The protrusive phase and full development of integrin-dependent adhesions in colon epithelial cells require FAK- and ERK-mediated actin spike formation: deregulation in cancer cells

V G Brunton, V J Fincham, G W McLean, S J Winder, C Paraskeva, J F Marshall, M C Frame

Research output: Contribution to journalArticlepeer-review

Abstract

Integrins play an important role in tumour progression by influencing cellular responses and matrix-dependent adhesion. However, the regulation of matrix-dependent adhesion assembly in epithelial cells is poorly understood. We have investigated the integrin and signalling requirements of cell-matrix adhesion assembly in colon carcinoma cells after plating on fibronectin. Adhesion assembly in these, and in the adenoma cells from which they were derived, was largely dependent on alpha v beta 6 integrin and required phosphorylation of FAK on tyrosine-397. The rate of fibronectin-induced adhesion assembly and the expression of both alpha v beta 6 integrin and FAK were increased during the adenoma-to-carcinoma transition. The matrix-dependent adhesion assembly process, particularly the final stages of complex protrusion that is required for optimal cell spreading, required the activity of extracellular signal-regulated kinase (ERK). Furthermore, phosphorylated ERK was targeted to newly forming cell--matrix adhesions in the carcinoma cells but not the adenoma cells, and inhibition of FAK--tyrosine-397 phosphorylation or MEK suppressed the appearance of phosphorylated ERK at peripheral sites. In addition, inhibition of MEK--ERK activation blocked the formation of peripheral actin microspikes that were necessary for the protrusive phase of cell-matrix adhesion assembly. Thus, MEK--ERK--dependent peripheral actin re-organization is required for the full development of integrin-induced adhesions and this pathway is stimulated in an in vitro model of colon cancer progression.
Original languageEnglish
Pages (from-to)215-26
Number of pages12
JournalNeoplasia
Volume3
Issue number3
DOIs
Publication statusPublished - 2001

Keywords

  • Actins
  • Adenoma
  • Animals
  • Antigens, Neoplasm
  • Cell Adhesion Molecules
  • Cell Line, Transformed
  • Colonic Neoplasms
  • Disease Progression
  • Epithelial Cells
  • Fibronectins
  • Focal Adhesion Kinase 1
  • Focal Adhesion Protein-Tyrosine Kinases
  • Focal Adhesions
  • Humans
  • Integrins
  • MAP Kinase Signaling System
  • Mice
  • Mice, Nude
  • Mitogen-Activated Protein Kinase Kinases
  • Neoplasm Invasiveness
  • Phosphorylation
  • Protein-Tyrosine Kinases
  • Receptor Protein-Tyrosine Kinases
  • Tumor Cells, Cultured
  • Up-Regulation

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