A novel role for FAK as a protease-targeting adaptor protein: regulation by p42 ERK and Src

Neil O Carragher, M Andrew Westhoff, Valerie J Fincham, Michael D Schaller, Margaret C Frame

Research output: Contribution to journalArticlepeer-review

Abstract

Cell migration on extracellular matrix requires the turnover of integrin-dependent adhesions. The nonreceptor tyrosine kinases Src and FAK regulate focal-adhesion turnover by poorly understood mechanisms. ERK/MAP kinase-mediated activation of the protease Calpain 2 also promotes focal-adhesion turnover; however, it is not known if this is linked to the activities of Src and FAK. Calpain 2 has previously been demonstrated to colocalize with focal-adhesion structures and can cleave several focal-adhesion complex components, including FAK. Studies utilizing Calpain inhibitors or Calpain-deficient cells confirm that Calpain's role in regulating focal-adhesion turnover is necessary for cell migration. We have identified a novel and kinase-independent function for FAK as an adaptor molecule that mediates the assembly of a complex consisting of at least Calpain 2 and p42ERK. Mutation of proline residues (Pro2) in the amino-terminal region of FAK blocks direct binding with Calpain 2 and also prevents formation of the Calpain 2/p42ERK complex in cells. We show that both complex formation and MEK/ERK activity are associated with Calpain-mediated proteolysis of FAK and focal adhesion turnover during transformation and migration. Furthermore, FAK is necessary for recruiting both Calpain 2 and p42ERK/MAPK to peripheral adhesion sites facilitating maximal Calpain activity.
Original languageEnglish
Pages (from-to)1442-50
Number of pages9
JournalCurrent biology : CB
Volume13
Issue number16
Publication statusPublished - 19 Aug 2003

Keywords

  • Adaptor Proteins, Vesicular Transport
  • Amino Acid Sequence
  • Animals
  • Calpain
  • Cell Movement
  • Cells, Cultured
  • Chick Embryo
  • Focal Adhesion Protein-Tyrosine Kinases
  • Focal Adhesions
  • Gene Targeting
  • Macromolecular Substances
  • Mitogen-Activated Protein Kinase 1
  • Mutagenesis, Site-Directed
  • Proline
  • Protein-Tyrosine Kinases
  • Transformation, Genetic
  • src-Family Kinases

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