Tumor Angiogenesis Is Differentially Regulated by Phosphorylation of Endothelial Cell Focal Adhesion Kinase Tyrosines-397 and -861
| Autor: | Natalia Bodrug, Ana Rita Pedrosa, Isabelle Fernandez, Kairbaan Hodivala-Dilke, Annika N. Alexopoulou, Maddy Parsons, Bernardo Tavora, Thomas Iskratsch, Edward P. Carter, Vassiliki Kostourou, Silvia Batista, Paraskivi Natalia Georgiou, Delphine M. Lees, Louise E. Reynolds, Jesus Gomez-Escudero, Bryan Serrels |
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| Rok vydání: | 2019 |
| Předmět: |
Vascular Endothelial Growth Factor A
0301 basic medicine Cancer Research Angiogenesis Focal adhesion Neovascularization 03 medical and health sciences 0302 clinical medicine Cell Movement medicine Animals Phosphorylation Protein kinase B PI3K/AKT/mTOR pathway Cell Proliferation Mice Knockout Neovascularization Pathologic Chemistry Angiotensin II Integrin beta1 Endothelial Cells Epithelial Cells Receptor TIE-2 Vascular Endothelial Growth Factor Receptor-2 Xenograft Model Antitumor Assays Mice Mutant Strains Cell biology Vascular endothelial growth factor A 030104 developmental biology Oncology Focal Adhesion Kinase 1 030220 oncology & carcinogenesis Tyrosine medicine.symptom rhoA GTP-Binding Protein Proto-oncogene tyrosine-protein kinase Src |
| Zdroj: | Cancer Research. 79:4371-4386 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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