Clinical & Experimental Metastasis

, Volume 20, Issue 4, pp 291–300 | Cite as

Activation of c-Met in colorectal carcinoma cells leads to constitutive association of tyrosine-phosphorylated β-catenin

  • Matthew H. Herynk
  • Rachael Tsan
  • Robert Radinsky
  • Gary E. Gallick


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 


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Copyright information

© Kluwer Academic Publishers 2003

Authors and Affiliations

  • Matthew H. Herynk
    • 1
  • Rachael Tsan
    • 2
  • Robert Radinsky
    • 1
    • 3
  • Gary E. Gallick
    • 1
  1. 1.The Program in Cancer BiologyUniversity of Texas Graduate School of Biomedical Sciences at HoustonHoustonUSA
  2. 2.Department of Cancer BiologyUniversity of Texas M. D. Anderson Cancer CenterUSA
  3. 3.Cancer PharmacologyAmgen IncThousand OaksUSA

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