Signaling, mitogenesis and the cytoskeleton: where the action is.

Stimulation of mitogenesis by the epidermal growth factor (EGF) operates through a pathway involving the receptor, the small G-protein Ras and protein kinases of the MAP kinase cascade. It is proposed that two of the critical steps of that pathway utilize localization of components to the plasma membrane where Ras is located: recruitment of the nucleotide exchange protein Sos to the phosphorylated EGF receptor via a complex with the SH2/SH3-containing protein Grb2 and recruitment of the protein kinase Raf to activated Ras. Moreover, it is then proposed that Raf associates with the cytoskeleton at the membrane as it is being activated. Other signaling elements, including class I receptor kinases, nonreceptor tyrosine kinases and tyrosine phosphatases, are known to function at specific cellular sites. These observations have led us to propose that localization of signaling components, and particularly sites at membrane-microfilament interfaces, play critical roles in cellular regulation.