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Regulation of c‐Src by binding to the PDZ domain of AF‐6
Author(s) -
Radziwill Gerald,
Weiss Andreas,
Heinrich Jochen,
Baumgartner Martin,
Boisguerin Prisca,
Owada Koji,
Moelling Karin
Publication year - 2007
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7601706
Subject(s) - biology , pdz domain , proto oncogene tyrosine protein kinase src , domain (mathematical analysis) , binding site , microbiology and biotechnology , genetics , phosphorylation , mathematical analysis , mathematics
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, P SD‐95; discs large, D lg; zonula occludens‐1, Z O‐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.