The Insulin Receptor: Both a Prototypical and Atypical Receptor Tyrosine Kinase

Abstract

Unlike prototypical receptor tyrosine kinases (RTKs), which are single-chain polypeptides, the insulin receptor (InsR) is a preformed, covalently linked tetramer with two extracellular a subunits and two membrane-spanning, tyrosine kinase-containing b subunits. A single molecule of insulin binds asymmetrically to the ectodomain, triggering a conformational change that is transmitted to the cytoplasmic kinase domains, which facilitates their trans-phosphorylation. As in prototypical RTKs, tyrosine phosphorylation in the juxtamembrane region of InsR creates recruitment sites for downstream signaling proteins (IRS [InsR substrate] proteins, Shc) containing a phosphotyrosine-binding (PTB) domain, and tyrosine phosphorylation in the kinase activation loop stimulates InsR's catalytic activity. For InsR, phosphorylation of the activation loop, which contains three tyrosine residues, also creates docking sites for adaptor proteins (Grb10/14, SH2B2) that possess specialized Src homology-2 (SH2) domains, which are dimeric and engage two phosphotyrosines in the activation loop.

The neuropilin-like protein ESDN regulates insulin signaling and sensitivity

“…As such, ESDN-IR interaction alters the balance of regulatory molecules that interact with IR through these adaptors. Grb10 binds to activated receptor and inhibits its catalytic activity (8,16), and as such its reduced association with the receptor could contribute to the effect of ESDN deficiency on insulin signaling. Yet, the loss of the stimulatory effect of ESDN gene deletion on IR signal transduction by APS siRNA points to APS as the key mediator of ESDN effect on insulin responses.…”

“…Of note, the ESDN effects appear to be cell and growth factor dependent, and distinct molecular mechanisms are implicated in its regulatory effects on VEGF, PDGF, EGF, and insulin signaling. These may be explained by variances in experimental settings or, more importantly, reflect interspecies differences or idiosyncratic differences in the structure and interacting partners of various RTKs (16).…”

“…IR belongs to the RTK family of surface receptors, but, unlike typical members of this family, at the basal (non-insulin-binding) state it is composed of two extracellular ␣-subunits and two transmembrane ␤-subunits linked by disulfide bonds (16,37). Upon binding to insulin, the receptor undergoes tyrosine phosphorylation (starting with Tyr 1146 in the mouse) and activation of the kinase domain.…”

Harnessing Structural Data of Insulin and Insulin Receptor for Therapeutic Designs

“…In the absence of insulin binding, the TM domains of IR form an obligate homodimer. The conformational switch induced by insulin binding [14], coupled with the obligate nature of the IR oligomerization [13], play critical roles in the trans-phosphorylation of the two tyrosine kinase domains of IR. This mechanism is different from the dimerization of many other receptor tyrosine kinases that can only occur upon ligand binding, in which the dimerization facilitates the trans-phosphorylation of one cytoplasmic by the other, and vice versa [30].…”

“…These constraints are released upon the binding of insulin. The binding of insulin to the alpha-subunits triggers a conformational change on the beta-subunits, autotrans-phosphorylation of the tyrosine kinase domains of IR, and a series of signaling events involving multiple phosphorylation and dephosphorylation [13].…”