Cdc42 and PAK-mediated Signaling Leads to Jun Kinase and p38 Mitogen-activated Protein Kinase Activation

TLDR

PAK family kinases are proposed targets of the Cdc42 and Rac GTPases, as suggested by in‑vitro studies. In vivo, Cdc42 activates PAK‑3, and together with constitutively active PAK‑3 they stimulate JNK1 and p38 MAPK, mimicking IL‑1 signaling; dominant‑negative Cdc42 blocks IL‑1–induced JNK1 activation, indicating that Cdc42/PAK mediate cytokine‑driven transcriptional regulation.

Abstract

The PAK family of protein kinases has been suggested as a potential target of the Cdc42 and Rac GTPases based on studies in vitro. We show that PAK-3 is activated by Cdc42 in vivo. Both, activated (GTPase-defective) Cdc42 and a constitutively active PAK-3 mutant stimulated the activity of Jun kinase 1 (JNK1) in transfected cells. Activated Cdc42 also stimulated the activity of the related p38 mitogen-activated protein kinase but was a less effective activator of ERK2. The effect of Cdc42 on JNK activity was similar to that of the potent inflammatory cytokine interleukin-1 (IL-1). The observation that a dominant-negative Cdc42 mutant inhibited IL-1 activation of JNK1 indicates a role for Cdc42 in IL-1 signaling. These results suggest that Cdc42 and PAK may mediate the effects of cytokines on transcriptional regulation.