MULTIPLE HEMOPOIETINS, WITH THE EXCEPTION OF INTERLEUKIN-4, INDUCE MODIFICATION OF SHC AND MSOS1, BUT NOT THEIR TRANSLOCATION

She, grb2, and Son-of-sevenless (mSos1) proteins are potential upstrea m regulators of p21(ras). We show that p52(She) and p46(She) comprise a significant portion of two of the major protein substrates phosphory lated on tyrosine in response to interleukin-2 (IL-2), IL-3, granulocy te-macrophage colony stimulating factor (GM-CSF), Steel factor (SLF), and colony stimulating factor-1 (CSF-1). Once tyrosine phosphorylated, p52(She) and p46(She) associated with grb2. However, in contrast to p ublished results with epidermal growth factor, treatment with GMCSF, I L-3, and SLF failed to induce significant biochemically detectable tra nslocation of She, grb2, or mSos1 from the cytosol to the plasma membr ane. In addition, we did not observe significant epidermal growth fact or-induced translocation of Sos1 to the membrane in Rat-1 cells. Treat ment with SLF or IL-3 did increase tyrosine phosphorylation of membran e-localized p52(She), which could then associate with grb2, although t he majority of tyrosine-phosphorylated She was located in the cytosol. SLF, IL-3, and phorbol ester induced a decrease in the electrophoreti c mobility of mSos1. This occurred with slower kinetics than p21(ras) activation and unlike hemopoietin-induced activation of p21(ras) was p artially inhibited by a specific protein kinase C inhibitor. Thus, gro wth factor-induced modification of mSos1 may represent a downstream ev ent, subsequent to p21(ras) activation. Significantly, IL-4, a cytokin e that fails to activate p21(ras), also failed to induce significant t yrosine phosphorylation of She or a shift in mSos1 mobility for the fi rst time correlating these events with the ability of a growth factor to activate p21(ras). Together, these data suggest that the current mo del for regulation of p21(ras), which proposes a stable association of She-grb2-Sos1 complexes at the plasma membrane, may be an oversimplif ication.