A FAK/Src chimera with gain-of-function properties promotes formation of large peripheral adhesions associated with dynamic actin assembly

Cell Motil Cytoskeleton. 2008 Jan;65(1):25-39. doi: 10.1002/cm.20241.

Abstract

Formation of a complex between the tyrosine kinases FAK and Src is a key integrin-mediated signaling event implicated in cell motility, survival, and proliferation. Past studies indicate that FAK functions in the complex primarily as a "scaffold," acting to recruit and activate Src within cell/matrix adhesions. To study the cellular impact of FAK-associated Src signaling we developed a novel gain-of-function approach that involves expressing a chimeric protein with the FAK kinase domain replaced by the Src kinase domain. This FAK/Src chimera is subject to adhesion-dependent activation and promotes tyrosine phosphorylation of p130Cas and paxillin to higher steady-state levels than is achieved by wild-type FAK. When expressed in FAK -/- mouse embryo fibroblasts, the FAK/Src chimera resulted in a striking cellular phenotype characterized by unusual large peripheral adhesions, enhanced adhesive strength, and greatly reduced motility. Live cell imaging of the chimera-expressing FAK -/- cells provided evidence that the large peripheral adhesions are associated with a dynamic actin assembly process that is sensitive to a Src-selective inhibitor. These findings suggest that FAK-associated Src kinase activity has the capacity to promote adhesion integrity and actin assembly.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Actins / metabolism*
  • Animals
  • Cells, Cultured
  • Focal Adhesion Kinase 1 / deficiency
  • Focal Adhesion Kinase 1 / genetics
  • Focal Adhesion Kinase 1 / physiology*
  • Focal Adhesions / enzymology*
  • Focal Adhesions / genetics
  • Genes, src / physiology
  • Mice
  • Phenotype
  • Proto-Oncogene Proteins pp60(c-src) / genetics
  • Proto-Oncogene Proteins pp60(c-src) / physiology*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / physiology*
  • Signal Transduction / genetics

Substances

  • Actins
  • Recombinant Fusion Proteins
  • Focal Adhesion Kinase 1
  • Proto-Oncogene Proteins pp60(c-src)