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

doi:10.1158/0008-5472.CAN-18-3934

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

50 Citations (Scopus)

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, ECCreþ;FAK^Y397F/Y397F-mutant mice. Conversely, ECCreþ;FAK^Y861F/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.

Original language	English
Pages (from-to)	4371-4386
Number of pages	16
Journal	Cancer Research
Volume	79
Issue number	17
DOIs	https://doi.org/10.1158/0008-5472.CAN-18-3934
Publication status	Published - 1 Sept 2019

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Pedrosa, A. R., Bodrug, N., Gomez-Escudero, J., Carter, E. P., Reynolds, L. E., Georgiou, P. N., Fernandez, I., Lees, D. M., Kostourou, V., Alexopoulou, A. N., Batista, S., Tavora, B., Serrels, B., Parsons, M., Iskratsch, T., & Hodivala-Dilke, K. M. (2019). Tumor angiogenesis is differentially regulated by phosphorylation of endothelial cell focal adhesion kinase tyrosines-397 and -861. Cancer Research, 79(17), 4371-4386. https://doi.org/10.1158/0008-5472.CAN-18-3934

@article{556e390f3d834433962e96451e3199b4,

title = "Tumor angiogenesis is differentially regulated by phosphorylation of endothelial cell focal adhesion kinase tyrosines-397 and -861",

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{\th};FAKY397F/Y397F-mutant mice. Conversely, ECCre{\th};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 Vegfa{\th}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{\th}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.",

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

year = "2019",

month = sep,

day = "1",

doi = "10.1158/0008-5472.CAN-18-3934",

language = "English",

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Pedrosa, AR, Bodrug, N, Gomez-Escudero, J, Carter, EP, Reynolds, LE, Georgiou, PN, Fernandez, I, Lees, DM, Kostourou, V, Alexopoulou, AN, Batista, S, Tavora, B, Serrels, B, Parsons, M , Iskratsch, T & Hodivala-Dilke, KM 2019, 'Tumor angiogenesis is differentially regulated by phosphorylation of endothelial cell focal adhesion kinase tyrosines-397 and -861', Cancer Research, vol. 79, no. 17, pp. 4371-4386. https://doi.org/10.1158/0008-5472.CAN-18-3934

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.

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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 -

Tumor angiogenesis is differentially regulated by phosphorylation of endothelial cell focal adhesion kinase tyrosines-397 and -861

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