IRS Molecules Participate in GH Signaling

Cheryl Farley Combat Diabetes In 10 Days Or Less

Alternative Cure for Diabetes

Get Instant Access

Insulin receptor substrates-1 and -2 (IRS-1 and -2) are nontransmembrane proteins of 160-180 kDa that become tyrosine phosphorylated at multiple sites in response to insulin, IGF-1, IL-4, and several other cytokines. Upon tyrosine phosphorylation, these proteins function as adaptors, providing docking sites for associations with signaling molecules such as the p85 subunit of PI-3-kinase, the adaptor Grb2, and the SH2 domain tyrosine phosphatase SHP-2. The IRS-mediated, insulin-induced activation of PI-3-kinase is of potential importance for insulin-induced glucose transport (Fig. 6). Targeted disruption of IRS-1 in mice leads to growth retardation and mild insulin resistance; however, knockout of the gene encoding IRS-2 results in a phenotype quite similar to human type 2 diabetes mellitus, with peripheral insulin resistance and inadequate pancreatic P-cell growth and insulin production to overcome the resistance.

GH promotes tyrosine phosphorylation of IRS-1 and IRS-2 and their association with PI-3-kinase in abroad range of GH-responsive cell types, suggesting a possible mechanism to account for some of the insulinomimetic and insulin-antagonistic metabolic effects of GH. Further, GH-induced lipid synthesis and GH's inhibition of noradrenaline-induced lipoly-sis in rat adipocytes are blocked by the PI-3-kinase inhibitor wortmannin. It is uncertain whether the requirement for GHR tyrosine residues 333 and/or 338 (which are phosphorylated in GH-treated cells) for GH-induced lipogenesis and protein synthesis is related to the activation of IRS-1 and/or IRS-2. While IRS proteins may have a role in potentiating GH-induced metabolic effects (given their likely importance in insulin-induced metabolic signaling), studies employing PI-3-kinase inhibitors and a dominantnegative form of the PI-3-kinase p85 subunit suggest that PI-3-kinase may not be involved in GH-mediated glucose transport in 3T3-L1 adipocytes. Thus, the linkage of IRS-1 and -2 to this important metabolic effect of GH is brought into question.

Recently, however, IRS-1 has been implicated as important in augmenting GH-induced cell proliferation. In vitro affinity precipitation experiments indicate that amino-terminal regions of IRS-1, which include the pleckstrin homology (PH), phosphotyro-sine-binding (PTB), and Shc and /RS-1 NPXY binding ('SAIN') domains, specifically interact with JAK2, but that IRS-1 tyrosine phosphorylation and JAK2 tyrosine phosphorylation are not necessary for these interactions. This is particularly interesting in that the PTB and SAIN domains of IRS-1 are known to mediate the interaction of IRS-1 with the insulin receptor in a phosphotyrosine-dependent manner. Using IRS-1- and IRS-2-deficient 32D cells as a vehicle for reconstitution of IRS-1, it was further observed that cell proliferation and GH-induced activation of the MAP kinases ERK1 and ERK2 were both increased in cells transfected with IRS-1 in comparison to those lacking IRS-1. While the mechanism of IRS-1's enhancement of GH-induced ERK activation and the relationship of this activation to enhanced GH-induced proliferation are still unclear, these findings raise the possibility that IRS-1 may primarily modulate GH's proliferative effects, rather than its metabolic effects.

Was this article helpful?

0 0
Tips and Tricks For Boosting Your Metabolism

Tips and Tricks For Boosting Your Metabolism

So maybe instead of being a pencil-neck dweeb, youre a bit of a fatty. Well, thats no problem either. Because this bonus will show you exactly how to burn that fat off AS you put on muscle. By boosting your metabolism and working out the way you normally do, you will get rid of all that chub and gain the hard, rippled muscles youve been dreaming of.

Get My Free Ebook

Post a comment