A Rac1/PAK1 cascade controls β-catenin activation in colon cancer cells

P21-activated kinase 1 (PAK1) is associated with colon cancer progression and metastasis, whereas the molecular mechanism remains elusive. Here, we show that downregulation of PAK1 in colon cancer cells reduces total β-catenin level, as well as cell proliferation. Mechanistically, PAK1 directly phosphorylates β-catenin proteins at Ser675 site and this leads to more stable and transcriptional active β-catenin. Corroborating these results, PAK1 is required for full Wnt signaling, and superactivation of β-catenin is achieved by simultaneous knockdown of adenomatous polyposis coli protein and activation of PAK1. Moreover, we show that Rac1 functions upstream of PAK1 in colon cancer cells and contributes to β-catenin phosphorylation and accumulation. We conclude that a Rac1/PAK1 cascade controls β-catenin S675 phosphorylation and full activation in colon cancer cells. Supporting this conclusion, overexpression of PAK1 is observed in 70% of colon cancer samples and is correlated with massive β-catenin accumulation.