RAS PROTEINS AND MITOGENIC SIGNALS TRANSDUCTION

Ras proteins are key elements in growth factors signal transduction, from receptor tyrosine kinases to the stimulation of immediate early genes transcription. The major players in this pathway have now been identified. The binding of epidermal growth factor to its receptor induces the dimerization and trans-phosphorylation of the receptor, providing a binding site for Grb2. Grb2 forms a complex with the Pas exchange factors Sos; thus, binding of Grb2 to the receptor at the plasma membrane recruits Sos in a position where it can promote GDP --> GTP exchange on Ras. GTP-bound Pas is then able to activate Raf, probably by recruting Raf at the plasma mem membrane where other kinases such as PKC or Src may contribute to the activation. Activation of Raf triggers a cascade of phosphorylations, leading to MAPkinases activation and phosphorylation of ternary complex factors such as Elk-1 or Sap-1, controlling c-fos transcription. However, the precise physiological role of GAP proteins, stimulating GTP hydrolysis on Ras, the way Ras proteins are specifically targeted to the plasma membrane, the function of Pas in non-dividing cells such as neurons, and the physiological specificities of the three different H-Ras, K-Ras and N-Ras proteins, are not yet understood.