DIRECT INTERACTION OF THE WISKOTT-ALDRICH SYNDROME PROTEIN WITH THE GTPASE CDC42

Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency disorde r with the most severe pathology in the T lymphocytes and platelets. T he disease arises from mutations in the gene encoding the WAS protein. T lymphocytes of affected males with WAS exhibit a severe disturbance of the actin cytoskeleton, suggesting that the WAS protein could regu late its organization. We show here that WAS protein interacts with a member of the Rho family of GTPases, Cdc42. This interaction, which is guanosine 5'-triphosphate (GTP)-dependent, was detected in cell lysat es, in transient transfections and with purified recombinant proteins. A weaker interaction was also detected with Rad using WAS protein fro m cell lysates. It was also found that different mutant WAS proteins f rom three affected males retained their ability to interact with Cdc42 and that the level of expression of the WAS protein in these mutants was only 2-5% of normal. Taken together these data suggest that the WA S protein might function as a signal transduction adaptor downstream o f Cdc42, and in affected males, the cytoskeletal abnormalities may res ult from a defect in Cdc42 signaling.