APC inhibits ERK pathway activation and cellular proliferation induce by RAS

Ki Sook Park, Soung Hoo Jeon, Sung Eun Kim, Young Yil Bahk, Sheri L. Holmer, Bart O. Williams, Kwang Chul Chung, Young Joon Surh, Kang Yell Choi

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Abstract

Inactivating mutations in the adenomatous polyposis coli gene (APC), and activating mutations in RAS, occur in a majority of colorectal carcinomas. However, the relationship between these changes and tumorigenesis is poorly understood. RAS-induced activation of the ERK pathway was reduced by overexpressing APC in DLD-1 colorectal cancer cells. ERK activity was increased by Cre-virus-induced Apc knockout in primary Apcflox/flox mouse embryonic fibroblasts, indicating that APC inhibits ERK activity. ERK activity was increased by overexpression and decreased by knock down of β-catenin. The activation of Raf1, MEK and ERK kinases by β-catenin was reduced by co-expression of APC. These results indicate that APC inhibits the ERK pathway by an action on β-catenin. RAS-induced activation of the ERK pathway was reduced by the dominant negative form of TCF4, indicating that the ERK pathway regulation by APC/β-catenin signaling is, at least, partly caused by effects on β-catenin /TCF4-mediated gene expression. The GTP loading and the protein level of mutated RAS were decreased in cells with reduced ERK activity as a result of APC overexpression, indicating that APC regulates RAS-induced ERK activation at least partly by reduction of the RAS protein level. APC regulates cellular proliferation and transformation induced by activation of both RAS and β-catenin signaling.

Original languageEnglish
Pages (from-to)819-827
Number of pages9
JournalJournal of cell science
Volume119
Issue number5
DOIs
Publication statusPublished - 2006 Mar 1

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All Science Journal Classification (ASJC) codes

  • Cell Biology

Cite this

Park, K. S., Jeon, S. H., Kim, S. E., Bahk, Y. Y., Holmer, S. L., Williams, B. O., Chung, K. C., Surh, Y. J., & Choi, K. Y. (2006). APC inhibits ERK pathway activation and cellular proliferation induce by RAS. Journal of cell science, 119(5), 819-827. https://doi.org/10.1242/jcs.02779