RAC REGULATION OF ACTIN POLYMERIZATION AND PROLIFERATION BY A PATHWAYDISTINCT FROM JUN KINASE

The RAC guanine nucleotide binding proteins regulate multiple biologic al activities, including actin polymerization, activation of the Jun k inase (JNK) cascade, and cell proliferation. RAC effector loop mutants were identified that separate the ability of RAC to interact with dif ferent downstream effecters. One mutant of activated human RAC protein , RAC(V12H40) (with valine and histidine substituted at position 12 an d 40, respectively), was defective in binding to PAK3, a Ste20-related p21-activated kinase (PAK), but bound to PORI, a RAG-binding protein. This mutant failed to stimulate PAK and JNK activity but still induce d membrane ruffling and mediated transformation. A second mutant, RAC( V12L37) (with leucine substituted at position 37), which bound PAK but not PORI, induced JNK activation but was defective in inducing membra ne ruffling and transformation, These results indicate that the effect s of RAC on the JNK cascade and on actin polymerization and cell proli feration are mediated by distinct effector pathways that diverge at th e level of RAC itself.