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.

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

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

Access to Document

10.1038/ncomms11017

Fingerprint Dive into the research topics of 'VEGFR2 pY949 signalling regulates adherens junction integrity and metastatic spread'. Together they form a unique fingerprint.

Cite this

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, [11017]. https://doi.org/10.1038/ncomms11017

VEGFR2 pY949 signalling regulates adherens junction integrity and metastatic spread. / Li, Xiujuan; Padhan, Narendra; Sjöström, Elisabet O.; Roche, Francis P.; Testini, Chiara; Honkura, Naoki; Sáinz-Jaspeado, Miguel; Gordon, Emma; Bentley, Katie; Philippides, Andrew; Tolmachev, Vladimir; Dejana, Elisabetta; Stan, Radu V.; Vestweber, Dietmar; Ballmer-Hofer, Kurt; Betsholtz, Christer; Pietras, Kristian; Jansson, Leif; Claesson-Welsh, Lena.

In: Nature Communications, Vol. 7, 11017, 23.03.2016.

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

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

Li, Xiujuan ; Padhan, Narendra ; Sjöström, Elisabet O. ; Roche, Francis P. ; Testini, Chiara ; Honkura, Naoki ; Sáinz-Jaspeado, Miguel ; Gordon, Emma ; Bentley, Katie ; Philippides, Andrew ; Tolmachev, Vladimir ; Dejana, Elisabetta ; Stan, Radu V. ; Vestweber, Dietmar ; Ballmer-Hofer, Kurt ; Betsholtz, Christer ; Pietras, Kristian ; Jansson, Leif ; Claesson-Welsh, Lena. / VEGFR2 pY949 signalling regulates adherens junction integrity and metastatic spread. In: Nature Communications. 2016 ; Vol. 7.

@article{ee7076841e084dbb9156d2326aee1b57,

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",

year = "2016",

month = mar,

day = "23",

doi = "10.1038/ncomms11017",

language = "English",

volume = "7",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

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

N2 - 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.

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.

UR - http://www.scopus.com/inward/record.url?scp=84962295137&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84962295137&partnerID=8YFLogxK

U2 - 10.1038/ncomms11017

DO - 10.1038/ncomms11017

M3 - Article

C2 - 27005951

AN - SCOPUS:84962295137

VL - 7

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 11017

ER -