An inside view: VEGF receptor trafficking and signaling

Abstract

Vascular endothelial growth factors (VEGF) and their receptors play a central role in the development of cardiovascular system and in vasculature-related processes in the adult organism. Given the critical role of this signaling cascade, intricate control systems have evolved to regulate its function. A new layer of added complexity has been the demonstration of the importance of endocytosis and intracellular trafficking of VEGF receptors in the regulation of VEGF signaling. In this review, we consider an evolving link between VEGF receptor endocytosis, trafficking, and signaling and their biological function.

FIGURE 1. VEGF-R2 interacting proteins

Inactive VEGFR2. In resting endothelial cells, VEGFR2 is found in complexes with VE-cadherin and β1-integrins. This brings VEGFR2 close to DEP1 and TCPTP tyrosine phosphatases, thereby maintaining its inactive state. CD47-bound Tsp2 also prevents VEGFR2 activation. Active VEGFR2. VEGFR2 monomers dimerize after VEGF-A binding, leading to phosphorylation of tyrosine kinase domain tyrosines 1054 and 1059 and internalization into clathrin pathway in association with neuropin-1and its cytoplasmic partner synectin. Uncertainty in this function of neuropilin is indicated by Nrp1? Dimerized VEGF-A-bound VEGFR2 in endosomes signals via three key phosphotyrosine sites: Y951, 1175, and 1214.

FIGURE 2. VEGF-R2 trafficking and signaling

VEGFR2 in early Rab5/AAPL endosomes in a complex with synectin and myosin VI. Neuropilin-1 probably serves as a bridge between VEGFR2-containing endosomes and synectin/myosin VI complex. VEGFR2 is partially deactivated on Y1175 site due to proximity to PTP1b leading to decreased ERK signaling. VEGFR2 endosomes undergo APPL to EEA1 conversion. VEGFR2 activity is still partially impaired. Synectin-/myosin VI-dependent trafficking of VEGFR2 away from subplasma membrane regions and close proximity to PTP1b result in increased phosphorylation of Y1175 site and full activation of ERK signaling.