Coordination of VEGF receptor trafficking and signaling by coreceptors

During development, regeneration and in certain pathological settings, the vasculature is expanded and remodeled substantially. Proper morphogenesis and function of blood vessels are essential in multicellular organisms. Upon stimulation with growth factors including vascular endothelial growth factors (VEGFs), the activation, internalization and sorting of receptor tyrosine kinases (RTKs) orchestrate developmental processes and the homeostatic maintenance of all organs including the vasculature. Previously, RTK signaling was thought to occur exclusively at the plasma membrane, a process that was subsequently terminated by endocytosis and receptor degradation. However, this model turned out to be an oversimplification and there is now a substantial amount of reports indicating that receptor internalization and trafficking to intracellular compartments depends on coreceptors leading to the activation of specific signaling pathways. Here we review the latest findings concerning endocytosis and intracellular trafficking of VEGFRs. The body of evidence is compelling that VEGF receptor trafficking is coordinated with other proteins such as Neuropilin-1, ephrin-B2, VE-cadherin and protein phosphatases.