Ligand-independent activation of c-Met by fibronectin and α5 Β1-integrin regulates ovarian cancer invasion and metastasis

A. K. Mitra, K. Sawada, P. Tiwari, K. Mui, K. Gwin, E. Lengyel

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152 Scopus citations

Abstract

The role of the fibronectin receptor, α 5 Β 1-integrin, as an adhesion receptor and in angiogenesis is well established. However, its role in cancer cell invasion and metastasis is less clear. We describe a novel mechanism by which fibronectin regulates ovarian cancer cell signaling and promotes metastasis. Fibronectin binding to α 5 Β 1-integrin led to a direct association of α 5-integrin with the receptor tyrosine kinase, c-Met, activating it in a hepatocyte growth factor/scatter factor (HGF/SF) independent manner. Subsequently, c-Met associated with Src, and activated Src and focal adhesion kinase (FAK). Inhibition of α 5 Β 1-integrin decreased the phosphorylation of c-Met, FAK and Src, both in vitro and in vivo. Independent activation of c-Met by its native ligand, HGF/SF, or overexpression of a constitutively active FAK in HeyA8 cells could overcome the effect of α 5 Β 1-integrin inhibition on tumor cell invasion, indicating that α 5 Β 1-integrin is upstream of c-Met, Src and FAK. Inhibition of α 5 Β 1-integrin on cancer cells in two xenograft models of ovarian cancer metastasis resulted in a significant decrease of tumor burden, which was independent of the effect of α 5 Β 1-integrin on angiogenesis. These data suggest that fibronectin promotes ovarian cancer invasion and metastasis through an α 5 Β 1-integrin/c-Met/FAK/Src-dependent signaling pathway, transducing signals through c-Met in an HGF/SF-independent manner.

Original languageEnglish (US)
Pages (from-to)1566-1576
Number of pages11
JournalOncogene
Volume30
Issue number13
DOIs
StatePublished - Mar 31 2011

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Keywords

  • FAK
  • Src
  • c-Met
  • fibronectin
  • ovarian cancer
  • αβ-integrin

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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