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

Carragher, N.O., Westhoff, M.A., Fincham, V.J., Schaller, M.D. and Frame, M.C. (2003) A novel role for FAK as a protease-targeting adaptor protein: Regulation by p42 ERK and Src. Current Biology, 13, pp. 1442-1450. (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 1, 2 and 3. ERK/MAP kinase-mediated activation of the protease Calpain 2 also promotes focal-adhesion turnover 4, 5 and 6; 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 [7] and can cleave several focal-adhesion complex components, including FAK 8, 9, 10, 11, 12 and 13. Studies utilizing Calpain inhibitors or Calpain-deficient cells confirm that Calpain's role in regulating focal-adhesion turnover is necessary for cell migration 10, 11 and 14. 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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: UNSPECIFIED
• Authors: Carragher, N.O., Westhoff, M.A., Fincham, V.J., Schaller, M.D., and Frame, M.C.
• College/School: College of Medical Veterinary and Life Sciences
• Journal Name: Current Biology
• ISSN: 0960-9822