Tumor angiogenesis is differentially regulated by phosphorylation of endothelial cell focal adhesion kinase tyrosines-397 and -861
2019
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, ECCre+;FAKY397F/Y397F mutant mice Conversely, ECCre+;FAKY861F/Y861F mice exhibit normal tumor growth with an initial reduction in angiogenesis that recovered in end stage tumors. Mechanistically, FAK-Y397F EC exhibited increased Tie-2 expression, reduced Vegfr-2 expression, decreased β1-integrin activation, and disrupted downstream FAK/Src/PI3K(p55)/Akt signalling. In contrast, FAK-Y861F ECs showed decreased Vegfr-2 and Tie-2 expression with an enhancement in β1-integrin activation. This corresponds with a decrease in Vegf-a-stimulated response, but an increase in Vegf-a+Ang-2- or conditioned medium from tumor cells- stimulated cellular/angiogenic responses, mimicking responses in end stage tumors with elevated Ang-2 levels. Mechanistically, FAK-Y861F but not FAK-Y397F EC showed enhanced p190RhoGEF/P130Cas-dependent signalling that is required for the elevated responses to Vegf-a+Ang-2. This study establishes the differential requirements of EC-FAK-Y397 and EC-FAK-Y861-phosphorylation in the regulation of EC-signalling and tumor angiogenesis in vivo.
Keywords:
- Correction
- Source
- Cite
- Save
- Machine Reading By IdeaReader
55
References
23
Citations
NaN
KQI