title: Compensatory role for Pyk2 during angiogenesis in adult mice lacking endothelial cell FAK.
abstract: Focal adhesion kinase (FAK) plays a critical role during vascular development because knockout of FAK in endothelial cells (ECs) is embryonic lethal. Surprisingly, tamoxifen-inducible conditional knockout of FAK in adult blood vessels (inducible EC-specific FAK knockout [i-EC-FAK-KO]) produces no vascular phenotype, and these animals are capable of developing a robust growth factor-induced angiogenic response. Although angiogenesis in wild-type mice is suppressed by pharmacological inhibition of FAK, i-EC-FAK-KO mice are refractory to this treatment, which suggests that adult i-EC-FAK-KO mice develop a compensatory mechanism to bypass the requirement for FAK. Indeed, expression of the FAK-related proline-rich tyrosine kinase 2 (Pyk2) is elevated and phosphorylated in i-EC-FAK-KO blood vessels. In cultured ECs, FAK knockdown leads to increased Pyk2 expression and, surprisingly, FAK kinase inhibition leads to increased Pyk2 phosphorylation. Pyk2 can functionally compensate for the loss of FAK because knockdown or pharmacological inhibition of Pyk2 disrupts angiogenesis in i-EC-FAK-KO mice. These studies reveal the adaptive capacity of ECs to switch to Pyk2-dependent signaling after deletion or kinase inhibition of FAK.
authors.affiliation: Moores UCSD Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Sara M
authors.initials: SM
authors.lastname: Weis
authors.forename: Ssang-Taek
authors.initials: ST
authors.lastname: Lim
authors.forename: Kimberly M
authors.initials: KM
authors.lastname: Lutu-Fuga
authors.forename: Leo A
authors.initials: LA
authors.lastname: Barnes
authors.forename: Xiao Lei
authors.initials: XL
authors.lastname: Chen
authors.forename: Joachim R
authors.initials: JR
authors.lastname: Göthert
authors.forename: Tang-Long
authors.initials: TL
authors.lastname: Shen
authors.forename: Jun-Lin
authors.initials: JL
authors.lastname: Guan
authors.forename: David D
authors.initials: DD
authors.lastname: Schlaepfer
authors.forename: David A
authors.initials: DA
authors.lastname: Cheresh
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology; D042783:Endothelial Cells / Q000378:metabolism*; D051417:Focal Adhesion Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D051418:Focal Adhesion Kinase 2 / Q000378:metabolism*; D006801:Humans; D016023:Integrins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic; D015398:Signal Transduction
chemical_list: D016023:Integrins; D051417:Focal Adhesion Kinase 1; D051418:Focal Adhesion Kinase 2; C496051:Ptk2 protein, mouse; C496053:Ptk2b protein, mouse