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Article

  • The EMBO Journal (2007) 26, 2633 - 2644
  • doi:10.1038/sj.emboj.7601706

Published online: 10 May 2007

Regulation of c-Src by binding to the PDZ domain of AF-6

Gerald Radziwill1, Andreas Weiss1, Jochen Heinrich1, Martin Baumgartner1, Prisca Boisguerin2, Koji Owada3 and Karin Moelling1

  1. Institute of Medical Virology, University of Zurich, Zurich, Switzerland
  2. Institute of Medical Immunology, Berlin, Germany
  3. Department of Molecular Bioregulation, Kyoto Pharmaceutical University, Kyoto, Japan

Correspondence to:

Karin Moelling, Institute of Medical Virology, University of Zurich, Gloriastrasse 30/32, Zurich 8006, Switzerland. Tel.: +41 44 634 2652/53; Fax: +41 44 634 4967; E-mail: moelling@immv.unizh.ch

Gerald Radziwill, Institute of Medical Virology, University of Zurich, Gloriastrasse 30/32, Zurich 8006, Switzerland. Tel.: +41 44 634 2652/53; Fax: +41 44 634 4967; E-mail: radziwil@immv.unizh.ch

Received 16 August 2006; Accepted 10 April 2007

c-Src is a tightly regulated non-receptor tyrosine kinase. We describe the C-terminus of c-Src as a ligand for a PDZ (postsynaptic density 95, PSD-95; discs large, Dlg; zonula occludens-1, ZO-1) domain. The C-terminal residue Leu of c-Src is essential for binding to a PDZ domain. Mutation of this residue does not affect the intrinsic kinase activity in vitro, but interferes with c-Src regulation in cells. As a candidate PDZ protein, we analysed AF-6, a junctional adhesion protein. The AF-6 PDZ domain restricts the number of c-Src substrates, whereas knockdown of AF-6 has the opposite effect. Binding of c-Src to the AF-6 PDZ domain interferes with phosphorylation of c-Src at Tyr527 by the C-terminal kinase, and reduces c-Src autophosphorylation at Tyr416, resulting in a moderately activated c-Src kinase. Unphosphorylated Tyr527 allows binding of c-Src to AF-6. This can be overcome by overexpression of CSK or strong activation of c-Src. c-Src is recruited by AF-6 to cell–cell contact sites, suggesting that c-Src is regulated by a PDZ protein in special cellular locations. We identified a novel type of c-Src regulation by interaction with a PDZ protein.

  • Keywords:

    • cell junction,
    • PDZ domain,
    • signal transduction,
    • Src protein kinase