The 70 kDa S6 kinase complexes with and is activated by the Rho family G proteins Cdc42 and Rac1

The 70 kDa ribosomal S6 kinase (pp70(S6k)) plays an important role in the progression of cells through G1 phase of the cell cycle. However, little is known of the signaling molecules that mediate its activation. We demonstrate that Rho family G proteins regulate pp70(S6k) activity in vivo. Activated alleles of Cdc42 and Rac1, but not RhoA, stimulate pp70(S6k) activity in multiple cell types. Activation requires an intact effector domain and isoprenylation of Cdc42 and Rac1. Coexpression of Dbl, an exchange factor for Cdc42, also activates pp70(S6k). Growth factor-induced activation of pp70(S6k) is abrogated by dominant negative alleles of Cdc42 and Rad. In addition, Cdc42 and Rad form a GTP-dependent complex with the catalytically inactive form of pp70(S6k) in vitro and in vivo, suggesting a mechanism by which these G proteins activate pp70(S6k).