Neuropilin Functions as an Essential Cell Surface Receptor

Abstract

The Neuropilins (Nrps) are a family of essential cell surface receptors involved in multiple fundamental cellular signaling cascades. Nrp family members have key functions in VEGF-dependent angiogenesis and semaphorin-dependent axon guidance, controlling signaling and cross-talk between these fundamental physiological processes. More recently, Nrp function has been found in diverse signaling and adhesive functions, emphasizing their role as pleiotropic co-receptors. Pathological Nrp function has been shown to be important in aberrant activation of both canonical and alternative pathways. Here we review key recent insights into Nrp function in human health and disease.The Nrps 2 are essential cell surface receptors with pleiotropic function in human health, functioning in many key biological processes including in the cardiovascular, neuronal, and immune systems (1). The two Nrp family members, Nrp1 and Nrp2, are type I transmembrane proteins that are conserved in all vertebrates and are ϳ40% identical at the amino acid level with a conserved domain structure. The Nrp extracellular region possesses five structured domains that are essential for ligand binding, a single transmembrane domain, and a short intracellular domain that possesses a PSD-95/Dlg/ZO-1 (PDZ)-binding motif (1).

Netrins & Semaphorins: Novel regulators of the immune response

“…Recently, vascular endothelial growth factor family (VEGF) members have been described to bind to neuropilins to form receptor complexes with semaphorins. Through these interactions, they can regulate key events in angiogenesis [33]. With the exception of Semaphorin 3E, class 3 semaphorins must interact with a neuropilin co-receptor in order to transduce a signal to the plexin receptor.…”

Uses and abuses of macropinocytosis

“…The sequence of CendRs is derived from a C-terminal motif of proteins that bind to Neuropilin receptors (of which there are two isoforms, neuropilin 1 and neuropilin 2). Neuropilins are important during angiogenesis and axon guidance, where they act as receptors for a number of extracellular polypeptide signals (Guo and Vander Kooi, 2015). Uptake of CendR peptides depends both on Neuropilins and the cytoplasmic protein GIPC1, and involves the extension of lamellopodia and their inward folding.…”

VEGF-A121a binding to Neuropilins – A concept revisited

“…They serve as co-receptors for the Plexins in Semaphorin binding on neuronal and vascular endothelial cells, and for the VEGFRs in VEGF binding on vascular and lymphatic endothelial cells, and thus regulate the initiation and coordination of cell signaling by Semaphorins and VEGFs. 2 There is conflicting evidence in the literature as to whether only heparin-binding VEGF-A isoforms – that is, isoforms with domains encoded by exons 6 and/or 7 plus 8a – bind to Neuropilins on endothelial cells. While it is clear that VEGF-A165a binds to both NRP1 and NRP2, published studies do not all agree on the ability of VEGF-A121a to bind NRPs.…”