VEGFR2 pY949 signalling regulates adherens junction integrity and metastatic spread

Xiujuan Li; Narendra Padhan; Elisabet O Sjöström; Francis P Roche; Chiara Testini; Naoki Honkura; Miguel Sáinz-Jaspeado; Emma Gordon; Katie Bentley; Andrew Philippides; Vladimir Tolmachev; Elisabetta Dejana; Radu V Stan; Dietmar Vestweber; Kurt Ballmer-Hofer; Christer Betsholtz; Kristian Pietras; Leif Jansson; Lena Claesson-Welsh

doi:10.1038/ncomms11017

VEGFR2 pY949 signalling regulates adherens junction integrity and metastatic spread

Xiujuan Li, Narendra Padhan, Elisabet O Sjöström, Francis P Roche, Chiara Testini, Naoki Honkura, Miguel Sáinz-Jaspeado, Emma Gordon, Katie Bentley, Andrew Philippides, Vladimir Tolmachev, Elisabetta Dejana, Radu V Stan, Dietmar Vestweber, Kurt Ballmer-Hofer, Christer Betsholtz, Kristian Pietras, Leif Jansson, Lena Claesson-Welsh

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

Abstract

The specific role of VEGFA-induced permeability and vascular leakage in physiology and pathology has remained unclear. Here we show that VEGFA-induced vascular leakage depends on signalling initiated via the VEGFR2 phosphosite Y949, regulating dynamic c-Src and VE-cadherin phosphorylation. Abolished Y949 signalling in the mouse mutant Vegfr2(Y949F/Y949F) leads to VEGFA-resistant endothelial adherens junctions and a block in molecular extravasation. Vessels in Vegfr2(Y949F/Y949F) mice remain sensitive to inflammatory cytokines, and vascular morphology, blood pressure and flow parameters are normal. Tumour-bearing Vegfr2(Y949F/Y949F) mice display reduced vascular leakage and oedema, improved response to chemotherapy and, importantly, reduced metastatic spread. The inflammatory infiltration in the tumour micro-environment is unaffected. Blocking VEGFA-induced disassembly of endothelial junctions, thereby suppressing tumour oedema and metastatic spread, may be preferable to full vascular suppression in the treatment of certain cancer forms.

Original language	English
Article number	11017
Journal	Nature Communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms11017
Publication status	Published - 2016 Mar 23

Subject classification (UKÄ)

Cell and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Li, X., Padhan, N., Sjöström, E. O., Roche, F. P., Testini, C., Honkura, N., Sáinz-Jaspeado, M., Gordon, E., Bentley, K., Philippides, A., Tolmachev, V., Dejana, E., Stan, R. V., Vestweber, D., Ballmer-Hofer, K., Betsholtz, C., Pietras, K., Jansson, L., & Claesson-Welsh, L. (2016). VEGFR2 pY949 signalling regulates adherens junction integrity and metastatic spread. Nature Communications, 7, Article 11017. https://doi.org/10.1038/ncomms11017

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title = "VEGFR2 pY949 signalling regulates adherens junction integrity and metastatic spread",

abstract = "The specific role of VEGFA-induced permeability and vascular leakage in physiology and pathology has remained unclear. Here we show that VEGFA-induced vascular leakage depends on signalling initiated via the VEGFR2 phosphosite Y949, regulating dynamic c-Src and VE-cadherin phosphorylation. Abolished Y949 signalling in the mouse mutant Vegfr2(Y949F/Y949F) leads to VEGFA-resistant endothelial adherens junctions and a block in molecular extravasation. Vessels in Vegfr2(Y949F/Y949F) mice remain sensitive to inflammatory cytokines, and vascular morphology, blood pressure and flow parameters are normal. Tumour-bearing Vegfr2(Y949F/Y949F) mice display reduced vascular leakage and oedema, improved response to chemotherapy and, importantly, reduced metastatic spread. The inflammatory infiltration in the tumour micro-environment is unaffected. Blocking VEGFA-induced disassembly of endothelial junctions, thereby suppressing tumour oedema and metastatic spread, may be preferable to full vascular suppression in the treatment of certain cancer forms.",

author = "Xiujuan Li and Narendra Padhan and Sj{\"o}str{\"o}m, {Elisabet O} and Roche, {Francis P} and Chiara Testini and Naoki Honkura and Miguel S{\'a}inz-Jaspeado and Emma Gordon and Katie Bentley and Andrew Philippides and Vladimir Tolmachev and Elisabetta Dejana and Stan, {Radu V} and Dietmar Vestweber and Kurt Ballmer-Hofer and Christer Betsholtz and Kristian Pietras and Leif Jansson and Lena Claesson-Welsh",

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Li, X, Padhan, N, Sjöström, EO, Roche, FP, Testini, C, Honkura, N, Sáinz-Jaspeado, M, Gordon, E, Bentley, K, Philippides, A, Tolmachev, V, Dejana, E, Stan, RV, Vestweber, D, Ballmer-Hofer, K, Betsholtz, C, Pietras, K, Jansson, L & Claesson-Welsh, L 2016, 'VEGFR2 pY949 signalling regulates adherens junction integrity and metastatic spread', Nature Communications, vol. 7, 11017. https://doi.org/10.1038/ncomms11017

TY - JOUR

T1 - VEGFR2 pY949 signalling regulates adherens junction integrity and metastatic spread

AU - Li, Xiujuan

AU - Padhan, Narendra

AU - Sjöström, Elisabet O

AU - Roche, Francis P

AU - Testini, Chiara

AU - Honkura, Naoki

AU - Sáinz-Jaspeado, Miguel

AU - Gordon, Emma

AU - Bentley, Katie

AU - Philippides, Andrew

AU - Tolmachev, Vladimir

AU - Dejana, Elisabetta

AU - Stan, Radu V

AU - Vestweber, Dietmar

AU - Ballmer-Hofer, Kurt

AU - Betsholtz, Christer

AU - Pietras, Kristian

AU - Jansson, Leif

AU - Claesson-Welsh, Lena

PY - 2016/3/23

Y1 - 2016/3/23

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AB - The specific role of VEGFA-induced permeability and vascular leakage in physiology and pathology has remained unclear. Here we show that VEGFA-induced vascular leakage depends on signalling initiated via the VEGFR2 phosphosite Y949, regulating dynamic c-Src and VE-cadherin phosphorylation. Abolished Y949 signalling in the mouse mutant Vegfr2(Y949F/Y949F) leads to VEGFA-resistant endothelial adherens junctions and a block in molecular extravasation. Vessels in Vegfr2(Y949F/Y949F) mice remain sensitive to inflammatory cytokines, and vascular morphology, blood pressure and flow parameters are normal. Tumour-bearing Vegfr2(Y949F/Y949F) mice display reduced vascular leakage and oedema, improved response to chemotherapy and, importantly, reduced metastatic spread. The inflammatory infiltration in the tumour micro-environment is unaffected. Blocking VEGFA-induced disassembly of endothelial junctions, thereby suppressing tumour oedema and metastatic spread, may be preferable to full vascular suppression in the treatment of certain cancer forms.

U2 - 10.1038/ncomms11017

DO - 10.1038/ncomms11017

M3 - Article

C2 - 27005951

SN - 2041-1723

VL - 7

JO - Nature Communications

JF - Nature Communications

M1 - 11017

ER -

VEGFR2 pY949 signalling regulates adherens junction integrity and metastatic spread

Abstract

Subject classification (UKÄ)

UN SDGs

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