P21-activated kinase 1 (PAK1) is associated with colon cancer progression and metastasis, whereas the molecular mechanism remains elusive. Here, we show that down-regulation of PAK1 in colon cancer cells reduces total beta-catenin level, as well as cell proliferation. Mechanistically, PAK1 directly phosphorylates beta-catenin proteins at Ser675 site and this leads to more stable and transcriptional active beta-catenin. Corroborating these results, PAK1 is required for full Wnt signaling, and superactivation of beta-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 beta-catenin phosphorylation and accumulation. We conclude that a Rac1/PAK1 cascade controls beta-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 beta-catenin accumulation. Oncogene (2012) 31, 1001-1012; doi:10.1038/onc.2011.294; published online 8 August 2011