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Neuropilin-1 (NRP1) is a transmembrane receptor playing a pivotal role in the control of semaphorins and VEGF signaling pathways. The exact mechanism controlling semaphorin receptor complex formation is unknown. A structural analysis and modeling of NRP1 revealed a putative dimerization GxxxG motif potentially important for NRP1 dimerization and oligomerization. Our data show that this motif mediates the dimerization of the transmembrane domain of NRP1 as demonstrated by a dimerization assay (ToxLuc assay) performed in natural membrane and FRET analysis. A synthetic peptide derived from the transmembrane segment of NRP1 abolished the inhibitory effect of Sema3A. This effect depends on the capacity of the peptide to interfere with NRP1 dimerization and the formation of oligomeric complexes. Mutation of the GxxxG dimerization motif in the transmembrane domain of NRP1 confirmed its biological importance for Sema3A signaling. Overall, our results shed light on an essential step required for semaphorin signaling and provide novel evidence for the crucial role of transmembrane domain of bitopic protein containing GxxxG motif in the formation of receptor complexes that are a prerequisite for cell signaling.

Neuropilin-1 (NRP1) is a transmembrane receptor playing a pivotal role in the control of semaphorins and VEGF signaling pathways. The exact mechanism controlling semaphorin receptor complex formation is unknown. A structural analysis and modeling of NRP1 revealed a putative dimerization GxxxG motif potentially important for NRP1 dimerization and oligomerization. Our data show that this motif mediates the dimerization of the transmembrane domain of NRP1 as demonstrated by a dimerization assay (ToxLuc assay) performed in natural membrane and FRET analysis. A synthetic peptide derived from the transmembrane segment of NRP1 abolished the inhibitory effect of Sema3A. This effect depends on the capacity of the peptide to interfere with NRP1 dimerization and the formation of oligomeric complexes. Mutation of the GxxxG dimerization motif in the transmembrane domain of NRP1 confirmed its biological importance for Sema3A signaling. Overall, our results shed light on an essential step required for semaphorin signaling and provide novel evidence for the crucial role of transmembrane domain of bitopic protein containing GxxxG motif in the formation of receptor complexes that are a prerequisite for cell signaling.

Knocking down a human gene by RNA silencing has been the focus of a number of laboratories since the discovery of the RNAi mechanism more than 10 years ago. In their remarkable work, M. Davis and collaborators show for the first time the induction of an RNAi pathway in humans following systemic administration of nanoparticles. In a clinical trial, they demonstrate the accumulation of the particles in the tumor, as well as the downregulation of mRNA and protein expression of the target gene. Moreover, they successfully linked these observations to the induction of mRNA cleavage by the delivered siRNA in the tumor.

VEGFC is a crucial player of lymphangiogenesis. Besides VEGFR2 and VEGFR3, it also binds NRP2. NRP2 enhances VEGFC/VEGFR3 effects in developmental lymphangiogenesis, but its role in adult and tumoral lymphangiogenesis is not known. In their study, Bagri and colleagues demonstrate that blocking NRP2 results in a decrease of metastasis formation, a phenomenon relying on tumoral lymphangiogenesis. Thus they identified NRP2 as an attractive new target for modulating metastasis.

Blood vessel leakiness can be induced through the co-receptor NRP1 independently of VEGFR.