Neuropilin-1/GIPC1 signaling regulates α5β1 integrin traffic and function in endothelial cells

Valdembri, D. et al. (2009) Neuropilin-1/GIPC1 signaling regulates α5β1 integrin traffic and function in endothelial cells. PLoS Biology, 7(1), e1000025. (doi:10.1371/journal.pbio.1000025)

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Publisher's URL: http://dx.doi.org/10.1371/journal.pbio.1000025

Abstract

Neuropilin 1 (Nrp1) is a coreceptor for vascular endothelial growth factor A165 (VEGF-A165, VEGF-A164 in mice) and semaphorin 3A (SEMA3A). Nevertheless, <i>Nrp1</i> null embryos display vascular defects that differ from those of mice lacking either VEGF-A164 or Sema3A proteins. Furthermore, it has been recently reported that Nrp1 is required for endothelial cell (EC) response to both VEGF-A165 and VEGF-A121 isoforms, the latter being incapable of binding Nrp1 on the EC surface. Taken together, these data suggest that the vascular phenotype caused by the loss of <i>Nrp1</i> could be due to a VEGF-A164/SEMA3A-independent function of <i>Nrp1</i> in ECs, such as adhesion to the extracellular matrix. By using RNA interference and rescue with wild-type and mutant constructs, we show here that Nrp1 through its cytoplasmic SEA motif and independently of VEGF-A165 and SEMA3A specifically promotes α5β1-integrin-mediated EC adhesion to fibronectin that is crucial for vascular development. We provide evidence that <i>Nrp1</i>, while not directly mediating cell spreading on fibronectin, interacts with α5β1 at adhesion sites. Binding of the homomultimeric endocytic adaptor GAIP interacting protein C terminus, member 1 (GIPC1), to the SEA motif of Nrp1 selectively stimulates the internalization of active α5β1 in Rab5-positive early endosomes. Accordingly, GIPC1, which also interacts with α5β1, and the associated motor myosin VI (Myo6) support active α5β1 endocytosis and EC adhesion to fibronectin. In conclusion, we propose that <i>Nrp1</i>, in addition to and independently of its role as coreceptor for VEGF-A165 and SEMA3A, stimulates through its cytoplasmic domain the spreading of ECs on fibronectin by increasing the Rab5/GIPC1/Myo6-dependent internalization of active α5β1. <i>Nrp1</i> modulation of α5β1 integrin function can play a causal role in the generation of angiogenesis defects observed in <i>Nrp1</i> null mice.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Anderson, Professor Kurt and Norman, Professor James
Authors: Valdembri, D., Caswell, P.T., Anderson, K.I., Schwarz, J.P., König, I., Astanina, E., Caccavari, F., Norman, J.C., Humphries, M.J., Bussolino, F., and Serini, G.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:PLoS Biology
Publisher:Public Library of Science
ISSN:1544-9173
ISSN (Online):1545-7885
Copyright Holders:Copyright © 2009 The Authors
First Published:First published in PLoS Biology 7(1):e1000025
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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