Axl is essential for VEGF-A-dependent activation of PI3K/Akt

• DOI: 10.1038/emboj.2012.21
• Publication Date: 2012-02-10T15:29:19Z
• Authors: Guo-Xiang Ruan; Andrius Kazlauskas
• Keywords: Mice, Knockout; Vascular Endothelial Growth Factor A; 0303 health sciences; Amino Acid Motifs; Endothelial Cells; Neovascularization, Physiologic; Receptor Protein-Tyrosine Kinases; Vascular Endothelial Growth Factor Receptor-2; Axl Receptor Tyrosine Kinase; Mice; Phosphatidylinositol 3-Kinases; 03 medical and health sciences; Cell Movement; Proto-Oncogene Proteins; Animals; Fibroblast Growth Factor 2; Proto-Oncogene Proteins c-akt; Signal Transduction

Herein, we report that vascular endothelial growth factor A (VEGF-A) engages the PI3K/Akt pathway by a previously unknown mechanism that involves three tyrosine kinases. Upon VEGF-A-dependent activation of VEGF receptor-2 (VEGFR-2), and subsequent TSAd-mediated activation of Src family kinases (SFKs), SFKs engage the receptor tyrosine kinase Axl via its juxtamembrane domain to trigger ligand-independent autophosphorylation at a pair of YXXM motifs that promotes association with PI3K and activation of Akt. Other VEGF-A-mediated signalling pathways are independent of Axl. Interfering with Axl expression or function impairs VEGF-A- but not bFGF-dependent migration of endothelial cells. Similarly, Axl null mice respond poorly to VEGF-A-induced vascular permeability or angiogenesis, whereas other agonists induce a normal response. These results elucidate the mechanism by which VEGF-A activates PI3K/Akt, and identify previously unappreciated potential therapeutic targets of VEGF-A-driven processes.