title: SH2- and SH3-mediated interactions between focal adhesion kinase and Src.
abstract: Intramolecular SH2 and SH3 interactions mediate enzymatic repression of the Src kinases. One mechanism of activation is disruption of these interactions by the formation of higher affinity SH2 and SH3 interactions with specific ligands. We show that a consensus Src SH3-binding site residing upstream of the Src SH2-binding site in FAK can function as a ligand for the Src SH3 domain. Surface plasmon resonance experiments indicate that a FAK peptide containing both the Src SH2- and SH3-binding sites exhibits increased affinity for Src. Furthermore, the presence of both sites in vitro more potently activates c-Src. A FAK mutant (FAKPro-2) with substitutions destroying the SH3-binding site shows reduced binding to Src in vivo. This mutation also reduces Src-dependent tyrosine phosphorylation on the mutant itself and downstream substrates, such as paxillin. These observations suggest that an SH3-mediated interaction between Src-like kinases and FAK may be important for complex formation and downstream signaling in vivo.
authors.affiliation: Department of Cell Biology and Anatomy, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors.forename: J W
authors.initials: JW
authors.lastname: Thomas
authors.forename: B
authors.initials: B
authors.lastname: Ellis
authors.forename: R J
authors.initials: RJ
authors.lastname: Boerner
authors.forename: W B
authors.initials: WB
authors.lastname: Knight
authors.forename: G C
authors.initials: GC
authors.lastname: White
authors.forename: M D
authors.initials: MD
authors.lastname: Schaller
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002642:Chick Embryo; D051416:Focal Adhesion Protein-Tyrosine Kinases; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism; D018909:src Homology Domains
chemical_list: D015815:Cell Adhesion Molecules; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D051416:Focal Adhesion Protein-Tyrosine Kinases; D016392:Proto-Oncogene Proteins pp60(c-src)