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Neuropilin-1 mediates PDGF stimulation of vascular smooth muscle cell migration and signalling via p130Cas

Pellet-Many, C; Frankel, P; Evans, IM; Herzog, B; Junemann-Ramirez, M; Zachary, IC; (2011) Neuropilin-1 mediates PDGF stimulation of vascular smooth muscle cell migration and signalling via p130Cas. BIOCHEM J , 435 609 - 618. 10.1042/BJ20100580. Green open access

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Abstract

NRP1 (neuropilin-1) is a co-receptor for members of the VEGF (vascular endothelial growth factor) family in endothelial cells, but is increasingly implicated in signalling induced by other growth factors. NRP1 is expressed in VSMCs (vascular smooth muscle cells), but its function and the mechanisms involved are poorly understood. The present study aimed to determine, the role of NRP1 in the migratory response of HCASMCs (human coronary artery smooth muscle cells) to PDGF (platelet-derived growth factor), and to identify the signalling mechanisms involved. NRP1 is highly expressed in HAoSMCs (human aortic smooth muscle cells) and HCASMCs, and modified in VSMCs by CS (chondroitin sulfate)-rich O-linked glycosylation at Ser(612). HCASMC migration induced by PDGF-BB and PDGF-AA was inhibited by NRP1 siRNA (small interfering RNA), and by adenoviral overexpression of an NRP1 mutant lacking the intracellular domain (Ad.NRP1 Delta C). NRP1 co-immunoprecipitated with PDGFR alpha (PDGF receptor alpha), and immunofluorescent staining indicated that NRP1 and PDGFR alpha co-localized in VSMCs. NRP1 siRNA also inhibited PDGF-induced PDGFR alpha activation. NRP1-specific siRNA, Ad.NRP1 Delta C and removal of CS glycans using chondroitinase all inhibited PDGF-BB and -AA stimulation of tyrosine phosphorylation of the adapter protein, p130(Cas) (Cas is Crk-associated substrate), with little effect on other major signalling pathways, and p130(Cas) knockdown inhibited HCASMC migration. Chemotaxis and p130(Cas) phosphorylation induced by PDGF were inhibited by chondroitinase, and, additionally, adenoviral expression of a non-glycosylatable NRP1S612A mutant inhibited chemotaxis, but not p130(Cas) phosphorylation. These results indicate a role for NRP1 and NRP1 glycosylation in mediating PDGF-induced VSMC migration, possibly by acting as a co-receptor for PDGFR alpha and via selective mobilization of a novel p130(Cas) tyrosine phosphorylation pathway.

Type: Article
Title: Neuropilin-1 mediates PDGF stimulation of vascular smooth muscle cell migration and signalling via p130Cas
Open access status: An open access version is available from UCL Discovery
DOI: 10.1042/BJ20100580
Publisher version: http://dx.doi.org/10.1042/BJ20100580
Language: English
Additional information: The author(s) has paid for this article to be freely available under the terms of the Creative Commons Attribution Non-Commercial Licence (http://creativecommons.org/licenses/by-nc/2.5/) which permits unrestricted non-commercial use, distribution and reproduction in any medium, provided the original work is properly cited.
Keywords: chemotaxis, glycosylation, neuropilin-1 (NRP1), p130(Cas), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), ENDOTHELIAL GROWTH-FACTOR, SEMAPHORIN-III, TUMOR-CELLS, RECEPTOR, BINDING, ANGIOGENESIS, VEGF(165), VEGF
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Experimental and Translational Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science > Pre-clinical and Fundamental Science
URI: https://discovery.ucl.ac.uk/id/eprint/1081077
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