TY - JOUR
T1 - Tumor angiogenesis is differentially regulated by phosphorylation of endothelial cell focal adhesion kinase tyrosines-397 and -861
AU - Pedrosa, Ana Rita
AU - Bodrug, Natalia
AU - Gomez-Escudero, Jesus
AU - Carter, Edward P.
AU - Reynolds, Louise E.
AU - Georgiou, Paraskivi Natalia
AU - Fernandez, Isabelle
AU - Lees, Delphine M.
AU - Kostourou, Vassiliki
AU - Alexopoulou, Annika N.
AU - Batista, Silvia
AU - Tavora, Bernardo
AU - Serrels, Bryan
AU - Parsons, Maddy
AU - Iskratsch, Thomas
AU - Hodivala-Dilke, Kairbaan M.
PY - 2019/9/1
Y1 - 2019/9/1
N2 - 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, ECCreþ;FAKY397F/Y397F-mutant mice. Conversely, ECCreþ;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 b1 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 b1 integrin activation. This corresponds with a decrease in Vegfa-stimulated response, but an increase in VegfaþAng2- 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 VegfaþAng2. 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.
AB - 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, ECCreþ;FAKY397F/Y397F-mutant mice. Conversely, ECCreþ;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 b1 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 b1 integrin activation. This corresponds with a decrease in Vegfa-stimulated response, but an increase in VegfaþAng2- 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 VegfaþAng2. 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.
UR - http://www.scopus.com/inward/record.url?scp=85071787308&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-18-3934
DO - 10.1158/0008-5472.CAN-18-3934
M3 - Article
C2 - 31189647
AN - SCOPUS:85071787308
SN - 0008-5472
VL - 79
SP - 4371
EP - 4386
JO - Cancer Research
JF - Cancer Research
IS - 17
ER -