7. Neuropilins and the primary cilium

VEGF can also bind to neuropilins (NRP), a family of transmembrane glycoproteins that play key role in axonal guidance, angiogenesis, tumorigenesis and immunological response [65]. NRPs have been characterized as co-receptors for VEGFRs and plexins, the receptors of the extracellular secreted ligands, belonging to class III semaphorins [60]. In turn, semaphorins are a class of secreted and membrane proteins that were originally identified as axonal growth cone guidance molecules. At least two neuropilin genes, NRP1 and NRP2, have been identified [66]. Genetic studies in mice have confirmed that NRPs are key components of vasculogenesis, angiogenesis and lymphangiogenesis [65, 66]. Nevertheless, NRPs can bind to growth factors such as VEGF, placental growth factor (PlGF), hepatocyte growth factor (HGF) and fibroblast growth factor (FGF), among others. And due to VEGF binding, NRPs can also modulate blood flow [65].

In endothelial cells, NRPs are thought to increase signaling through the VEGFRs acting as a coreceptor of VEGF and by stabilizing the VEGF/VEGFR complexes and therefore enhancing VEGF activity. Thus, the interaction of VEGF-A165 with NRP1 is required for stable binding of VEGF-A165 to VEGFR-2, full activation of VEGFR-2 and downstream signaling and biological responses [65, 67].

Limited information about the localization of NRP in primary cilium is available. Before presenting those evidences, we should give some information about hedgehog (HH) signaling. Briefly, HH signaling is essential for tissue patterning and organ formation during embryonic and postnatal development, as well as in cancer development and tissue homeostasis renewal and repair in adult animals [68]. The HH pathway acts via activation of transcriptional effectors, such as the glioblastoma (Gli) proteins, a family of transcription factors whose target genes remain enigmatic. The Gli protein family includes Gli1, Gli2 and Gli3 [69].

Referring to the primary cilium, studies conducted by Pinskey et al. [68] found that NRP1 and NRP2 promote the activation of Gli transcription factor. Interestingly, the authors found that a conserved 12 amino acid region of the NRP1 cytoplasmic domain between amino acids 890 and 902 is responsible for the HH-signal promotion. Considering that an intact primary cilium is a main component of the HH signaling, they also looked for the localization of NRP1 in this subcellular compartment and showed the unique evidence until now about the localization of NRP1, but not NRP2, in the primary cilium [68]. Despite the fact that the localization of NRP1 in the primary cilium was not required for HH signaling promotion, it is intriguing why NRP1 is present in primary cilium and what would be its physiological relevance there. This observation is important considering that NRP1, as indicated previously, may interact with growth factors, such as VEGF, PlGF, HGF and FGF, among others, regulating their action. Still more questions than answers emerge and more investigation is required to lighten these intriguing possibilities.
