Regulation of insulin receptor function

Abstract

Resistance to the biological actions of insulin contributes to the development of type 2 diabetes and risk of cardiovascular disease. A reduced biological response to insulin by tissues results from an impairment in the cascade of phosphorylation events within cells that regulate the activity of enzymes comprising the insulin signaling pathway. In most models of insulin resistance, there is evidence that this decrement in insulin signaling begins with either the activation or substrate kinase activity of the insulin receptor (IR), which is the only component of the pathway that is unique to insulin action. Activation of the IR can be impaired by post-translational modifications of the protein involving serine phosphorylation, or by binding to inhibiting proteins such as PC-1 or members of the SOCS or Grb protein families. The impact of these processes on the conformational changes and phosphorylation events required for full signaling activity, as well as the role of these mechanisms in human disease, is reviewed in this article.

TANK-binding kinase 1 mediates phosphorylation of insulin receptor at serine residue 994: a potential link between inflammation and insulin resistance

“…In particular, the phosphorylation of three tyrosine (Tyr) residues (1158, 1162, and 1163) in the kinase domain results in maximum tyrosine kinase activity and enable the subsequent phosphorylation of several endogenous proteins including the IR substrates family of proteins (IRS-1 to -4; White & Kahn 1994, Youngren 2007. Phosphorylation of the IR at Tyr972 serves as a binding site for the phosphotyrosine-binding domains of IRS-1 facilitating the subsequent phosphorylation of this substrate on numerous Tyr sites.…”

“…Phosphorylation of the IR at Tyr972 serves as a binding site for the phosphotyrosine-binding domains of IRS-1 facilitating the subsequent phosphorylation of this substrate on numerous Tyr sites. These events are essential for further signal transduction and consequently for insulin action (Youngren 2007). In addition to Tyr, the IR undergoes serine (Ser) and threonine (Thr) phosphorylation, which is detected both in the basal state and in response to stimulation of cells by phorbol esters (Bollag et al 1986, Takayama et al 1988, cAMP analogues (Stadtmauer & Rosen 1986), and insulin itself (Kasuga et al 1982, Häring et al 1984, Pillay et al 1991.…”

“…Ser/Thr phosphorylation of the IR may also participate in the regulation of insulin signaling and action in vivo. In fact, impaired activation of IR associated with excessive Ser/Thr phosphorylation has been reported in animal models of insulin resistance as well as in certain types of insulin-resistant states in humans (Li et al 2002, Johnston et al 2003, Taniguchi et al 2006, Youngren 2007. IR Ser994 is one of the potential inhibitory sites of the IR kinase as determined by site-directed mutagenesis (Strack et al 1997(Strack et al , 2000.…”

Insulin-Like Growth Factor 1 Receptor and p38 Mitogen-Activated Protein Kinase Signals Inversely Regulate Signal Transducer and Activator of Transcription 3 Activity to Control Human Dental Pulp Stem Cell Quiescence, Propagation, and Differentiation

“…The observed nuclear localization of p38 MAPK represents the active form of this kinase [52,53] and suggests that p38 MAPK is constitutively active in DPCs and, as such, may contribute to their quiescence. IGF-1R expression by the mitotically quiescent cells suggests that in addition to its known function in controlling the cell cycle, cell survival, motility, and attachment [54], IGF-1R may also function to maintain odontoblasts quiescence and preserve their undifferentiated phenotype.…”

Insulin resistance induced by antiretroviral drugs: Current understanding of molecular mechanisms

“…15 In the post-prandial phase, in response to glucose, the pancreas releases insulin into the bloodstream. Insulin then binds to its receptor.…”