Abstract
ABSTRACTCell surface receptors can undergo recycling or proteolysis but the cellular decision-making events that sort between these pathways remain poorly defined. Vascular endothelial growth factor A (VEGF-A) and vascular endothelial growth factor receptor 2 (VEGFR2) regulate signal transduction and angiogenesis, but how signaling and proteolysis is regulated is not well understood. Here, we provide evidence that a pathway requiring the E1 ubiquitin-activating enzyme UBA1 controls basal VEGFR2 levels, hence metering plasma membrane receptor availability for the VEGF-A-regulated endothelial cell response. VEGFR2 undergoes VEGF-A-independent constitutive degradation via a UBA1-dependent ubiquitin-linked pathway. Depletion of UBA1 increased VEGFR2 recycling from endosome-to-plasma membrane and decreased proteolysis. Increased membrane receptor availability after UBA1 depletion elevated VEGF-A-stimulated activation of key signaling enzymes such as PLCγ1 and ERK1/2. Although UBA1 depletion caused an overall decrease in endothelial cell proliferation, surviving cells showed greater VEGF-A-stimulated responses such as cell migration and tubulogenesis. Our study now suggests that a ubiquitin-linked pathway regulates the balance between receptor recycling and degradation which in turn impacts on the intensity and duration of VEGF-A-stimulated signal transduction and the endothelial response.
Highlights
Vascular endothelial growth factor A (VEGF-A) is an important regulator of animal health and disease (Ferrara, 1999)
We hypothesized that ubiquitination of basal vascular endothelial growth factor receptor 2 (VEGFR2) targets this membrane receptor for trafficking and proteolysis
To identify ubiquitin-linked regulators, we evaluated the requirement for E1 ubiquitin-activating enzymes in controlling VEGFR2 levels in human umbilical vein endothelial cells (HUVECs)
Summary
Vascular endothelial growth factor A (VEGF-A) is an important regulator of animal health and disease (Ferrara, 1999). VEGF binding to a vascular endothelial growth factor receptor (VEGFR) can trigger multiple signal transduction pathways and cellular responses in. VEGF-A binding to VEGFR2 on endothelial cells causes a diverse range of pro-angiogenic responses (Olsson et al, 2006; Shibuya, 2010). Highly studied, it is not well understood how the endothelial cell integrates multiple pathways to direct THE sprouting of new blood vessels upon encountering ligands such as VEGF-A
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