APC inhibits ERK pathway activation and cellular proliferation induced by RAS

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Published on: October 5, 2020

Ki-Sook Park1, Soung Hoo Jeon, Sung-Eun Kim

  • 1Division of Molecular and Cellular Biology, Department of Biotechnology, Yonsei University, Seoul 120-752, Korea.

Journal of Cell Science
|February 16, 2006
PubMed

Insights

Adenomatous polyposis coli (APC) inhibits the ERK pathway by regulating beta-catenin and RAS signaling. This finding clarifies the relationship between APC mutations and colorectal cancer development.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Cell Signaling

Background:

  • Colorectal carcinomas frequently harbor inactivating mutations in the adenomatous polyposis coli (APC) gene and activating mutations in RAS.
  • The precise relationship between these genetic alterations and colorectal cancer (CRC) tumorigenesis remains incompletely understood.

Purpose of the Study:

  • To elucidate the functional relationship between APC, RAS, and the ERK signaling pathway in colorectal cancer.
  • To investigate the role of APC in regulating beta-catenin and TCF4-mediated gene expression in the context of RAS signaling.

Main Methods:

  • Overexpression and knockdown of APC and beta-catenin in colorectal cancer cell lines (DLD-1).
  • Cre-virus-induced Apc knockout in mouse embryonic fibroblasts.
  • Assessment of ERK, Raf1, and MEK kinase activity.
  • Analysis of beta-catenin/TCF4-mediated gene expression.
  • Evaluation of GTP loading and protein levels of mutated RAS.

Main Results:

  • Overexpression of APC reduced RAS-induced ERK pathway activation, while Apc knockout increased ERK activity, indicating APC's inhibitory role.
  • APC inhibited ERK activity by acting on beta-catenin, and this regulation was partly mediated through beta-catenin/TCF4-dependent gene expression.
  • APC overexpression decreased RAS protein levels and GTP loading, suggesting APC regulates RAS-induced ERK activation by modulating RAS protein stability.

Conclusions:

  • APC acts as a negative regulator of the ERK signaling pathway, primarily through its interaction with beta-catenin.
  • APC's inhibitory effect on ERK signaling is crucial for controlling cellular proliferation and transformation driven by aberrant RAS and beta-catenin signaling in colorectal cancer.

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