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

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.

• Authors: G Zhu, Y Wang, B Huang, J Liang, Y Ding, A Xu, W Wu
• Journal: Oncogene (Oncogene) Vol. 31 Issue 8 Pg. 1001-12 (Feb 23 2012) ISSN: 1476-5594 [Electronic] England
• PMID: 21822311 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CCND1 protein, human
• RAC1 protein, human
• beta Catenin
• Cyclin D1
• PAK1 protein, human
• p21-Activated Kinases
• rac1 GTP-Binding Protein

Topics

• Animals
• Cell Proliferation
• Colonic Neoplasms (enzymology, metabolism)
• Cyclin D1 (metabolism)
• Enzyme Activation
• Gene Expression
• HCT116 Cells
• HEK293 Cells
• Humans
• Mice
• Phosphorylation
• Promoter Regions, Genetic
• Protein Binding
• Protein Stability
• Transcriptional Activation
• Wnt Signaling Pathway
• beta Catenin (genetics, metabolism)
• p21-Activated Kinases (genetics, metabolism)
• rac1 GTP-Binding Protein (genetics, metabolism)