The Role of Neuropilins in TGF-β Signaling and Cancer Biology

The neuropilins (Nrps) interact with a number of growth factors (GFs) and/or their receptors. This includes vascular endothelial growth factor (VEGF), transforming growth factor β1 (TGF-β1), hepatocyte growth factor (HGF), platelet-derived growth factor (PDGF), and epidermal growth factor receptor (EGFR). These interactions can involve one or both homologues, Nrp1 and Nrp2, and generally enhance the response to these GFs. Here, we will review non-VEGF interactions, with emphasis on TGF-β. We found that both Nrp1 and Nrp2 bind active TGF-β1 and its latent form denoted latency associated peptide (LAP)-TGF-β1. The Nrps also bind to the signaling TGF-β receptors (TβRI and TβRII) and the co-receptor betaglycan (TβRIII). Studies by us and others established that Nrp1 and Nrp2 augment TGF-β canonical (Smad2/3-dependent) or noncanonical signaling. This was observed in fibroblasts, hepatic stellate cells, lymphocytes, endothelial cells, cardiomyocytes, and several types of cancer cells. TGF-β1-mediated effects that were reduced by Nrp1 or Nrp2 knockdown and/or enhanced by their overexpression include collagen production, epithelial-to-mesenchymal transition (EMT), endothelial-to-mesenchymal transition (EndMT), cancer cell activities (e.g., migration and invasion), and regulatory T-cell-mediated suppression. TGF-β markedly upregulated the expression of Nrp2 on cancer cells, which promoted EMT. Conventional CD4+ T lymphocytes induced to express Nrp1 acquired immunosuppressive activity. These effects appear cell type and context dependent, and in some cases Nrps did not enhance or reduced canonical signaling. In conclusion, the Nrps impact on the stimulatory capacity of TGF-β and other GFs, and this is relevant to angiogenesis, wound healing, cancer biology, immunity, and other processes. As such, the Nrps are important targets for drug development.