Compensatory role for Pyk2 during angiogenesis in adult mice lacking endothelial cell FAK.
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.
Weis
Sara M
SM
Moores UCSD Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
Lim
Ssang-Taek
ST
Lutu-Fuga
Kimberly M
KM
Barnes
Leo A
LA
Chen
Xiao Lei
XL
Göthert
Joachim R
JR
Shen
Tang-Long
TL
Guan
Jun-Lin
JL
Schlaepfer
David D
DD
Cheresh
David A
DA
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
D016023:Integrins; D051417:Focal Adhesion Kinase 1; D051418:Focal Adhesion Kinase 2; C496051:Ptk2 protein, mouse; C496053:Ptk2b protein, mouse