Neuropilin-1 (NRP1) is a protein that plays diverse roles in the body, influencing many biological processes. This versatile molecule is involved in the development of the nervous and cardiovascular systems. Beyond its developmental functions, NRP1 also participates in regulating the immune system. NRP1’s broad impact on health highlights its importance in maintaining bodily functions.
Understanding Neuropilin-1
NRP1 is a type I transmembrane glycoprotein found on the surface of various cell types, including neuronal, endothelial, and immune cells. It measures between 130 to 140 kDa. The protein features a large N-terminal extracellular domain, a single transmembrane domain, and a short intracellular domain. The extracellular domain contains five subdomains: two complement-binding (a1a2), two coagulation factor V/VIII (b1b2), and one meprin (c) domain. The a and b domains are involved in binding to other molecules, while the c domain facilitates NRP1’s ability to form homodimers or heterodimers with NRP2, which is important for its functions.
NRP1 functions as a co-receptor, working alongside other receptors to amplify or modulate signals. It binds to various ligands, including members of the semaphorin family and vascular endothelial growth factor (VEGF) family proteins. This interaction enhances the signaling pathways of its partners, allowing NRP1 to influence a wide range of cellular activities.
NRP1’s Diverse Roles in the Body
In the nervous system, NRP1 plays a role in axon guidance, directing the growth of nerve fibers during development. This involves mediating the chemorepulsant activity of semaphorins, which are molecules that guide axons away from certain areas. NRP1 also forms complexes with other receptors to mediate these guidance cues.
NRP1 also plays a part in blood vessel formation, known as angiogenesis. It acts as a co-receptor for various vascular endothelial growth factor (VEGF) family members, enhancing their signaling to promote new blood vessel development. Its expression in blood vessels across different tissues, particularly in the developing embryo, highlights its involvement in the cardiovascular system.
NRP1 also regulates the immune system. It is expressed on various immune cells, including macrophages, dendritic cells (DCs), and T cell subsets, such as regulatory T cells. NRP1 can mediate interactions between dendritic cells and T lymphocytes, which is important for initiating a primary immune response. Its influence extends to regulating cell migration and communication between immune cells.
How NRP1 Influences Disease
NRP1’s involvement extends to various disease states, particularly cancer progression and viral infections. In cancer, NRP1 influences tumor cell proliferation, migration, invasion, and metastasis. Elevated NRP1 levels are observed in numerous human tumors and often correlate with a poorer prognosis and increased metastasis. For instance, in prostate cancer, NRP1 promotes tumor vascularization and inhibits tumor cell apoptosis.
NRP1 interacts with several signaling pathways, including those involving vascular endothelial growth factor (VEGF), semaphorins, and transforming growth factor-beta (TGF-β). This modulates the tumor microenvironment and promotes angiogenesis, which feeds tumor growth. In gastric cancer, NRP1 has been shown to induce epithelial-mesenchymal transition (EMT), a process that enhances the migration and invasion of cancer cells.
NRP1 has also been identified as a co-receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19. The SARS-CoV-2 spike protein binds directly to NRP1 on the cell surface. This interaction significantly enhances the virus’s ability to infect cells and spread. NRP1 is abundantly expressed in the respiratory and olfactory epithelium, and studies suggest it may facilitate the virus’s entry into the central nervous system through the nasal cavity.
NRP1 as a Therapeutic Target
The multifaceted roles of NRP1 in disease make it a promising target for therapeutic interventions. Researchers are exploring ways to modulate NRP1 activity to treat conditions like cancer and viral infections. One approach involves blocking NRP1’s function, such as using monoclonal antibodies or small molecule inhibitors that disrupt its binding to ligands. A synthetic peptide has shown the ability to block NRP1 activity and induce programmed cell death in tumor cells with high NRP1 expression.
For viral infections, particularly SARS-CoV-2, interrupting the interaction between the viral spike protein and NRP1 could reduce viral entry and spread. Compounds that target the VEGF-A binding site on NRP1 have been identified, showing potential to inhibit both VEGF-A signaling and the entry of viruses utilizing the SARS-CoV-2 spike protein. These strategies are being investigated in preclinical settings, aiming to develop therapies that could inhibit tumor growth or prevent viral-induced complications.