The proteins Grb2-Sem-5, Shc and Sos have been implicated in the signalling pathway from tyrosine kinase receptors to Ras. Grb2-Sem-5 binds directly to murine Sos1, a Ras exchange factor, through two SH3 domains. Sos is also associated with ligand-activated tyrosine kinase receptors which bind Grb2-Sem-5, and with the Grb2-Sem-5 binding protein, Shc. Ectopic expression of Drosophila Sos stimulates morphological transformation of rodent fibroblasts. These data define a pathway by which tyrosine kinases act through Ras to control cell growth and differentiation.

ras‐related GTPases participate in signaling for a variety of cellular processes. The GTPases cycle between a GTP‐bound active state and a GDP‐bound inactive state. This cycling is partially controlled by guanine nucleotide dissociation stimulators (GDS, also known as exchange factors). We report on the molecular cloning of cDNAs encoding a new mammalian GDS protein, using sequences derived from the yeast ras GDS proteins as probes. The encoded protein stimulates the dissociation of guanine nucleotides from the ras‐related ralA and ralB GTPases at a rate at least 30‐fold faster than the intrinsic nucleotide dissociation rate. This new GDS, ralGDS, is at least 20‐fold more active on the ralA and ralB GTPases than on any other GTPase tested, including other members of the ras family (H‐ras, N‐ras, K‐ras, R‐ras, rap1a and rap2), members of the rho family (rhoA, rhoB and CDC42‐Hs) and members of the rab family (rab3a and ypt1). While the ralGDS protein is phosphorylated on serine residues, we find no evidence that phosphorylation affects the activity of insect cell‐expressed ralGDS towards the ralA or ralB GTPase. The 3600 nucleotide ralGDS mRNA and the 115 kDa protein were found in all tissues and cell lines examined.

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