Neuropilin-1/GIPC1 Signaling Regulates α5β1 Integrin Traffic and Function in Endothelial Cells

• DOI: 10.1371/journal.pbio.1000025
• Publication Date: 2009-01-23T13:01:41Z
• Authors: Donatella Valdembri; Patrick T Caswell; Kurt I Anderson; Juliane P Schwarz; Ireen König; Elena Astanina; Francesca Caccavari; Jim C Norman; Martin J Humphries; Federico Bussolino; Guido Serini
• Keywords: Neuropilin

Neuropilin 1 (Nrp1) is a coreceptor for vascular endothelial growth factor A165 (VEGF-A165, VEGF-A164 in mice) and semaphorin 3A (SEMA3A). Nevertheless, Nrp1 null embryos display defects that differ from those of mice lacking either or Sema3A proteins. Furthermore, it has been recently reported required cell (EC) response to both VEGF-A165 VEGF-A121 isoforms, the latter being incapable binding on EC surface. Taken together, these data suggest phenotype caused by loss could be due VEGF-A164/SEMA3A-independent function ECs, such as adhesion extracellular matrix. By using RNA interference rescue with wild-type mutant constructs, we show here through its cytoplasmic SEA motif independently SEMA3A specifically promotes alpha5beta1-integrin-mediated fibronectin crucial development. We provide evidence Nrp1, while not directly mediating spreading fibronectin, interacts alpha5beta1 at sites. Binding homomultimeric endocytic adaptor GAIP interacting protein C terminus, member (GIPC1), selectively stimulates internalization active Rab5-positive early endosomes. Accordingly, GIPC1, which also alpha5beta1, associated motor myosin VI (Myo6) support endocytosis fibronectin. In conclusion, propose addition role SEMA3A, domain ECs increasing Rab5/GIPC1/Myo6-dependent alpha5beta1. modulation integrin can play causal generation angiogenesis observed mice.