Abstract
Vascular endothelial growth factor receptor-2 (VEGFR2) and its ligands (VEGFs) are crucial players in vasculogenesis and angiogenesis. General blocking of this signaling system with antibodies or small molecule inhibitors is an established strategy to treat cancer and age-related macular degeneration. Nevertheless, the activated receptor can signal to discrete downstream signaling pathways and the equilibrium between these pathways is modulated by coreceptors and distinct isoforms of VEGF. Here we investigated the influence of Rab GTPase activating proteins (RabGAPs) on VEGFR2 signaling, tube formation, and migration of endothelial cells. We demonstrate that members of the TBC1D10 subfamily of RabGAPs have opposite effects. Whereas TBC1D10A leads to increased Erk1/2 signaling, TBC1D10B lowered Erk1/2 and p38 signaling and reduced tube formation in vitro. TBC1D10A is a RabGAP acting on RAB13 that was shown before to play a role in angiogenesis and we could indeed show colocalization of these two proteins with VEGFR2 in activated cells. In addition, we observed that cells expressing TBC1D10B show lower expression of VEGFR2 and NRP1 on filopodia of activated cells. Taken together, our systematic analysis of influence of RabGAPs on VEGFR2 signaling identifies the TBC1D10 subfamily members as modulators of angiogenesis.
Highlights
Vasculogenesis, angiogenesis, and lymphangiogenesis are essential processes during development, regeneration, and certain pathological conditions in multicellular organisms
In tip cells of developing vessel sprouts, Vascular endothelial growth factor receptor-2 (VEGFR2) is rapidly activated and internalized, whereas it is co-localized with vascular endothelial-phosphotyrosine phosphatase (VE-PTP) in neighboring stalk cells leading to reduced signaling[10]
VEGFR2 is an important player in this context, and here we addressed the influence of Rab GTPase activating proteins (RabGAPs) on VEGFR2-based signaling, migration, and tube formation
Summary
Vasculogenesis, angiogenesis, and lymphangiogenesis are essential processes during development, regeneration, and certain pathological conditions in multicellular organisms. Several tyrosine and serine phosphorylation sites have been identified in VEGFR2 that link to downstream signaling pathways or degradation. Phosphorylated Y1175 binds to phospholipase Cγ (PLCγ), leading to activation of Erk1/2 pathways, and is important for proliferation and differentiation of endothelial cells during development[6]. In tip cells of developing vessel sprouts, VEGFR2 is rapidly activated and internalized, whereas it is co-localized with vascular endothelial-phosphotyrosine phosphatase (VE-PTP) in neighboring stalk cells leading to reduced signaling[10]. Rab GTPases are small GTPase that localize to specific intracellular compartments where they regulate cargo trafficking They are excellent markers to monitor trafficking of RTKs. It was shown before that VEGFR2 colocalizes with several Rab GTPases and that these colocalizations are linked to signaling events. This complex translocates to Rab13-positive vesicles and moves to the leading edge of migrating cells[20]
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