Multifaceted signaling of the cell surface receptor neuropilin-1 (NRP1): pathophysiological roles and therapeutic...

Neuropilin-1 (NRP1) is a developmentally conserved cell surface receptor that functionally acts to bind various ligands like class 3 semaphorins and several members of the VEGF family to engage in different signaling pathways that control cell migration and motility. Due to its widespread expression, NRP1 is implicated in immune function, axonal guidance, viral entry, tumor progression and angiogenesis. NRP1 is dysregulated across multiple cancer types and promotes tumor progression in a context-dependent manner in tumor cells and the tumor microenvironment, including endothelial, stromal, and immune-cell compartments. NRP1 is also involved in different autoimmune disorders, anosmia, and cardiovascular disorders. Phage display studies revealed that peptides containing C-terminal CendR motifs engage NRP1 for tissue penetration. Apart from cell-penetrating peptides, monoclonal antibodies against NRP1 also present a promising target for cancer therapeutics. Importantly, NRP1 in SARS-CoV-2 infection act as an auxiliary host factor, and furin cleavage of the viral spike protein exposes a C-terminal CendR motif that can bind NRP1, thereby facilitating viral entry. However, NRP1 is not an independent receptor comparable to ACE2, thus, NRP1-targeted antiviral strategies need further investigations. Given the above, the review provides comprehensive narrative of different signaling mechanisms of NRP1 in different diseases and how this cell surface receptor can be utilized in various therapeutic approaches to combat these diseases.