Neuropilin-1/GIPC1 Signaling Regulates A5b1 Integrin Traffic And Function In Endothelial Cells

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 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 Nrp1 could be due to
a VEGF-A164/SEMA3A-independent function of Nrp1 in ECs, such as adhesion to the extracellular matrix. By using RNA interference and rescue with
wild-type and mutant constructs, the authors show here that Nrp1 through its cytoplasmic SEA motif and independently of VEGF-A165 and SEMA3A
specifically promotes a5b1-integrin-mediated EC adhesion to fibronectin that is crucial for vascular development. They provide evidence that Nrp1,
while not directly mediating cell spreading on fibronectin, interacts with a5b1 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 a5b1 in
Rab5-positive early endosomes. Accordingly, GIPC1, which also interacts with a5b1, and the associated motor myosin VI (Myo6) support active a5b1
endocytosis and EC adhesion to fibronectin. In conclusion, they propose that Nrp1, 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 a5b1. Nrp1 modulation of a5b1 integrin function can play a causal role in the generation of angiogenesis defects observed in
Nrp1 null mice.



Citation:

"Neuropilin-1/GIPC1 signaling regulates a5b1 integrin traffic and
function in endothelial cells."Valdembri D, Caswell PT, Anderson KI, Schwarz JP, KoВЁ nig I, et al. (2009)
PLoS Biol 7(1): e1000025. doi:10.1371/journal.pbio.1000025

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