title: The role of focal adhesion kinase catalytic activity on the proliferation and migration of squamous cell carcinoma cells.
abstract: Focal adhesion kinase (FAK) is upregulated in several epithelial tumours and there has been considerable interest in developing small molecule kinase inhibitors of FAK. However, FAK also has important adaptor functions within the cell, integrating signals from both integrins and growth factors. To investigate the role of FAKs kinase domain, we generated fak-deficient squamous cell carcinoma (SCC) cell lines. Re-expression of a wild type or kinase dead FAK allowed us to delineate its kinase dependent functions. In addition, we used the novel FAK kinase inhibitor PF-562,271. The kinase activity of FAK was important for tumour cell migration and polarity but more striking was its requirement for the anchorage independent 3 dimensional (3D) proliferation of SCC cells and their growth as xenografts in mice. Inhibition of FAK activity and prevention of growth in 3D correlated with Src inhibition. We further identified a mechanism whereby FAK regulates proliferation in 3D via regulation of the kinase activity of Src. This was dependent on the kinase activity of FAK and its resulting phosphorylation on Y397 that provides a high affinity binding site for Src. These data support the further development of FAK kinase inhibitors as agents that have the potential to inhibit both tumour cell migration and proliferation.
authors.affiliation: Edinburgh Cancer Research Centre, Institute for Genetics & Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Alan
authors.initials: A
authors.lastname: Serrels
authors.forename: Kenneth
authors.initials: K
authors.lastname: McLeod
authors.forename: Marta
authors.initials: M
authors.lastname: Canel
authors.forename: Andrew
authors.initials: A
authors.lastname: Kinnaird
authors.forename: Kathryn
authors.initials: K
authors.lastname: Graham
authors.forename: Margaret C
authors.initials: MC
authors.lastname: Frame
authors.forename: Valerie G
authors.initials: VG
authors.lastname: Brunton
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement; D016764:Cell Polarity; D049109:Cell Proliferation / Q000187:drug effects*; D000069439:Dasatinib; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D007211:Indoles; C527797:N-methyl-N-(3-((2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino)-methyl)-pyridin-2-yl)-methanesulfonamide; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D013844:Thiazoles; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019061:src-Family Kinases; D000069439:Dasatinib