MEMBRANE TARGETING OF THE NUCLEOTIDE EXCHANGE FACTOR SOS IS SUFFICIENT FOR ACTIVATING THE RAS SIGNALING PATHWAY

Activation of growth factor receptors results in tyrosine autophosphor ylation and recruitment of SH2 domain-containing effecters, including Grb2. Grb2 recruitment mediates activation of the Ras nucleotide excha nger Sos by an unknown mechanism. To examine the role of membrane recr uitment, we prepared Sos derivatives containing either myristoylation or farnesylation signals. This resulted in plasma membrane targeting o f Sos and stimulation of the Ras signaling pathway, including ERK and AP-1 activities leading to oncogenic transformation. Sos derivatives w ith nonfunctional myristoylation or farnesylation sequences were inact ive. Farnesylation of Sos also activated pas signaling in yeast. In bo th mammalian cells and yeast, membrane-targeted Sos derivatives lackin g the C-terminal region were considerably more active. Therefore, targ eting of Sos to the plasma membrane in the vicinity of Ras appears to be the primary mechanism leading to activation of the Ras pathway. A s econdary mechanism could involve relief of the inhibitory effect of th e Sos C-terminal region.