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, 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 ECs exhibit increased Tie2 expression, reduced Vegfr2 expression, decreased β1 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 β1 integrin activation. This corresponds with a decrease in Vegfa-stimulated response, but an increase in Vegfa+Ang2- 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 Vegfa+Ang2. 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. SIGNIFICANCE: Distinct motifs of the focal adhesion kinase differentially regulate tumor blood vessel formation and remodeling.
Highlights
Deciphering the molecular mechanisms that control tumour angiogenesis is fundamental to understanding its regulation [1, 2]
Our data demonstrate that phosphorylation of endothelial cells (EC)-Focal Adhesion Kinase (FAK)-Y397 and Y861 act as critical regulators of tumour angiogenesis through distinct molecular mechanisms where FAK lies upstream of growth factor receptor regulation, signalling and responses (Figure 7)
Our results show that in ECCre+;FAKY397F/Y397F mice, angiogenesis is constitutively disrupted, corresponding with reduced tumour growth
Summary
Systems Oncology Group Champalimaud Research Champalimaud Centre for the Unknown Av. Brasilia, Doca de Pedroucos 1400-038 Lisbon, Portugal. Word count- 7414 words (Introduction, materials and methods, results, discussion and figure legends) 7 main figures and 8 supplementary figures
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