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

Curr Biol. 2003 Aug 19;13(16):1442-50. doi: 10.1016/s0960-9822(03)00544-x.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

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

Substances

  • Adaptor Proteins, Vesicular Transport
  • Macromolecular Substances
  • Proline
  • Protein-Tyrosine Kinases
  • Focal Adhesion Protein-Tyrosine Kinases
  • src-Family Kinases
  • Mitogen-Activated Protein Kinase 1
  • Calpain