ACTIONS OF RHO-FAMILY SMALL G-PROTEINS AND P21-ACTIVATED PROTEIN-KINASES ON MITOGEN-ACTIVATED PROTEIN-KINASE FAMILY MEMBERS

The mitogen-activated protein (MAP) kinases are a family of serine/thr eonine kinases that are regulated by distinct extracellular stimuli. T he currently known members include extracellular signal-regulated prot ein kinase 1 (ERK1), ERK2, the c-Jun N-terminal kinase/stress-activate d protein kinases (JNK/SAPKs), and p38 MAP kinases. We find that overe xpression of the Ste20-related enzymes p21-activated kinase 1 (PAK1) a nd PAK2 in 293 cells is sufficient to activate JNK/SAPK and to a lesse r extent p38 MAP kinase but not ERK2. Rat MAP/ERK kinase kinase 1 can stimulate the activity of each of these MAP kinases. Although neither activated Rac nor the PAKs stimulate ERK2 activity, overexpression of either dominant negative Rac2 or the N-terminal regulatory domain of P AI(1 inhibits Ras-mediated activation of ERK2, suggesting a permissive role for Rac in the control of the ERK pathway. Furthermore, constitu tively, active Rac2, Cdc42hs, and RhoA synergize with an activated for m of Raf to increase ERK2 activity. These findings reveal a previously unrecognized connection between Rho family small G proteins and the E RK pathway.