VEGFR2 trafficking: Speed doesn’t kill

Vascular endothelial growth factor-A (VEGF-A) plays a central role in formation of the blood vasculature. The growth factor acts on endothelial cells via a receptor tyrosine kinase, VEGF receptor 2 (VEGFR2) and a non-tyrosine kinase receptor neuropilin-1 (NRP1). Both of these are vital to VEGF-A signaling as a deletion or mutations in either receptor lead to a variety of vascular defects. Given the critical importance of the VEGF signaling system to vascular development and its exquisite sensitivity to the level of the ligand (even a 50% reduction in VEGF levels during development leads to embryonic lethality), it is not surprising that the system is tightly regulated at a number of levels. One such recently appreciated regulatory mechanism is the spatial control of VEGFR2 signaling activities. Upon VEGF binding VEGFR2 undergoes endocytosis that is the beginning, rather than the ending, of a series of complicated events that control the downstream sig-naling pathways. Whereas some downstream pathways may reach full potential at the plasma membrane level, others approach their peak activity only after VEGFR2 enters a particular cellular compartment. VEGF-induced ERK activation is an example of a signaling pathway that mainly takes place in a specific endo-somal compartment. While endosomal activation of ERK has been observed before, what is unusual about VEGFR2/ ERK signaling is that the full activation of this pathway is regulated by the speed of trafficking of VEGFR2/NRP1 in the cytoplasm. 3 Upon binding VEGF-A 165 , VEGFR2 and NRP1 undergo endocytosis as a complex. NRP1 possesses an N-terminal VEGF binding site that allows it to bind VEGF-A 165 and a C-terminal PDZ binding domain. Once the VEGF-A 165-VEGFR2-NRP1 complex enters the Rab5+ sorting endosomes, NRP1 via its PDZ binding site binds a PDZ domain protein synectin. Synectin, in turn, links the entire complex to myosin-VI, a reverse transport motor that allows rapid movement of the VEGFR2-containing endo-somes away from the plasma membrane. 4 This is a key step, as Rab5+ endosomes near the plasma membrane are also targeted by the protein tyrosine phosphatase PTP1b that can specifically dephosphory-late VEGFR2 at Tyr 1175 , the site involved in activation of the ERK signaling cascade. We have shown that deletion of the NRP1 cytoplasmic domain in arterial endothelial cells gives rise to delayed trafficking of VEGFR2, which causes prolonged exposure of VEGFR2 to PTP1b and a decrease in Tyr 1175 phosphorylation (Fig. 1). This, in turn, leads to reduced ERK1/2 …