Research ArticleCell Biology

Phosphoproteomic Analysis Implicates the mTORC2-FoxO1 Axis in VEGF Signaling and Feedback Activation of Receptor Tyrosine Kinases

Sci. Signal.  16 Apr 2013:
Vol. 6, Issue 271, pp. ra25
DOI: 10.1126/scisignal.2003572

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Combining Forces Against Angiogenesis

Pathological angiogenesis contributes to the growth of solid tumors, which has led to the development of several antiangiogenic therapies that target the VEGF (vascular endothelial growth factor) signaling pathway, which promotes angiogenesis. Zhuang et al. mapped the signaling networks activated in endothelial cells by VEGF through its receptor tyrosine kinases and found that VEGF promoted the survival of endothelial cells by stimulating the kinase activity of PI3K (phosphatidylinositol 3-kinase) and of mTORC2 (mammalian target of rapamycin complex 2). Because VEGF-activated endothelial cells exposed to mTOR kinase inhibitors exhibited increased activity of multiple receptor tyrosine kinases and PI3K, the cells were less susceptible to the toxic effects of mTOR inhibition. However, combining mTOR and PI3K inhibitors effectively reduced endothelial cell survival. Thus, understanding the signaling pathways that are activated by VEGF can identify potential therapeutic strategies to treat pathological angiogenesis.