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.

RTK signaling requires C3ar1/C5ar1 and IL‐6R joint signaling to repress dominant PTEN, SOCS1/3 and PHLPP restraint

“…They are consistent with PMEFs and SMCs locally producing C3a/C5a from endogenously synthesized complement and autocrine C3ar1/C5ar1 signaling regulating growth as characterized in immune cells . siRNA experiments in our prior study on VEGFR2 signaling validated the integral role C3ar1/C5ar1 signaling in cell growth.…”

“…It similarly blocked PDGF‐BB‐induced growth of primary WT SMCs which express PDGFR‐ββ (not shown). Genetic deficiency of C3ar1/C5ar1 signaling had a similar, albeit less complete abrogating effect (Figure E), as observed for VEGFR2 signaling and linked to compensatory pathways.…”

“…Cellular homeostasis and proliferation are regulated by the growth factors which confer their activities via inducing RTK signaling. In previous work, we studied signaling by VEGFR2 and found that VEGFR2’s survival and growth functions in vascular endothelial cells (ECs) depend on joint signaling through two other receptor systems: C3a and C5a receptor (C3ar1/C5ar1), G protein‐coupled‐receptors (GPCRs), and IL‐6 receptor (IL‐6R) associated glycoprotein‐130 (gp130) . Our experiments provided the multiple lines of evidence that these receptor systems are physically interactive with VEGFR2 in a signaling platform.…”

“…As indicated (Introduction), our previous study on VEGFR2 signaling interlinked IL‐6R‐gp130 signaling as well as C3ar1/C5ar1 signaling as requisite processes in VEGFR2 signaling in ECs . Based on that, we next examined whether the same interdependence applies to EGFR and PDGFR signaling.…”

“…We showed that in ECs that anti‐VEGFR2 immunoprecipitates (IPs) brought down C3ar1, C5ar1, and gp130 associated with IL‐6R . Anti‐EGFR IPs in mIMCD3 cells (Figure D) and anti‐PDGF IPs in NIH‐3T3 cells (Figure E) (both of which express IL‐6R) similarly brought down C3ar1, C5ar1, and gp130, but did not bring down a nonrelevant protein, that is, CD59.…”