Neuropilins are multifunctional coreceptors involved in tumor initiation, growth, metastasis and immunity

Abstract

The neuropilins (Nrps) are multifunctional proteins involved in development, immunity and cancer. Neuropilin-1 (Nrp1), or its homologue neuropilin-2 (Nrp2), are coreceptors that enhance responses to several growth factors (GFs) and other mediators. Nrps are coreceptors for the class 3 semaphorins (SEMA3), involved in axonal guidance, and several members of the vascular endothelial growth factor (VEGF) family. However, recent findings reveal they have a much broader spectrum of activity. They bind transforming growth factor β1 (TGF-β1) and its receptors, hepatocyte growth factor (HGF) and its receptor (cMet), platelet derived growth factor (PDGF) and its receptors, fibroblast growth factors (FGFs), and integrins. Nrps also promote Hedgehog signaling. These ligands and pathways are all relevant to angiogenesis and wound healing. In the immune system, the Nrps are expressed primarily by dendritic cells (DCs) and regulatory T cells (Tregs), and exert mainly inhibitory effects. In cancer, Nrps have been linked to a poor prognosis, which is consistent with their numerous interactions with ligands and receptors that promote tumor progression. We hypothesize that Nrps boost responses by capturing ligands, regulating GF receptor expression, endocytosis and recycling, and possibly also by signaling independently. Importantly, they promote epithelial-mesenchymal transition (EMT), and the survival of cancer stem cells. The recent finding that Nrps bind and internalize cell-penetrating peptides (CPPs) with arginine/lysine-rich C-terminal motifs (C-end rule; e.g., RXXR) is of interest. These CPPs can be coupled to large drugs for cancer therapy. Almost all studies have been preclinical, but findings suggest Nrps are excellent targets for anti-cancer drug development.

Figure 1. Neuropilin (Nrp) structure and hypothetical model of interaction with multiple growth factors

A. The general domain structure of Nrp1 and Nrp2 is shown. There are five extracellular domains, a single-pass TMD domain, and a short cytosolic tail lacking tyrosine kinase activity. Nrp1 and Nrp2a (but not Nrp2b) have a C-terminal SEA-sequence motif that binds to synectin. There are also splice variants of the Nrps (not shown), including soluble forms lacking the c domain, TMD and cytoplasmic segments. SEMA3s bind to the a1/a2/b1 segment, and VEGFs binds to b1/b2. The binding sites of other GFs are not well characterized. CendR peptides bind to the b1 domain (see text). The c domain contributes to receptor dimerization. B. The Nrps bind ligands of at least five major types of soluble mediators, as well as their signaling receptors. The figure presents a hypothetical model of how these signaling pathways may interact. This includes TGF-β1, VEGF family, HGF, PDGF-BB, and the SEMA3 family. See Table 1 for a list of ligands and references. Except for SEMA3s, the Nrps are not essential for receptor signaling but they enhance the response. The GF signaling pathways intersect extensively with numerous potential outcomes. TGF-β exerts antiproliferative and immunosuppressive effects through canonical (Smad2/3) signaling. However, TGF-β noncanonical signaling (or other GF pathways) can inhibit Smad2/3 signaling. Notably, p130Cas is phosphorylated in response to Nrp-binding GFs, and can block Smad2/3 signaling while favoring noncanonical signaling. SEMA3s interact with Nrps and plexins (the signaling receptors) to activate signaling pathways that regulate axonal guidance, as well as endothelial, immune and tumor cell responses, usually in an inhibitory way. Abbreviations: CendR; C-end rule peptides; cMet, hepatocyte growth factor receptor; EMT, epithelial-to-mesenchymal transition; FAK, focal adhesion kinase; GF, growth factor; HGF, hepatocyte growth factor; Nrp1, neuropilin-1; Nrp2, neuropilin-2; p-, phosphorylated form; p130Cas, Crk-associated substrate; PDGF, platelet-derived growth factor; PDGFR; PDGF receptor; Pyk2, proline-rich tyrosine kinase 2; SEMA3, class 3 semaphorin; TGF-β, transforming growth factor-β; TGF-βRI, TGF-β receptor type 1 (also denoted ALK5); TGF-βRII, TGF-β receptor type 2; TMD; transmembrane domain; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor.