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

Author:

Hwang Ming-Shih1ORCID,Strainic Michael G.1ORCID,Pohlmann Elliot1,Pluskota Elzbieta2,Ramirez-Bergeron Diana L.3ORCID,Plow Edward F.2ORCID,Medof M. Edward1ORCID

Affiliation:

1. Department of Pathology, Case Western Reserve University Cleveland, OH 44106, USA

2. Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland OH 44195, USA

3. Case Cardiovascular Research Institute and University Hospitals, Case Western Reserve University School of Medicine and University Hospitals, Cleveland, Ohio 44106, USA

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-IP analyses, confocal microscopy, ligand pull-down, and BRET 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-6Rgp130 joint-activation is needed to enable physiologic VEGFR2 function.

Funder

National Institutes of Health

Publisher

The Company of Biologists

Subject

Cell Biology

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