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

Ana-Rita Pedrosa, Natalia Bodrug, Jesus Gomez-Escudero, Edward P Carter, Louise E Reynolds, Paraskivi Natalia Georgiou, Isabelle Fernandez, Delphine M Lees, Vassiliki Kostourou, Annika N Alexopoulou, Silvia Batista, Bernardo Tavora, Bryan Serrels, Maddy Parsons, Thomas Iskratsch, Kairbaan M Hodivala-Dilke

Research output: Contribution to journalArticlepeer-review

47 Citations (SciVal)

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.

Original languageEnglish
Pages (from-to)4371-4386
Number of pages16
JournalCancer Research
Volume79
Issue number17
DOIs
Publication statusPublished - 1 Sept 2019

Bibliographical note

©2019 American Association for Cancer Research.

Keywords

  • Angiotensin II/pharmacology
  • Animals
  • Cell Movement/genetics
  • Cell Proliferation/genetics
  • Endothelial Cells/metabolism
  • Epithelial Cells/metabolism
  • Focal Adhesion Kinase 1/genetics
  • Integrin beta1/metabolism
  • Mice, Knockout
  • Mice, Mutant Strains
  • Neovascularization, Pathologic/drug therapy
  • Phosphorylation
  • Receptor, TIE-2/genetics
  • Tyrosine/metabolism
  • Vascular Endothelial Growth Factor A/pharmacology
  • Vascular Endothelial Growth Factor Receptor-2/genetics
  • Xenograft Model Antitumor Assays
  • rhoA GTP-Binding Protein/metabolism

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