Receptor tyrosine kinase activity, insulin

Chakravorty, A. Joslyn, M.L Davis, J.S. Characterization of insulin and insulin-like growth factor-I actions in the bovine luteal cell Regulation of receptor tyrosine kinase activity, phosphatidylinositol 3-kinase, and deoxyribonucleic acid synthesis. Endocrinology, 133, 1331-1340 (1993)... 

Wilden, P.A. Kahn, C.R. The level of insulin receptor tyrosine kinase activity modulates the activities of phosphatidylinositol 3-kinase, microtubule-associated protein, and S6 kinases. Mol. Endocrinol., 8, 558-567 (1994)... 

I Insulin binding activates I receptor tyrosine kinase activity in the intracellular domain of the 3 subunit of the insulin receptor. 

G. S. Hotamisligil, P. Peraldi, A. Budavari, R Ellis, M. F. White and B. M. Spic eiman. IRS-l-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science, 271 (5249), 665-668, 1996. 

In Xenopus o(x es (126,134), treatment with metformin has been shown to increase insulin receptor tyrosine kinase activity associated with activation of phospholipase C and increased levels of IPg and intracellular Ca. Thus metformin, through increasing receptor tyrosine kinase activity, may facilitate IRS protein phosphorylation and activation of phosphatidylinositol-3-kinase, leading to increased glucose uptake. 

Insulin exerts its effects by altering the state of phosphorylation of certain intracellular enzymes by a mechanism that does not involve cAMP but that requires specific binding to surface receptors with tyrosine kinase activity. Insulin exerts acute (minutes), delayed-onset (hours), and longterm (days) effects entirely by way of a single receptor. 

Insulin binding activates receptor tyrosine kinase activity and earn phorylation cascade that modulates various intracellular proteins. Fo insulin binding inhibits hormone-sensitive lipase in adipocytes. It appa so by activating a phosphatase that dephosphorylates the lipase. In adi... 

Davis CM and Vincent JB (1997a) Chromium oligopeptide activates insulin receptor tyrosine kinase activity. Biochemistry 36 4382 -4385. 

Taghon MS, Sadler SE. 1994. Insulin-like growth factor 1 receptor-mediated endocytosis in Xenopus laevis oocytes. A role for receptor tyrosine kinase activity. Dev Biol 163(l) 66-74. 

Nojiri H, Stroud MR, Hakomori S A specific type of ganglioside as a modulator of insulin-dependent cell growth and insulin receptor tyrosine kinase activity Possible association of ganglioside-induced inhibition of insulin receptor function and monocytic differentiation induction in HL60 cells. J. Biol. Chem. 1991 266 4531-4537. 

Insulin Receptor. Figure 1 Structure and function of the insulin receptor. Binding of insulin to the a-subunits (yellow) leads to activation of the intracellular tyrosine kinase ((3-subunit) by autophosphorylation. The insulin receptor substrates (IRS) bind via a phospho-tyrosine binding domain to phosphorylated tyrosine residues in the juxtamembrane domain of the (3-subunit. The receptor tyrosine kinase then phosphorylates specific tyrosine motifs (YMxM) within the IRS. These tyrosine phosphorylated motifs serve as docking sites for some adaptor proteins with SRC homology 2 (SH2) domains like the regulatory subunit of PI 3-kinase. 

Concanavalin A is a plant lectin from the jack bean (Canavalia ensiformis) which binds with high affinity to mannose residues of glycoproteins. Concanavalin A is known to stimulate the tyrosine kinase activity of the INSR (3-subunit with consecutive activation of kinases downstream the insulin receptor (IRS, PI 3-kinase). It is believed that Concanavalin A stimulates the activation and autophosphorylation of the INSR kinase through aggregation of the receptor, although the precise mechanism of action is unclear. 

Vanadate (sodium orthovanadate or peroxovanadate) exhibits insulin-like effects in vitro (activation of insulin receptor tyrosine kinase, PI 3-kinase, Akt) and in vivo (diabetic rats, humans). These effects can be explained at least in part by the inhibition of phosphotyrosine phosphatases which deactivate the INSR tyrosine kinase. 

Figure 3. MAP kinase regulatory pathway. The MAP kinase signaling pathway begins with activation of the receptor tyrosine kinase (RTK) by exogenous signals, such as growth factors and insulin. The signal is then transmitted into the cell via activation of the Raf serine/threonine kinase either directly by the RTK or through the GTP-binding protein, Ras. The signal is then transmitted to the nucleus and to other cytoplasmic proteins via MAPKK and MAPK.

Hubbard, S. R., Crystal structure of the activated insulin receptor tyrosine kinase in complex with peptide substrate and ATP analog, EMBO J., 16, 5572-5581, 1997. 

The cytoplasmic domain of the P-subunit displays three distinct sub-domains (a) the juxtam-embrane domain , implicated in recognition/binding of intracellular substrate molecules (b) the tyrosine kinase domain, which (upon receptor activation) displays tyrosine kinase activity (c) the C-terminal domain, whose exact function is less clear, although site-directed mutagenesis studies implicate it promoting insulin s mitogenic effects. 

Figure 11.2 Structure of the insulin receptor (a). Binding of insulin promotes autophosphorylation of the (3-subunits, where each (3-subunit phosphorylates the other (3-subunit. Phosphate groups are attached to three specific tyrosine residues (tyrosines 1158, 1162 and 1163), as indicated in (b). Activation of the (3-subunit s tyrosine kinase activity in turn results in the phosphorylation of various intracellular (protein) substrates which trigger the mitogen-activated protein kinase and/or the phosphoinositide (PI-3) kinase pathway responsible for inducing insulin s mitogenic and metabolic effects. The underlying molecular events occurring in these pathways are complex (e.g. refer to Combettes-Souverain, M. and Issad, T. 1998. Molecular basis of insulin action. Diabetes and Metabolism, 24, 477-489)...

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