Characterization Of The Mechanism That Rac1/PAK1Regulates Canonical Wnt Signaling

Wnt/β-catenin signaling plays important roles in human colon tumorigenesis.Therefore, it is with great importance to understand the molecular process of coloncancer progression and to find potential targets of cancer therapy by identifying andcharacterizing new regulators of Wnt/β-catenin signaling.Here, our study focused on the oncogenic function and molecular mechanism ofPAK1, a family member of PAK (p21-activated kinase), in colon cancer. In this study,we provide strong evidence to show that PAK1is also involved in controllingproliferation of colon cancer cells. Down-regulation of PAK1by shRNA,over-expression of dominant negative PAK1or treatment of a specific inhibitor IPA-3inSW480cells all reduced total β-catenin level, as well as cell proliferation. Further studyindicated that PAK1could directly phosphorylate β-catenin protein at Ser675site andthis lead to more stable and transcriptional active β-catenin. What’s more, Rac1, a smallG protein, functioned upstream of PAK1and contributed to β-catenin phosphorylationand accumulation. Corroborating these results, superactivation of β-catenin wasachieved by simultaneous knockdown of APC and activation of PAK1. Supporting thisconclusion, overexpression of PAK1was observed in70%of colon cancer samples andwas correlated with massive-catenin accumulation. Thus, we conclude that aRac1/PAK1cascade controls-catenin S675phosphorylation and full activation incolon cancer cells. What’s more, PAK1could be activated by Wnt signaling and wasinvolved in regulating-catenin accumulation.Our study not only enhanced our understanding of Wnt/β-catenin signalingtransduction, but also uncovered the function and mechanism of PAK1in colon cancerprogression and provided a potential therapeutic target for clinical treatment.