Neuropilin-1 (NRP1) is a protein on the surface of many cells that functions as a versatile receptor, receiving signals from outside the cell. It acts as a “co-receptor,” assisting other primary receptors in performing their duties more efficiently. This helper role makes NRP1 a participant in a wide range of biological processes.
The functions of NRP1 are diverse, shifting based on the specific biological context. In a healthy state, it is involved in the development of the nervous and vascular systems. However, this same protein can be implicated in disease. Its multi-purpose nature allows it to be co-opted by cancer cells to aid their growth and by certain viruses to help them enter and infect human cells.
Neuropilin-1’s Normal Biological Roles
Neuropilin-1 is a type I transmembrane protein, with a portion outside the cell, a part spanning the cell membrane, and a tail extending into the cell’s interior. This structure allows it to interact with molecules outside the cell and influence processes within it. It lacks its own enzymatic activity but can boost the function of the receptors it assists.
One of its well-documented roles is in axon guidance during embryonic development. This process is akin to wiring a complex electrical circuit, where NRP1 helps guide developing neurons to their precise destinations. It binds to signaling molecules called semaphorins, which act as repulsive cues, steering growing axons away from incorrect paths. This function ensures the nervous system forms correctly.
NRP1 is also involved in angiogenesis, the formation of new blood vessels. This process is for initial development and for tissue growth and repair in adults. On the surface of endothelial cells, NRP1 acts as a co-receptor for Vascular Endothelial Growth Factor (VEGF). It binds to the VEGF-A165 isoform, enhancing interaction with the primary receptor, VEGFR2, to stimulate the sprouting of new capillaries.
Involvement in Cancer Progression
The normal function of Neuropilin-1 in promoting blood vessel formation is exploited by cancerous tumors. To grow and survive, tumors require a dedicated blood supply, and they hijack the process of angiogenesis. Many tumor cells express high levels of NRP1 on their surface, which helps them foster the creation of their own vascular networks.
Heightened expression of NRP1 on cancer cells is frequently associated with more aggressive tumors and a poorer prognosis. The increased angiogenesis supports rapid tumor expansion. Tumor cells secrete VEGF, which then binds to NRP1 on nearby endothelial cells, stimulating the growth of blood vessels that feed the tumor. This creates a self-sustaining cycle that fuels the cancer’s progression.
NRP1 is also implicated in metastasis, the process by which cancer cells spread. The protein enhances the migration and invasion capabilities of cancer cells by participating in the epithelial-mesenchymal transition (EMT). This transition allows stationary cells to become migratory, detach from the primary tumor, and establish new tumors in distant organs.
A Gateway for Viral Entry
Neuropilin-1 also serves as an entry point for certain viruses to infect human cells. While many viruses have a primary receptor, some use co-receptors like NRP1 to make infection more efficient. This function gained attention during research into SARS-CoV-2, the virus that causes COVID-19.
For SARS-CoV-2, the primary receptor is Angiotensin-converting enzyme 2 (ACE2), but NRP1 acts as an additional host factor that facilitates viral entry. An analogy for this mechanism is to think of ACE2 as the main door to a cell and NRP1 as a side door. The virus’s spike protein, after being cleaved by a host enzyme called furin, exposes a sequence that binds directly to NRP1. This interaction enhances the virus’s ability to enter cells, particularly in tissues where NRP1 is abundant, and may help explain the virus’s ability to infect a wide range of tissues.
Targeting Neuropilin-1 for Therapy
Given its involvement in cancer and viral infections, Neuropilin-1 is an attractive target for new therapeutic strategies. The approach is to create drugs that block NRP1’s function. These therapies aim to prevent the protein from interacting with its binding partners, disrupting the pathological processes it enables.
In cancer therapy, the goal is to inhibit tumor growth by cutting off its blood supply. Monoclonal antibodies and small-molecule inhibitors have been developed to target NRP1. These molecules block the site where VEGF binds, preventing the angiogenic signaling that starves tumors and may inhibit metastasis.
For viral diseases, a similar blocking strategy is explored. By obstructing the site on NRP1 that viruses use for entry, therapeutic agents could close the “side door” to the cell. This would reduce the efficiency of viral infection and lessen disease severity. Research into NRP1 inhibitors is an active field, offering potential for future treatments.