section">PTM/processing</a> section describes post-translational modifications (PTMs). This subsection <strong>complements</strong> the information provided at the sequence level or describes modifications for which <strong>position-specific data is not yet available</strong>.<p><a href='/help/post-translational_modification' target='_top'>More...</a></p>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.9 Publications

Keywords - PTMi

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

Proteomic databases

Encyclopedia of Proteome Dynamics

More...EPDi		P06213

jPOST - Japan Proteome Standard Repository/Database

More...jPOSTi		P06213

MaxQB - The MaxQuant DataBase

More...MaxQBi		P06213

PaxDb, a database of protein abundance averages across all three domains of life

More...PaxDbi		P06213

PeptideAtlas

More...PeptideAtlasi		P06213

PRoteomics IDEntifications database

More...PRIDEi		P06213

ProteomicsDB human proteome resource

More...ProteomicsDBi		51872
51873 [P06213-2]

PTM databases

GlyConnect protein glycosylation platform

More...GlyConnecti		1402

iPTMnet integrated resource for PTMs in systems biology context

More...iPTMneti		P06213

Comprehensive resource for the study of protein post-translational modifications (PTMs) in human, mouse and rat.

More...PhosphoSitePlusi		P06213

<p>This section provides information on the expression of a gene at the mRNA or protein level in cells or in tissues of multicellular organisms.<p><a href='/help/expression_section' target='_top'>More...</a></p>Expressioni

<p>This subsection of the ‘Expression’ section provides information on the expression of a gene at the mRNA or protein level in cells or in tissues of multicellular organisms. By default, the information is derived from experiments at the mRNA level, unless specified ‘at protein level’. <br></br>Examples: <a href="http://www.uniprot.org/uniprot/P92958#expression">P92958</a>, <a href="http://www.uniprot.org/uniprot/Q8TDN4#expression">Q8TDN4</a>, <a href="http://www.uniprot.org/uniprot/O14734#expression">O14734</a><p><a href='/help/tissue_specificity' target='_top'>More...</a></p>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

Bgee dataBase for Gene Expression Evolution

More...Bgeei		ENSG00000171105 Expressed in 239 organ(s), highest expression level in oviduct epithelium

ExpressionAtlas, Differential and Baseline Expression

More...ExpressionAtlasi		P06213 baseline and differential

Genevisible search portal to normalized and curated expression data from Genevestigator

More...Genevisiblei		P06213 HS

Organism-specific databases

Human Protein Atlas

More...HPAi		HPA036302
HPA036303

<p>This section provides information on the quaternary structure of a protein and on interaction(s) with other proteins or protein complexes.<p><a href='/help/interaction_section' target='_top'>More...</a></p>Interactioni

<p>This subsection of the <a href="http://www.uniprot.org/help/interaction_section">'Interaction'</a> section provides information about the protein quaternary structure and interaction(s) with other proteins or protein complexes (with the exception of physiological receptor-ligand interactions which are annotated in the <a href="http://www.uniprot.org/help/function_section">'Function'</a> section).<p><a href='/help/subunit_structure' target='_top'>More...</a></p>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. 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 (By similarity). Interacts with the cone snail venom insulin Con-Ins G1 (PubMed:27617429).By similarity27 Publications

<p>This subsection of the '<a href="http://www.uniprot.org/help/interaction_section%27">Interaction</a> section provides information about binary protein-protein interactions. The data presented in this section are a quality-filtered subset of binary interactions automatically derived from the <a href="http://www.ebi.ac.uk/intact/">IntAct database</a>. It is updated on a monthly basis. Each binary interaction is displayed on a separate line.<p><a href='/help/binary_interactions' target='_top'>More...</a></p>Binary interactionsi

GO - Molecular functioni

View the complete GO annotation on QuickGO ...

Protein-protein interaction databases

The Biological General Repository for Interaction Datasets (BioGrid)

More...BioGridi		109854, 103 interactors

CORUM comprehensive resource of mammalian protein complexes

More...CORUMi		P06213

Database of interacting proteins

More...DIPi		DIP-480N

The Eukaryotic Linear Motif resource for Functional Sites in Proteins

More...ELMi		P06213

Protein interaction database and analysis system

More...IntActi		P06213, 59 interactors

Molecular INTeraction database

More...MINTi		P06213

STRING: functional protein association networks

More...STRINGi		9606.ENSP00000303830

Chemistry databases

BindingDB database of measured binding affinities

More...BindingDBi		P06213

<p>This section provides information on the tertiary and secondary structure of a protein.<p><a href='/help/structure_section' target='_top'>More...</a></p>Structurei

Secondary structure

11382
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details<