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¹ Moores UCSD Cancer Center, ² Department of Reproductive Medicine, and ³ Department of Pathology, University of California, San Diego, La Jolla, CA 92093
⁴ Department of Hematology, University Hospital of Essen, Essen 45122, Germany
⁵ Department of Internal Medicine and ⁶ Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109

Correspondence to D.A. Cheresh: dcheresh{at}ucsd.edu

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.

Abbreviations used in this paper: BAEC, bovine aortic endothelial cell; bFGF, basic fibroblast growth factor; EC, endothelial cell; HUVEC, human umbilical vein endothelial cell; i-EC-FAK-KO, inducible EC–specific FAK knockout; Pyk2, proline-rich tyrosine kinase 2; shRNA, short hairpin RNA; WT, wild type.

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