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.
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