Tumor Angiogenesis Is Differentially Regulated by Phosphorylation of Endothelial Cell Focal Adhesion Kinase Tyrosines-397 and -861
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- Ana-Rita Pedrosa
- 1Centre for Tumour Biology, Barts Cancer Institute–a CR-UK Centre of Excellence, Queen Mary University of London, London, United Kingdom.
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- Natalia Bodrug
- 1Centre for Tumour Biology, Barts Cancer Institute–a CR-UK Centre of Excellence, Queen Mary University of London, London, United Kingdom.
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- Jesus Gomez-Escudero
- 1Centre for Tumour Biology, Barts Cancer Institute–a CR-UK Centre of Excellence, Queen Mary University of London, London, United Kingdom.
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- Edward P. Carter
- 1Centre for Tumour Biology, Barts Cancer Institute–a CR-UK Centre of Excellence, Queen Mary University of London, London, United Kingdom.
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- Louise E. Reynolds
- 1Centre for Tumour Biology, Barts Cancer Institute–a CR-UK Centre of Excellence, Queen Mary University of London, London, United Kingdom.
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- Paraskivi Natalia Georgiou
- 1Centre for Tumour Biology, Barts Cancer Institute–a CR-UK Centre of Excellence, Queen Mary University of London, London, United Kingdom.
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- Isabelle Fernandez
- 1Centre for Tumour Biology, Barts Cancer Institute–a CR-UK Centre of Excellence, Queen Mary University of London, London, United Kingdom.
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- Delphine M. Lees
- 1Centre for Tumour Biology, Barts Cancer Institute–a CR-UK Centre of Excellence, Queen Mary University of London, London, United Kingdom.
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- Vassiliki Kostourou
- 1Centre for Tumour Biology, Barts Cancer Institute–a CR-UK Centre of Excellence, Queen Mary University of London, London, United Kingdom.
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- Annika N. Alexopoulou
- 1Centre for Tumour Biology, Barts Cancer Institute–a CR-UK Centre of Excellence, Queen Mary University of London, London, United Kingdom.
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- Silvia Batista
- 1Centre for Tumour Biology, Barts Cancer Institute–a CR-UK Centre of Excellence, Queen Mary University of London, London, United Kingdom.
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- Bernardo Tavora
- 1Centre for Tumour Biology, Barts Cancer Institute–a CR-UK Centre of Excellence, Queen Mary University of London, London, United Kingdom.
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- Bryan Serrels
- 2Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom.
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- Maddy Parsons
- 3Randall Centre for Cell and Molecular Biophysics, King's College London, London, United Kingdom.
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- Thomas Iskratsch
- 4Division of Bioengineering, School of Engineering and Materials Science, Queen Mary University of London, London, United Kingdom.
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- Kairbaan M. Hodivala-Dilke
- 1Centre for Tumour Biology, Barts Cancer Institute–a CR-UK Centre of Excellence, Queen Mary University of London, London, United Kingdom.
説明
<jats:title>Abstract</jats:title> <jats:sec> <jats:title /> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Significance:</jats:title> <jats:p>Distinct motifs of the focal adhesion kinase differentially regulate tumor blood vessel formation and remodeling.</jats:p> </jats:sec>
収録刊行物
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- Cancer Research
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Cancer Research 79 (17), 4371-4386, 2019-09-01
American Association for Cancer Research (AACR)