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VEGFR2 survival and mitotic signaling depends on joint activation of associated C3ar1/C5ar1 and IL-6R-gp130.


ABSTRACT: Purified vascular endothelial cell (EC) growth factor receptor-2 (VEGFR2) auto-phosphorylates upon VEGF-A occupation in vitro, arguing that VEGR2 confers its mitotic and viability signaling in and of itself. Herein, we show that, in ECs, VEGFR2 function requires concurrent C3a/C5a receptor (C3ar1/C5ar1) and IL-6 receptor (IL-6R)-gp130 co-signaling. C3ar1/C5ar1 or IL-6R blockade totally abolished VEGFR2 auto-phosphorylation, downstream Src, ERK, AKT, mTOR and STAT3 activation, and EC cell cycle entry. VEGF-A augmented production of C3a/C5a/IL-6 and their receptors via a two-step p-Tyk2/p-STAT3 process. Co-immunoprecipitation analyses, confocal microscopy, ligand pulldown and bioluminescence resonance energy transfer assays all indicated that the four receptors are physically interactive. Angiogenesis in murine day 5 retinas and in adult tissues was accelerated when C3ar1/C5ar1 signaling was potentiated, but repressed when it was disabled. Thus, C3ar1/C5ar1 and IL-6R-gp130 joint activation is needed to enable physiological VEGFR2 function.

SUBMITTER: Hwang MS 

PROVIDER: S-EPMC6451419 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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VEGFR2 survival and mitotic signaling depends on joint activation of associated C3ar1/C5ar1 and IL-6R-gp130.

Hwang Ming-Shih MS   Strainic Michael G MG   Pohlmann Elliot E   Kim Haesuk H   Pluskota Elzbieta E   Ramirez-Bergeron Diana L DL   Plow Edward F EF   Medof M Edward ME  

Journal of cell science 20190328 6


Purified vascular endothelial cell (EC) growth factor receptor-2 (VEGFR2) auto-phosphorylates upon VEGF-A occupation <i>in vitro</i>, arguing that VEGR2 confers its mitotic and viability signaling in and of itself. Herein, we show that, in ECs, VEGFR2 function requires concurrent C3a/C5a receptor (C3ar1/C5ar1) and IL-6 receptor (IL-6R)-gp130 co-signaling. C3ar1/C5ar1 or IL-6R blockade totally abolished VEGFR2 auto-phosphorylation, downstream Src, ERK, AKT, mTOR and STAT3 activation, and EC cell  ...[more]

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