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

Oncogene volume 31, pages 1001–1012 (2012)Cite this article

Abstract

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.

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Acknowledgements

We thank Drs Ye-Guang Chen, Jonathan Chernoff, Raymond Habas, Alan Hall, Tianhui Hu, Edward Leof, Chaojun Li, Randy Moon, Christof Niehrs, Roel Nusse and Thomas Rudel for reagents. This work was supported by grants to WW from the National Natural Science Foundation of China (No. 30730048, 30921004), the Major Science Programs of China (2006CB943402, 2011CB943803), Tsinghua University Initiative Scientific Research Program (2010THZ0) and Bayer Healthcare.

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  1. Protein Science Laboratory of the Ministry of Education, School of Life Sciences, Tsinghua University, Beijing, China

    G Zhu, Y Wang, B Huang, J Liang, Y Ding & W Wu

  2. Beijing Friendship Hospital, Beijing, China

    A Xu

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Correspondence to W Wu.

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Zhu, G., Wang, Y., Huang, B. et al. A Rac1/PAK1 cascade controls β-catenin activation in colon cancer cells. Oncogene 31, 1001–1012 (2012). https://doi.org/10.1038/onc.2011.294

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