RHO-FAMILY GTPASES REGULATE P38 MITOGEN-ACTIVATED PROTEIN-KINASE THROUGH THE DOWNSTREAM MEDIATOR PAK1

The stress-activated p38 mitogen-activated protein (MAP) kinase define s a subgroup of the mammalian MAP kinases that appear to play a key ro le in regulating inflammatory responses. Co-expression of constitutive ly active forms of Rac and Cdc42 leads to activation of p38 while domi nant negative Rac and Cdc42 inhibit the ability of interleukin-1 to in crease p38 activity. p21-activated kinase 1 (Pak1) is a potential medi ator of Rac/Cdc42 signaling, and we observe that Pak1 stimulates p38 a ctivity. A dominant negative Pak1 suppresses both interleukin-1- and R ac/Cdc42-induced p38 activity. Rac and Cdc42 appear to regulate a prot ein kinase cascade initiated at the level of Pak and leading to activa tion of p38 and JNK.