Src SH3/2 domain-mediated peripheral accumulation of Src and phospho-myosin is linked to deregulation of E-cadherin and the epithelial-mesenchymal transition

Egle Avizienyte, Valerie J Fincham, Valerie G Brunton, Margaret C Frame

Research output: Contribution to journalArticlepeer-review

Abstract

Elevated Src kinase in epithelial cancer cells induces adhesion changes that are associated with a mesenchymal-like state. We recently showed that Src induces dynamic integrin adhesions in KM12C colon cancer cells, whereas E-cadherin-dependent cell-cell contacts become disorganized. This promotes a fibroblastic-like morphology and expression of the mesenchymal marker vimentin. Furthermore, Src-induced deregulation of E-cadherin, and the associated mesenchymal transition, is dependent on integrin signaling (Avizienyte et al., Nat. Cell Biol. 2002, 4, 632-638), although the nature of downstream signals that mediate these Src- and integrin-dependent effects are unknown. Here we show that the SH2 and SH3 domains of Src mediate peripheral accumulation of phospho-myosin, leading to integrin adhesion complex assembly, whereas loss of SH2 or SH3 function restores normal regulation of E-cadherin and inhibits vimentin expression. Inhibitors of MEK, ROCK, or MLCK also suppress peripheral accumulation of phospho-myosin and Src-induced formation of integrin-dependent adhesions, whereas at the same time restoring E-cadherin redistribution to regions of cell-cell contact. Our data therefore implicate peripheral phospho-myosin activity as a point of convergence for upstream signals that regulate integrin- and E-cadherin-mediated adhesions. This further implicates spatially regulated contractile force as a determinant of epithelial cell plasticity, particularly in cancer cells that can switch between epithelial and mesenchymal-like states.
Original languageEnglish
Pages (from-to)2794-803
Number of pages10
JournalMolecular Biology of the Cell
Volume15
Issue number6
DOIs
Publication statusPublished - Jun 2004

Keywords

  • Cadherins
  • Cell Adhesion
  • Cell Differentiation
  • Cell Line, Tumor
  • Colonic Neoplasms
  • Epithelial Cells
  • Extracellular Signal-Regulated MAP Kinases
  • Humans
  • Integrins
  • MAP Kinase Signaling System
  • Mesoderm
  • Mitogen-Activated Protein Kinase Kinases
  • Myosin-Light-Chain Kinase
  • Myosins
  • Phosphorylation
  • Point Mutation
  • Proto-Oncogene Proteins pp60(c-src)
  • Serum
  • Transfection
  • Vimentin
  • src Homology Domains

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