Vascular endothelial growth factor and semaphorin induce neuropilin-1 endocytosis via separate pathways.
The neuropilin (Nrp)1 receptor is essential for both nervous and vascular system development. Nrp1 is unusually versatile, because it transmits both chemoattractive and repulsive signals in response to vascular endothelial growth factor (VEGF)-A and class 3 semaphorins, respectively. Both Nrp1 and VEGF receptor 2 undergo ligand-dependent endocytosis. We sought to establish the endocytic pathway of Nrp1 and to determine whether uptake is required for its signaling. Whereas Nrp1 underwent clathrin-dependent endocytosis in response to VEGFA(165) treatment, semaphorin 3C (sema3C) induced lipid raft-dependent endocytosis. The myosin VI PDZ (postsynaptic density 95, Disk large, Zona occludens-1) adaptor protein synectin was essential for Nrp1 trafficking. Sema3C failed to inhibit migration of synectin(-/-) endothelial cells, mirroring the lower migratory response of these cells to VEGFA(165). These results show that the endocytic pathway of Nrp1 is determined by its ligand and that the trafficking of Nrp1 is essential for its signaling.
Salikhova
Anna
A
Angiogenesis Research Center, Dartmouth Medical School, Lebanon, NH 03756, USA.
Wang
Ling
L
Lanahan
Anthony A
AA
Liu
Miaoliang
M
Simons
Michael
M
Leenders
William P J
WP
Mukhopadhyay
Debabrata
D
Horowitz
Arie
A
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D002478:Cells, Cultured; D002645:Chickens; D002966:Clathrin / Q000502:physiology; D004705:Endocytosis / Q000502:physiology*; D006801:Humans; D008024:Ligands; D021962:Membrane Microdomains / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009479:Neuropeptides / Q000172:deficiency / Q000235:genetics; D039942:Neuropilin-1 / Q000378:metabolism*; D021381:Protein Transport / Q000235:genetics / Q000502:physiology; D039961:Semaphorins / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D002966:Clathrin; C115271:Gipc1 protein, mouse; D008024:Ligands; D009479:Neuropeptides; D039961:Semaphorins; D042461:Vascular Endothelial Growth Factor A; C510203:semaphorin 3C protein, mouse; D039942:Neuropilin-1