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insulin receptor; IR; (INSR)

Function: - activated by insulin, IGF1 & IGF2 - has a tyrosine-protein kinase activity - mediates the metabolic functions of insulin - recruitment of GLUT-4 to the plasma membrane in adipocytes & skeletal muscle - binding to insulin stimulates association of the receptor with downstream mediators including IRS1 & phosphatidylinositol 3'-kinase (PI3K) - can activate PI3K either directly by binding to the p85 regulatory subunit, or indirectly via IRS1 - isoform short has a higher affinity for insulin - interacts with SORBS1 but dissociates from it following insulin stimulation - binds SH2B2 - interacts with the PID domains of IRS1 & SHC1 in vitro when autophosphorylated on Tyr - interacts with SH2 domains of 85 kD regulatory subunit of PI3K (PIK3R1) in vitro, when autophosphorylated on Tyr - interacts with SOCS7 - autophosphorylation activates the kinase activity - autophosphorylated on Tyr in response to insulin - phosphorylation of Tyr-999 is required for IRS1- & SHC1- binding Structure: - derived from single-chain precursor preproinsulin receptor - tetramer of 2 alpha & 2 beta chains linked by disulfide bonds - the alpha chains contribute to the formation of the ligand-binding domain - the beta chains carry the kinase domain - after being transported from the endoplasmic reticulum to the Golgi apparatus, the single glycosylated precursor is further glycosylated & then cleaved, followed by its transport to the plasma membrane - belongs to the protein kinase superfamily, Tyr protein kinase family, insulin receptor subfamily - contains 2 fibronectin F3 modules - contains 1 protein kinase domain - sequences surrounding the phosphorylated NPXY motif contribute differentially to either IRS1 or SHC1 recognition Compartment: membrane Alternative splicing: - named isoforms=2, long (HIR-B), short (HIR-A) Expression: - isoform long & isoform short are expressed in the peripheral nerve, kidney, liver, striated muscle, fibroblasts & skin - isoform short is expressed also in the spleen & lymphoblasts Pathology: - defects in INSR are the cause of a) insulin resistance b) Rabson-Mendenhall syndrome c) leprechaunism d) familial hyperinsulinemic hypoglycemia 5 e) insulin-resistant diabetes mellitus with acanthosis nigricans type A (IRAN type A) - defects in INSR may be associated with diabetes mellitus type 2

Interactions

molecular events

Related

insulin receptor gene

General

multisubunit protein tyrosine kinase receptor (RTK)

Properties

COMPARTMENT: cellular membrane STATE: active state MOTIF: ligand-binding site transmembrane domain Tyr phosphorylation site kinase domain MOTIF: ATP-binding site NAME: ATP-binding site SUBUNITS: insulin receptor alpha (2) MOTIF: ligand-binding site cysteine-rich region glycosylation site cysteine residue {C-TERMINAL} MODIFICATION: cysteine residue {N-TERMINAL} insulin receptor beta (2) STATE: active state MOTIF: glycosylation site cysteine residue {N-TERMINAL} MODIFICATION: cysteine residue {C-TERMINAL} transmembrane domain kinase domain MOTIF: ATP-binding site NAME: ATP-binding site binding site FOR-BINDING-OF: insulin receptor substrate 1 Tyr phosphorylation site GENE: insulin receptor gene

References

  1. Wikipedia: Insulin receptor http://en.wikipedia.org/wiki/Insulin_receptor

Component-of

molecular complex

Components

insulin receptor alpha (INSRA) insulin receptor beta (INSRA)