FUNCTIONAL ROLES OF THE SHC PHOSPHOTYROSINE BINDING AND SRC HOMOLOGY-2 DOMAINS IN INSULIN AND EPIDERMAL GROWTH-FACTOR SIGNALING

Shc is involved in the activation of Ras in response to many growth fa ctors. Shc contains two phosphotyrosine binding domains, an Src homolo gy 2 (SH2) domain in the carboxyl terminus of the protein and a phosph otyrosine binding (PTB) domain in the amino terminus. Since functional roles for these two domains have not been established, we microinject ed glutathione S-transferase fusion proteins of either the Shc PTB or SH2 domains into fibroblasts expressing insulin and epidermal growth f actor receptors and measured their effects on DNA synthesis. We found that the Shc PTB was necessary for insulin-induced mitogenic signaling , whereas the SH2 domain was not. In contrast, for epidermal growth fa ctor signaling, the Shc SH2 was functionally more important. These dif ferential modes of signal transduction may be an important factor in d etermining the specificity of the response of a cell to external stimu li.