A Rac1-PAK1 cascade controls beta-catenin activation in colon cancer cells.pdf.pdf

ORIGINAL ARTICLE A Rac1/PAK1 cascade controls b-catenin activation in colon cancer cells G Zhu 1, Y Wang 1, B Huang 1, J Liang 1, Y Ding 1,AXu 2and W Wu 1 1Protein Science Laboratory of the Ministry of Education, School of Life Sciences, Tsinghua University, Beijing, China and 2Beijing Friendship Hospital, Beijing, China 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 b-catenin level, as well as cell proliferation. Mechanisti- cally, PAK1 directly phosphorylates b-catenin proteins at Ser675 site and this leads to more stable and transcrip- tional active b-catenin. Corroborating these results, PAK1 is required for full Wnt signaling, and superactivation of b-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 b -catenin phosphorylation and accumulation. We conclude that a Rac1/PAK1 cascade controls b-catenin S675 phosphory- lation 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 b-catenin accumulation. Oncogene (2012) 31, 1001–1012; doi:.294; published online 8 August 2011 Keywords: colon cancer; b-catenin; PAK1; Rac1; phosphorylation Introduction Wnt/ b-catenin signaling controls the fundamental cellu- lar processes, including proliferation, during tissue homeo- stasis and its aberrant activation is implicated with a wide range of human cancers (Polakis, 2000; Logan and Nusse, 2004; Moon et al. , 2004; Clevers, 2006; MacDonald et al. , 2009). b-catenin is the major cellular effector of the Wnt signaling and is normally captured by the plex made of axin, APC (adenoma- tous polyposis coli protein), glycogen synt