Differential regulation of signaling pathways for insulin and insulin-likegrowth factor I

The insulin receptor CIR) and the insulin-like growth factor receptor I (IG F-IR) have different functions in cell growth, apoptosis, differentiation, and transformation. Although some of these differences may be explained by the relative level of receptor expression and receptor structure (alpha and beta subunits), they may also be attributed to differences in intracellula r signals generated by insulin and IGF-I. The presence of hybrid receptors (IR alpha beta subunits and IGF-IR alpha beta subunits) making up the heter otetramers has added a new dimension to our understanding of the functional roles of these receptors. However, to date the results of efforts to under stand the differences between these two closely related receptors have indi cated mostly similarities. For example, both receptors utilize IRS-1/IRS-2 and Shc as immediate downstream adaptors, leading to activation of the Ras, Raf, ERK kinases and PI-3 kinase pathways. We have used the yeast two hybr id system to identify proteins which bind to the activated IGF-IR but not t o the IR. The cytoplasmic domain of the IGF-IR was used to screen a human f etal brain library and two isoforms of the 14-3-3 family were identified. 1 4-3-3 proteins are a highly conserved family of proteins which have recentl y been shown to interact with other components of the mitogenic and apoptot ic signaling pathways, including Raf, BAD, Bcr/Bcr-Abl, middle-T antigen, K sr, PKC, PI-3 ki-nase, ASK1 kinase, and cdc25C phosphatase. We also identif ied human Grb10, an adaptor protein with SH2 domain associated with the IGF -IR beta subunit. Smith's laboratory showed that Grb10 preferentially binds to the IR in intact cells. Using the interaction trap screen (active cytop lasmic domain of the IGF-IR) 55PIK and SOCS-2 proteins were also identified . However, 55PIK and SOCS-2 also interact with the IR in the yeast two hybr id system. These studies raise the possibility that 14-3-3 and Grb10 may pl ay a role in insulin and IGF-I signal transduction suid may underlie the ob served differences.