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Tumor angiogenesis is differentially regulated by phosphorylation of endothelial cell focal adhesion kinase tyrosines-397 and -861

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Ana Rita Pedrosa, Natalia Bodrug, Jesus Gomez-Escudero, Edward P. Carter, Louise E. Reynolds, Paraskivi Natalia Georgiou, Isabelle Fernandez, Delphine M. Lees, Vassiliki Kostourou, Annika N. Alexopoulou, Silvia Batista, Bernardo Tavora, Bryan Serrels, Maddy Parsons, Thomas Iskratsch, Kairbaan M. Hodivala-Dilke

Original languageEnglish
Pages (from-to)4371-4386
Number of pages16
JournalCancer Research
Volume79
Issue number17
DOIs
Published1 Sep 2019

King's Authors

Abstract

Expression of focal adhesion kinase (FAK) in endothelial cells (EC) is essential for angiogenesis, but how FAK phosphorylation at tyrosine-(Y)397 and Y861 regulate tumor angiogenesis in vivo is unknown. Here, we show that tumor growth and angiogenesis are constitutively reduced in inducible, ECCreþ;FAKY397F/Y397F-mutant mice. Conversely, ECCreþ;FAKY861F/Y861F mice exhibit normal tumor growth with an initial reduction in angiogenesis that recovered in end-stage tumors. Mechanistically, FAK-Y397F ECs exhibit increased Tie2 expression, reduced Vegfr2 expression, decreased b1 integrin activation, and disrupted downstream FAK/Src/PI3K(p55)/Akt signaling. In contrast, FAK-Y861F ECs showed decreased Vegfr2 and Tie2 expression with an enhancement in b1 integrin activation. This corresponds with a decrease in Vegfa-stimulated response, but an increase in VegfaþAng2- or conditioned medium from tumor cell-stimulated cellular/angiogenic responses, mimicking responses in end-stage tumors with elevated Ang2 levels. Mechanistically, FAK-Y861F, but not FAK-Y397F ECs showed enhanced p190RhoGEF/P130Cas-dependent signaling that is required for the elevated responses to VegfaþAng2. This study establishes the differential requirements of EC-FAK-Y397 and EC-FAK-Y861 phosphorylation in the regulation of EC signaling and tumor angiogenesis in vivo.

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