REGULATION OF SOS ACTIVITY BY INTRAMOLECULAR INTERACTIONS

The guanine nucleotide exchange factor Sos mediates the coupling of re ceptor tyrosine kinases to Ras activation, To investigate the mechanis ms that control Sos activity, we have analyzed the contribution of var ious domains to its catalytic activity. Using human Sos1 (hSos1) trunc ation mutants, we show that Sos proteins lacking either the amino or t he carboxyl terminus domain, or both, display a guanine nucleotide exc hange activity that is significantly higher compared with that of the full-length protein, These results demonstrate that both the amino and the carboxyl terminus domains of Sos are involved in the negative reg ulation of its catalytic activity, Furthermore, in vitro Ras binding e xperiments suggest that the amino and carboxyl terminus domains exert negative allosteric control on the interaction of the Sos catalytic do main with Ras, The guanine nucleotide exchange activity of hSos1 was n ot augmented by growth factor stimulation, indicating that Sos activit y is constitutively maintained in a downregulated state, Deletion of b ath tile amino and the carboxyl terminus domains was sufficient to act ivate the transforming potential of Sos, These findings suggest a nove l negative regulatory role for the amino terminus domain of Sos and in dicate a cooperation between the amino and the carboxyl terminus domai ns in the regulation of Sos activity.