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Circulation Research. 2008
Published online before print August 21, 2008, doi: 10.1161/CIRCRESAHA.108.183327
A more recent version of this article appeared on September 12, 2008
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Submitted on April 19, 2008
Revised on August 8, 2008
Accepted on August 12, 2008

Vascular Endothelial Growth Factor and Semaphorin Induce Neuropilin-1 Endocytosis via Separate Pathways

Anna Salikhova ; Ling Wang ; Anthony A. Lanahan ; Miaoliang Liu ; Michael Simons ; William P. J. Leenders ; Debabrata Mukhopadhyay ; and Arie Horowitz *

From the Angiogenesis Research Center (A.S., A.A.L., M.L., M.S., A.H.), Dartmouth Medical School, Lebanon, NH; Department of Biochemistry and Molecular Biology (L.W., D.M.), Mayo Clinic Cancer Center, Rochester, Minn; and Department of Pathology (W.P.J.L.), Radboud University, Nijmegen Medical Centre, The Netherlands.

* To whom correspondence should be addressed. E-mail: arie.horowitz{at}dartmouth.edu.

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 determine the endocytic pathway of Nrp1 and to determine whether uptake is required for its signaling. Whereas Nrp1 underwent clathrin-dependent endocytosis in response to VEGFA165 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 VEGFA165. 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.
Key words: neuropilin-1 • VEGFR2 • endocytosis • lipid rafts




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[Abstract] [Full Text] [PDF]


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