title: Altering FAK-paxillin interactions reduces adhesion, migration and invasion processes.
abstract: Focal adhesion kinase (FAK) plays an important role in signal transduction pathways initiated at sites of integrin-mediated cell adhesion to the extracellular matrix. Thus, FAK is involved in many aspects of the metastatic process including adhesion, migration and invasion. Recently, several small molecule inhibitors which target FAK catalytic activity have been developed by pharmaceutical companies. The current study was aimed at addressing whether inhibiting FAK targeting to focal adhesions (FA) represents an efficient alternative strategy to inhibit FAK downstream pathways. Using a mutagenesis approach to alter the targeting domain of FAK, we constructed a FAK mutant that fails to bind paxillin. Inhibiting FAK-paxillin interactions led to a complete loss of FAK localization at FAs together with reduced phosphorylation of FAK and FAK targets such as paxillin and p130Cas. This in turn resulted in altered FA dynamics and inhibition of cell adhesion, migration and invasion. Moreover, the migration properties of cells expressing the FAK mutant were reduced as compared to FAK-/- cells. This was correlated with a decrease in both phospho-Src and phospho-p130Cas levels at FAs. We conclude that targeting FAK-paxillin interactions is an efficient strategy to reduce FAK signalling and thus may represent a target for the development of new FAK inhibitors.
authors.affiliation: CNRS, UMR 7213, Laboratoire de Biophotonique et Pharmacologie, Illkirch, France; Université de Strasbourg, Faculté de Pharmacie, Illkirch, France.
authors.forename: Thérèse B
authors.initials: TB
authors.lastname: Deramaudt
authors.affiliation: CNRS, UMR 7213, Laboratoire de Biophotonique et Pharmacologie, Illkirch, France; Université de Strasbourg, Faculté de Pharmacie, Illkirch, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Dujardin
authors.affiliation: CNRS, UMR 7213, Laboratoire de Biophotonique et Pharmacologie, Illkirch, France; Université de Strasbourg, Faculté de Pharmacie, Illkirch, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Noulet
authors.affiliation: CNRS, UMR 7213, Laboratoire de Biophotonique et Pharmacologie, Illkirch, France; Université de Strasbourg, Faculté de Pharmacie, Illkirch, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Martin
authors.affiliation: CNRS, UMR 7213, Laboratoire de Biophotonique et Pharmacologie, Illkirch, France; Université de Strasbourg, Faculté de Pharmacie, Illkirch, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Vauchelles
authors.affiliation: CNRS, UMR 7213, Laboratoire de Biophotonique et Pharmacologie, Illkirch, France; Université de Strasbourg, Faculté de Pharmacie, Illkirch, France.
authors.forename: Ken
authors.initials: K
authors.lastname: Takeda
authors.affiliation: CNRS, UMR 7213, Laboratoire de Biophotonique et Pharmacologie, Illkirch, France; Université de Strasbourg, Faculté de Pharmacie, Illkirch, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Rondé
mesh_terms: D000818:Animals; D001665:Binding Sites; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D050719:Crk-Associated Substrate Protein / Q000235:genetics* / Q000378:metabolism; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051417:Focal Adhesion Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D022001:Focal Adhesions / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D016297:Mutagenesis, Site-Directed; D051419:Paxillin / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011993:Recombinant Fusion Proteins; D015398:Signal Transduction; D019061:src-Family Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D050719:Crk-Associated Substrate Protein; D051419:Paxillin; D047428:Protein Kinase Inhibitors; C496062:Pxn protein, mouse; D011993:Recombinant Fusion Proteins; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D019061:src-Family Kinases