CELL ANCHORAGE PERMITS EFFICIENT SIGNAL-TRANSDUCTION BETWEEN RAS AND ITS DOWNSTREAM KINASES

Cell anchorage strongly affects the signal transduction cascade initia ted by peptide mitogens. For both epidermal growth factor and platelet -derived growth factor, activation of the consensus mitogen-activated protein kinase cascade is impaired when cells are held in suspension a s compared with cells anchored to a fibronectin substratum. Upstream e vents in the signaling cascade, including tyrosine phosphorylation of the mitogen receptor and GTP loading of Ras, are similar in anchored a nd suspended cells. However, propagation of the signal to Raf and subs equently to the downstream kinases MEK and mitogen-activated protein k inase is markedly attenuated in suspended cells. Thus, there seems to be a distinct anchorage-dependent step between Ras and Raf in the sign aling cascade initiated by peptide mitogens. These observations may ha ve important implications for understanding the anchorage dependence o f cell growth.