APC inhibits ERK pathway activation and cellular proliferation induced by RAS

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.

Loss of Apc allows phenotypic manifestation of the transforming properties of an endogenous K- ras oncogene in vivo

“…These observations provide a molecular explanation for our failure to see phenotypic changes after activation of K-ras V12 expression. These data also argue against the notion that Apc inhibits activation of the Raf-MEK-ERK pathway in vivo, as recently suggested (16). Interestingly, nuclear P-MEK and P-ERK were observed in goblet cell nuclei, suggesting that this pathway may be relevant to goblet cell differentiation (Fig.…”

H-Ras is degraded by Wnt/β-catenin signaling via β-TrCP-mediated polyubiquitylation

“…Our previous observations that Axin and Apc destabilize Ras (Park et al, 2006;Jeon et al, 2007) led us to investigate a mechanism for Ras degradation. The half-lives of both Ras and β-catenin werẽ 9 hours in HEK293 cells in which new protein synthesis was inhibited (Fig.…”

“…We also found that Axin and adenomatous polyposis coli (Apc), the negative regulators of Wnt/β-catenin signaling, increased degradation and polyubiquitylation of H-Ras by enhancing the β-TrCP-H-Ras interaction. The regulation of H-Ras stability by Wnt/β-catenin signaling controls cellular proliferation and transformation (Park et al, 2006;Jeon et al, 2007). β-TrCP and Axin synergistically affected cellular transformation, suggesting that these proteins are crucial signaling intermediates facilitating Wnt/β-catenin control of H-Ras stability and cellular transformation.…”

Akt is involved in the inhibition of cell proliferation by EGF

“…The ERK pathway is one of the major transforming signaling pathways, and the cross-talk between the ERK and the Wnt/β-catenin pathways was identified in several of our previous experiments (Yun et al, 2005;Park et al, 2006;Jeon et al, 2007). The ERK pathway is immediately activated by recombinant Wnt3a (Yun et al, 2005), and is also regulated by adenomatos polyposis coli (APC), the negative regulator of the Wnt/β-catenin pathway (Park et al, 2006).…”

“…The ERK pathway is immediately activated by recombinant Wnt3a (Yun et al, 2005), and is also regulated by adenomatos polyposis coli (APC), the negative regulator of the Wnt/β-catenin pathway (Park et al, 2006). Although both the Wnt/β-catenin pathway and the PI3K/Akt pathway are involved in tumor progression, the relationship between these two pathways is poorly understood.…”