GO:0038191 neuropilin binding: Mechanism, Genes and Research

Neuropilin binding (GO:0038191) is a molecular function that describes the binding to a member of the neuropilin family, which includes the transmembrane receptors neuropilin-1 (NRP1) and neuropilin-2 (NRP2). Neuropilins are best known as co-receptors for vascular endothelial growth factors (VEGFs) and semaphorins, and their binding interactions govern fundamental processes such as angiogenesis and axon guidance. The neuropilin family is characterized by distinct extracellular domains that determine ligand specificity, and structural studies have shown that neuropilin structure governs VEGF and semaphorin binding to regulate angiogenesis. Because neuropilin binding is central to both physiological and pathological signaling, it has become a focal point for research in cancer, neuroscience, and infectious disease [1,2,5,6]. In cancer, neuropilin binding contributes to tumor progression and immune evasion. For example, inhibition of VEGF binding to NRP2 enhances chemosensitivity and inhibits metastasis in triple-negative breast cancer, while therapeutic blocking of VEGF binding to NRP2 diminishes PD-L1 expression to activate antitumor immunity in prostate cancer. In non-small cell lung cancer, radiation-induced YAP/TEAD4 binding confers radioresistance by promoting NRP1 transcription. Beyond oncology, neuropilin binding is implicated in pain signaling: neuropilin-1 inhibition suppresses nerve growth factor signaling and nociception in pain models. Furthermore, neuropilin-1 acts as a host factor for SARS-CoV-2 infection and modulates hepatitis B virus entry, highlighting its broad relevance to human health. Understanding neuropilin binding at the molecular level is therefore essential for researchers aiming to dissect signaling pathways, identify therapeutic targets, and develop CRISPR-based models. This article provides a comprehensive overview of the GO:0038191 term, its mechanisms, key genes, disease associations, and experimental approaches, with all facts supported by peer-reviewed literature.

According to the Gene Ontology, neuropilin binding (GO:0038191) is defined as the binding to a member of the neuropilin family. This molecular function encompasses any interaction in which a protein or ligand selectively binds to neuropilin-1 (NRP1) or neuropilin-2 (NRP2). Neuropilins are cell-surface receptors that lack intrinsic catalytic activity but function as co-receptors for various ligands, including VEGFs and semaphorins. The binding event is mediated by specific extracellular domains of the neuropilin proteins, and the affinity and specificity of these interactions are critical for downstream signaling.

Neuropilin binding is critically important because it orchestrates diverse signaling pathways that influence development, immunity, and disease. Neuropilins act as co-receptors for VEGFs and semaphorins, thereby controlling angiogenesis and axon guidance. Dysregulation of these interactions contributes to cancer progression, where NRP2 binding to VEGF promotes chemoresistance and metastasis, and NRP1 transcription driven by YAP/TEAD4 confers radioresistance in lung cancer. Moreover, neuropilin binding is exploited by pathogens: NRP1 is a host factor for SARS-CoV-2 and modulates hepatitis B virus entry. In pain models, neuropilin-1 inhibition suppresses nerve growth factor signaling and nociception. Thus, understanding neuropilin binding offers opportunities for therapeutic intervention across oncology, infectious disease, and neuroscience.

The following genes and proteins are central to neuropilin binding and its downstream effects.

Neuropilin binding and expression are regulated at multiple levels. Transcriptionally, NRP1 is induced by radiation through YAP/TEAD4 binding in non-small cell lung cancer, while NRP2 transcription is regulated by Smad3 binding to its 5' untranslated region. At the protein level, neuropilin binding to ligands such as VEGF and semaphorins is governed by the structural domains of the neuropilin receptors. Additionally, therapeutic agents can block these interactions, as shown by inhibition of VEGF binding to NRP2 in breast and prostate cancer models [1,8]. These regulatory mechanisms provide multiple entry points for experimental manipulation.

Neuropilin binding plays a pivotal role in cancer progression. In triple-negative breast cancer, inhibition of VEGF binding to NRP2 enhances chemosensitivity and inhibits metastasis. In prostate cancer, therapeutic blocking of VEGF binding to NRP2 diminishes PD-L1 expression, thereby activating antitumor immunity. Radiation-induced YAP/TEAD4 binding promotes NRP1 transcription, conferring radioresistance in non-small cell lung cancer. These findings underscore the potential of targeting neuropilin binding as a therapeutic strategy in oncology.

Neuropilin binding is exploited by viruses to facilitate entry. NRP1 is a host factor for SARS-CoV-2 infection, interacting with the viral spike protein to promote viral entry. Similarly, neuropilin-1 modulates the entry of hepatitis B virus, highlighting its role in viral pathogenesis. These discoveries have spurred interest in developing inhibitors of neuropilin binding as antiviral agents.

Neuropilin-1 inhibition suppresses nerve growth factor signaling and nociception in pain models. This suggests that neuropilin binding contributes to pain perception and that targeting these interactions could offer analgesic strategies. Additionally, neuropilins are classic regulators of axon guidance through semaphorin binding, which is critical for neural development.

Binding assays such as surface plasmon resonance (SPR) and enzyme-linked immunosorbent assay (ELISA) are used to measure the affinity and specificity of neuropilin-ligand interactions. These methods have been instrumental in defining how neuropilin structure governs VEGF and semaphorin binding.

CRISPR knockout and knock-in screens enable systematic interrogation of genes involved in neuropilin binding. For example, knockout of NRP2 in breast cancer cells revealed enhanced chemosensitivity, and knockout of NRP1 in lung cells demonstrated its role in SARS-CoV-2 entry.

RNA-seq and ChIP-seq can identify transcriptional regulators of neuropilins. Studies have shown that YAP/TEAD4 binding promotes NRP1 transcription and Smad3 regulates NRP2 transcription by binding to its 5' UTR.

Mouse models of cancer, pain, and viral infection are used to study neuropilin binding in a physiological context. For instance, neuropilin-1 inhibition suppresses nociception in pain models, and blocking VEGF binding to NRP2 inhibits metastasis in breast cancer models.

Researchers studying neuropilin binding-related genes often need to determine whether a candidate gene is causally involved in a specific biological process or disease. This requires precise genetic manipulation, which can be achieved through CRISPR-based approaches. EDITGENE provides a comprehensive suite of services to support such investigations, from knockout and point mutation to knock-in and overexpression models, as well as library screening and bioinformatics analysis.

Neuropilin binding (GO:0038191) is a fundamental molecular function that mediates critical interactions between neuropilin receptors and ligands such as VEGFs and semaphorins. Its roles in angiogenesis, axon guidance, cancer progression, viral infection, and pain perception make it a high-priority target for basic and translational research [1,2,4,5,6,8]. Dysregulation of neuropilin binding contributes to chemoresistance, immune evasion, and radioresistance, underscoring the need for precise experimental models [1,3,8]. CRISPR-based approaches, including knockout, point mutation, knock-in, and overexpression, provide powerful tools to dissect the mechanisms and consequences of neuropilin binding. EDITGENE offers comprehensive services to support these studies, from custom cell line generation to library screening and bioinformatics. By leveraging these technologies, researchers can accelerate discoveries that may lead to novel therapeutics targeting neuropilin binding in human disease.