title: Cortactin as a target for FAK in the regulation of focal adhesion dynamics.
abstract: BACKGROUND
  Efficient cell movement requires the dynamic regulation of focal adhesion (FA) formation and turnover. FAs are integrin-associated sites of cell attachment and establish linkages to the cellular actin cytoskeleton. Cells without focal adhesion kinase (FAK), an integrin-activated tyrosine kinase, exhibit defects in FA turnover and cell motility. Cortactin is an actin binding adaptor protein that can influence FA dynamics. FAK and cortactin interact, but the cellular role of this complex remains unclear.
  
  
  RESULTS
  Using FAK-null fibroblasts stably reconstituted with green fluorescent protein (GFP) tagged FAK constructs, we find that FAK activity and FAK C-terminal proline-rich region 2 (PRR2) and PRR3 are required for FA turnover and cell motility. Cortactin binds directly to FAK PRR2 and PRR3 sites via its SH3 domain and cortactin expression is important in promoting FA turnover and GFP-FAK release from FAs. FAK-cortactin binding is negatively-regulated by FAK activity and associated with cortactin tyrosine phosphorylation. FAK directly phosphorylates cortactin at Y421 and Y466 and over-expression of cortactin Y421, Y466, and Y482 mutated to phenylalanine (3YF) prevented FAK-enhanced FA turnover and cell motility. However, phospho-mimetic cortactin mutated to glutamic acid (3YE) did not affect FA dynamics and did not rescue FA turnover defects in cells with inhibited FAK activity or with PRR2-mutated FAK that does not bind cortactin.
  
  
  CONCLUSIONS
  Our results support a model whereby FAK-mediated FA remodeling may occur through the formation of a FAK-cortactin signaling complex. This involves a cycle of cortactin binding to FAK, cortactin tyrosine phosphorylation, and subsequent cortactin-FAK dissociation accompanied by FA turnover and cell movement.
authors.affiliation: Moores University of California San Diego Cancer Center, University of California San Diego, La Jolla, California, USA.
authors.forename: Alok
authors.initials: A
authors.lastname: Tomar
authors.forename: Christine
authors.initials: C
authors.lastname: Lawson
authors.forename: Majid
authors.initials: M
authors.lastname: Ghassemian
authors.forename: David D
authors.initials: DD
authors.lastname: Schlaepfer
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002448:Cell Adhesion; D002465:Cell Movement; D051356:Cortactin / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology; D004789:Enzyme Activation; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology; D005353:Fibronectins / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D022001:Focal Adhesions / Q000201:enzymology*; D055785:Gene Knockdown Techniques; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010649:Phenylalanine / Q000235:genetics; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D055232:Proline-Rich Protein Domains; D011485:Protein Binding; D021381:Protein Transport; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D051356:Cortactin; D005353:Fibronectins; D019000:Phosphotyrosine; D010649:Phenylalanine; D051416:Focal Adhesion Protein-Tyrosine Kinases