DIFFERENTIAL INTERACTIONS OF HUMAN SOS1 AND SOS2 WITH GRB2

The guanine nucleotide exchange factor Son of sevenless (Sos) performs a crucial step in the coupling of receptor tyrosine kinases to Ras ac tivation, Mammalian cells contain two related but distinct Sos protein s, Sos1 and Sos2. Although they share a high degree of overall similar ity, it is not known to what extent their biological and biochemical p roperties overlap, In the present study, we have compared the interact ions of the two human homologues of Sos, hSos1 and hSos2, with the ada ptor protein Grb2. We show that hSos2 interacts with Grb2 via its prol ine-rich COOH-terminal domain and that this interaction is dependent o n the SH3 domains of Grb2. In general, these characteristics are simil ar to the ones reported previously for the interaction of hSos1 with G rb2. However, the apparent binding affinity of hSos2 for Grb2 is signi ficantly higher relative to that of hSos1 both in vitro and in vivo. T he region conferring this higher binding affinity has been mapped to r esidues 1126-1242 of the hSos2 COOH-terminal domain, These results sug gest that Sos1 and Sos2 may differentially contribute to receptor-medi ated Ras activation.