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Cancer Res. 2019 Sep 1;79(17):4371-4386. doi: 10.1158/0008-5472.CAN-18-3934. Epub 2019 Jun 12.

Tumor Angiogenesis Is Differentially Regulated by Phosphorylation of Endothelial Cell Focal Adhesion Kinase Tyrosines-397 and -861.

Author information

1
Centre for Tumour Biology, Barts Cancer Institute-a CR-UK Centre of Excellence, Queen Mary University of London, London, United Kingdom.
2
Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom.
3
Randall Centre for Cell and Molecular Biophysics, King's College London, London, United Kingdom.
4
Division of Bioengineering, School of Engineering and Materials Science, Queen Mary University of London, London, United Kingdom.
5
Centre for Tumour Biology, Barts Cancer Institute-a CR-UK Centre of Excellence, Queen Mary University of London, London, United Kingdom. k.hodivala-dilke@qmul.ac.uk.

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.

PMID:
31189647
DOI:
10.1158/0008-5472.CAN-18-3934
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