Activation of c-Met in colorectal carcinoma cells leads to constitutive association of tyrosine-phosphorylated β-catenin
10.1023/A:1024024218529 Cite this article as: Herynk, M.H., Tsan, R., Radinsky, R. et al. Clin Exp Metastasis (2003) 20: 291. doi:10.1023/A:1024024218529 Abstract
Increased expression and/or activity of c-Met, the receptor protein tyrosine kinase for hepatocyte growth factor/scatter factor, occurs commonly during colon tumor progression. To examine potential roles for c-Met in promoting metastasis, we compared the colon tumor cell line KM12C with low metastatic potential to the isogenic variants KM12L4 and KM12SM with high metastatic potential. KM12C cells express c-Met with low levels of tyrosine phosphorylation in the absence of HGF. The high metastatic cells express a c-Met that is constitutively tyrosine phosphorylated, they have increased colony formation, and are minimally responsive to HGF relative to the parental cells. Tyrosine-phosphorylated β-catenin was constitutively associated with c-Met in the more metastatic cells, but was inducible only after HGF addition in the less metastatic cells. Functions mediated by β-catenin, including cell–cell adhesion and migration, and activation of the tcf (T-cell factor) family of transcription factors, were also elevated in the more metastatic KM12SM and L4 cells. Furthermore, analysis of the known tcf transcriptional target genes, cyclin D1, c-Myc, and uPAR, demonstrated increased expression in the high metastatic cells, correlating with the levels of tcf activity. Collectively, these results suggest that endogenous activation of c-Met in highly metastatic KM12SM CRC cells results in increased survival and growth under anchorage independent conditions, increased
in vitro migration, and elevated levels of tcf target genes. Thus, β-catenin association with activated c-Met may contribute to a more aggressive liver metastatic phenotype of these cells. β-catenin c-Met colorectal carcinoma metastasis signal transduction tyrosine kinase receptor
This revised version was published online in July 2006 with corrections to the Cover Date.
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