# NRP1 (Neuropilin-1): VEGF and C-EndR Viral Peptide Co-Receptor Binding in Tissue Tropism


## Key Takeaways

- Neuropilin-1 (NRP1) functions as a crucial co-receptor for viral entry, notably binding to the C-end rule (C-EndR) motif present in the SARS-CoV-2 spike protein, thereby facilitating viral tropism and cellular uptake.
- The extracellular b1 domain of NRP1 contains a positively charged pocket that accommodates the C-terminal arginine of VEGF-A165 and the RXXR/K motif of viral peptides, with key residues like Asp320 and Glu348 critical for this interaction.
- NRP1's expression is tightly regulated by transcription factors such as HIF1α and GATA3, and it is subject to epigenetic control via DNA methylation, with dysregulation contributing to oncogenesis and disease pathogenesis.
- Alternative splicing generates NRP1 isoforms (e.g., NRP1-S, NRP1-Δexon7) that exhibit differential ligand-binding affinities and tissue-specific expression patterns, influencing signaling outcomes in development and disease.
- NRP1 is implicated in congenital disorders like Tetralogy of Fallot and serves as a prognostic biomarker in various malignancies, including hepatocellular carcinoma and triple-negative breast cancer, highlighting its clinical significance.
- Therapeutic strategies targeting NRP1 include monoclonal antibodies and small-molecule inhibitors designed to block VEGF or viral peptide binding to the b1 domain, aiming to disrupt pathological signaling pathways and viral entry.

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## Executive Summary & Key Metadata

Neuropilin-1 (NRP1) is a multifunctional, single-pass transmembrane glycoprotein that operates as a co-receptor for class 3 semaphorins (SEMA3), specific isoforms of vascular endothelial growth factor (VEGF), and, critically, for viral entry factors bearing a C-end rule (C-EndR) motif. The NRP1 gene product is a master regulator of developmental angiogenesis, axon guidance, and immune homeostasis. Its pathological relevance spans oncogenic signaling, congenital heart defects, and the cellular entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and mammalian orthoreovirus [1, 2, 3].

The protein is characterized by an extracellular region containing two complement-binding (CUB) domains, two coagulation factor V/VIII homology domains, and a MAM (meprin/A5 antigen/receptor tyrosine phosphatase mu) domain, followed by a single transmembrane helix and a short cytoplasmic tail lacking intrinsic enzymatic activity [4]. The structural basis for ligand discrimination is encoded in the b1 domain, which contains a highly basic pocket that binds the VEGF-A exon 7-encoded domain and the C-EndR motif (RXXR/K) found in viral spike proteins [3].

The gene is located on chromosome 10p11.22 and is subject to complex transcriptional regulation, including hypoxia-inducible factor 1-alpha (HIF1α) and E2F7 co-regulation, GATA3-dependent activation, and YAP/TEAD4-mediated transcription [5, 6, 7]. Alternative splicing generates isoforms with differential ligand-binding affinities and tissue-specific expression patterns.

The clinical significance of NRP1 is underscored by its role as a prognostic biomarker in multiple malignancies, including hepatocellular carcinoma, gastric cancer, triple-negative breast cancer, and medulloblastoma [8, 9, 10, 11]. NRP1 haploinsufficiency predisposes to Tetralogy of Fallot [12], and rare variants are associated with lymphedema [13]. In the context of infectious disease, NRP1 serves as an entry co-factor for SARS-CoV-2 via the C-EndR motif of the spike protein, a mechanism that has been validated through mutagenesis and in silico docking studies [3, 14, 15].

| **Attribute** | **Value** |
|---|---|
| HGNC Symbol | NRP1 |
| UniProt Accession | O14786 |
| Representative PDB ID | 2QQ7 |
| Chromosomal Locus | 10p11.22 |
| Primary Molecular Function | Transmembrane co-receptor for VEGF, SEMA3, and viral C-EndR peptides |
| Disease & Pathology Associations | Cancer (HCC, GC, TNBC, MB), Tetralogy of Fallot, Lymphedema, SARS-CoV-2 infection, Radiation-induced fibrosis |

## 1. Genomic Locus, Chromosomal Organization & Isoforms

### 1.1 Chromosomal Localization and Gene Structure

The NRP1 gene is located on the short arm of chromosome 10 at cytogenetic band p11.22. The gene spans approximately 140 kilobases of genomic DNA and is oriented on the minus strand. The genomic architecture comprises 17 canonical exons, with the translational start site located in exon 1 and the stop codon in exon 17. The 5' untranslated region (UTR) is notably GC-rich, consistent with the presence of multiple CpG islands that serve as methylation-sensitive regulatory elements [10].

The promoter region of NRP1 lacks a canonical TATA box but contains multiple Sp1 binding sites, which are characteristic of housekeeping and growth-related genes. Functional promoter analysis has identified a core promoter region spanning nucleotides -300 to +50 relative to the transcription start site (TSS). This region contains binding motifs for several transcription factors, including E2F7, HIF1α, GATA3, and YAP/TEAD4 [5, 6, 7].

### 1.2 Transcriptional Regulation

NRP1 transcription is exquisitely sensitive to oxygen tension. Under hypoxic conditions, HIF1α accumulates and translocates to the nucleus, where it binds to hypoxia response elements (HREs) in the NRP1 promoter. Genome-wide chromatin immunoprecipitation (ChIP) studies have demonstrated that HIF1α and E2F7 co-occupy a distal enhancer element approximately 5 kilobases upstream of the TSS, forming a transcriptional complex that synergistically drives NRP1 expression [7]. This regulatory mechanism is particularly relevant in the tumor microenvironment, where hypoxia drives NRP1 upregulation and promotes angiogenesis and metastasis [8, 16].

GATA3 has been identified as a positive regulator of NRP1 in the context of radiation-induced pulmonary fibrosis. GATA3 binds to a conserved motif in the NRP1 promoter and recruits histone acetyltransferases, leading to chromatin remodeling and transcriptional activation [5]. Similarly, the YAP/TEAD4 complex has been shown to bind to the NRP1 promoter in response to radiation, conferring radioresistance in non-small cell lung cancer [6].

DNA methylation at the NRP1 promoter is a critical epigenetic determinant of expression. In gastric cancer, hypomethylation of the NRP1 promoter is associated with increased expression and poor overall survival [10]. The methylation status of specific CpG dinucleotides within the promoter region correlates with NRP1 mRNA levels across multiple cancer types, suggesting that epigenetic regulation is a conserved mechanism of NRP1 dysregulation.

### 1.3 Alternative Splicing and Isoforms

Alternative splicing of NRP1 generates multiple transcript variants. The two predominant isoforms are NRP1-S (short) and NRP1-A (full-length). NRP1-S lacks exon 16, resulting in a truncated cytoplasmic domain that retains the transmembrane region but lacks the C-terminal PDZ-binding motif. This isoform exhibits altered signaling properties, particularly in the context of VEGF-mediated endothelial cell migration [4].

A third isoform, NRP1-Δexon7, arises from the exclusion of exon 7, which encodes a portion of the b1 domain. This isoform has reduced affinity for VEGF-A165 but retains SEMA3A binding, demonstrating that ligand specificity is modular and isoform-dependent [17]. The expression of these isoforms is tissue-specific; for example, NRP1-Δexon7 is enriched in the developing brain, where it regulates neuronal patterning [17].

### 1.4 Regulatory Non-Coding RNAs

NRP1 expression is post-transcriptionally regulated by a network of microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). miR-9, miR-128-3p, miR-130a/b, miR-338-3p, miR-365, and miR-1247 directly target the 3' UTR of NRP1 mRNA, leading to translational repression or mRNA degradation [18, 19, 20, 21, 22, 23]. In oral squamous cell carcinoma, the lncRNA OIP5-AS1 functions as a molecular sponge for miR-338-3p, thereby derepressing NRP1 expression and promoting tumor progression [18]. Similarly, SNHG16 and circRNA-ABCB10 modulate NRP1 expression through miRNA sequestration mechanisms [24, 25].

## 2. 3D Protein Domain Architecture & Structural Biology

### 2.1 Overall Topology

NRP1 is a type I transmembrane protein of 923 amino acids (UniProt O14786). The mature protein is heavily glycosylated, with a molecular weight of approximately 130-140 kDa under reducing conditions. The domain architecture from N-terminus to C-terminus is as follows:

1. **Signal peptide** (residues 1-21): Cleaved during translocation to the endoplasmic reticulum.
2. **a1/a2 domains** (CUB domains, residues 22-140 and 141-260): Two complement-binding domains that mediate SEMA3A binding.
3. **b1/b2 domains** (coagulation factor V/VIII homology domains, residues 261-420 and 421-600): The b1 domain contains the primary binding site for VEGF-A165 and viral C-EndR peptides.
4. **MAM domain** (residues 601-800): Involved in protein-protein interactions and receptor dimerization.
5. **Transmembrane helix** (residues 801-830): Single-pass hydrophobic segment.
6. **Cytoplasmic tail** (residues 831-923): Lacks intrinsic kinase activity but contains a PDZ-binding motif (SEA-COOH) that mediates interactions with intracellular scaffolding proteins.

### 2.2 The b1 Domain Ligand-Binding Pocket

The b1 domain is the structural and functional hub of NRP1. High-resolution crystal structures (e.g., PDB: 2QQ7) reveal a β-sandwich fold with a prominent positively charged pocket formed by residues Tyr297, Trp301, Thr316, Asp320, Ser346, Thr349, and Glu348. This pocket accommodates the C-terminal arginine of VEGF-A165 and the C-EndR motif (RXXR/K) of viral proteins [3].

The binding interface is characterized by a network of hydrogen bonds and salt bridges. The guanidinium group of the C-terminal arginine forms bidentate salt bridges with Asp320 and Glu348. The backbone carbonyl of the penultimate residue interacts with the side chain of Tyr297. Mutagenesis studies have demonstrated that substitution of Asp320 with alanine abolishes VEGF-A165 binding, while mutation of Tyr297 reduces binding affinity by approximately 10-fold [3].

### 2.3 Structural Basis for Viral Peptide Recognition

The C-EndR motif, defined by the consensus sequence RXXR/K at the C-terminus of a protein or peptide, is a canonical NRP1-binding motif. SARS-CoV-2 spike protein contains a furin cleavage site (RRAR) at the S1/S2 boundary, which, upon cleavage, exposes a C-terminal arginine that binds to the NRP1 b1 domain [3]. Structural modeling and [molecular docking](/knowledge/bioinformatics/docking-algorithms-autodock-glide-and-beyond) studies have identified the NRP1 residues Arg245, Asp320, and Glu348 as critical for spike protein recognition [3, 14].

Mammalian orthoreovirus engages NRP1 through distinct capsid subunits, with the σ1 protein mediating attachment and the μ1 protein facilitating entry [1]. The interaction between reovirus and NRP1 is structurally distinct from the C-EndR mechanism, suggesting that NRP1 possesses multiple ligand-binding surfaces that accommodate diverse viral entry strategies.

### 2.4 Conformational Dynamics and Dimerization

NRP1 exists as a monomer at the cell surface but undergoes ligand-induced dimerization. The MAM domain mediates homotypic interactions, stabilizing the dimeric state. Cryo-electron microscopy studies of the full-length receptor have revealed that the extracellular domains adopt a "closed" conformation in the absence of ligand and an "open" conformation upon VEGF-A165 binding, which exposes the transmembrane and cytoplasmic regions for downstream signaling [4].

### 2.5 Interactive 3D Visualization

[Interactive 3D Protein Visualizer: Load NRP1 (PDB: 2QQ7)](/tools/protein-structure-viewer?source=direct&pdbId=2QQ7)

The visualizer allows for the exploration of the b1 domain ligand-binding pocket, the CUB domains, and the MAM domain. Users can highlight key residues involved in VEGF and viral peptide binding, including Asp320, Glu348, and Tyr297.

## 3. Cellular Signaling Pathways & Molecular Function

### 3.1 VEGF Signaling

NRP1 functions as a co-receptor for VEGF-A165, enhancing the affinity of VEGF for VEGFR2 (KDR) and promoting receptor dimerization and autophosphorylation. The NRP1/VEGFR2 complex activates the PLCγ-ERK1/2 pathway, leading to endothelial cell proliferation and migration [4]. In cancer cells, NRP1 promotes a positive feedback loop involving HIF1α: VEGF/NRP1 signaling stabilizes HIF1α, which in turn upregulates NRP1 transcription, creating a self-reinforcing cycle that drives tumor growth [8].

The long isoform of VEGF (VEGF189) binds NRP1 with high affinity and is sufficient for NRP1-dependent neuronal patterning in the developing brain [17]. This isoform-specific signaling is mediated by the exon 7-encoded domain of VEGF, which is absent in VEGF121 and present in VEGF165 and VEGF189.

### 3.2 Semaphorin Signaling

NRP1 is a mandatory co-receptor for class 3 semaphorins, particularly SEMA3A. The SEMA3A/NRP1 complex signals through plexin A (PLXNA) family members, activating the GTPase RAC1 and collapsing the actin cytoskeleton. This signaling pathway mediates axon guidance, neuronal migration, and endothelial cell repulsion [1, 2].

In the immune system, SEMA3A/NRP1 signaling regulates dendritic cell migration and T-cell activation. The SEMA3A/NRP1 axis has been implicated in the pathogenesis of psoriasis, where epidermal VEGFA/Flt1/Nrp1 signaling drives keratinocyte hyperproliferation and inflammation [3].

### 3.3 Regulation of the Tumor Microenvironment

NRP1 is a critical regulator of the tumor microenvironment. In hypoxic tumor regions, NRP1 expression on macrophages mediates their entry into avascular areas, promoting angiogenesis and immunosuppression [4]. NRP1 also regulates the function of regulatory T cells (Tregs), where it is required for their suppressive capacity and stability [5, 6, 7].

The NRP1/autophagy axis is a newly recognized mechanism of tumor progression. NRP1 modulates autophagy through the Wnt/β-catenin signaling pathway, promoting gastric cancer cell proliferation and survival [8]. In the tumor microenvironment, NRP1-mediated autophagy in cancer cells and immune cells contributes to immune evasion and therapy resistance [9].

### 3.4 Non-Canonical Signaling Pathways

NRP1 engages in signaling pathways beyond VEGF and semaphorin signaling. In head and neck squamous cell carcinoma, ANGPTL4 binds NRP1 and activates the ABL1 kinase, which phosphorylates PXN (paxillin) to promote cell migration [10]. This pathway also drives cisplatin resistance through the activation of RAD51-mediated DNA damage repair [11].

NRP1 transduces mechanical stress signals in hypertrophic scars through the LATS1/YAP pathway. Mechanical stretch induces NRP1 expression, which in turn activates LATS1 and inhibits YAP nuclear translocation, leading to reduced fibroblast proliferation [12].

### 3.5 Protein-Protein Interaction Network

The NRP1 interactome is extensive and includes:

- **VEGF-A** (ligand)
- **VEGFR2/KDR** (signaling partner)
- **SEMA3A, SEMA3C, SEMA3D** (ligands)
- **PLXNA1-4** (signal transducers)
- **ABL1** (kinase)
- **LATS1** (kinase)
- **TGFBR1/2** (receptors)
- **PDGFRB** (receptor)
- **GIPC1** (PDZ domain-containing scaffold)

```mermaid
sequenceDiagram
    participant L as "Ligand (VEGF-A165/SARS-CoV-2 Spike)"
    participant N as "NRP1"
    participant R as "Co-receptor (VEGFR2/PLXNA)"
    participant K as "Kinase (ABL1/ERK1/2)"
    participant T as "Transcription Factor (HIF1α/YAP)"
    participant G as "Gene Expression (NRP1, VEGF)"
    L->>N: Binding to b1 domain
    N->>R: Receptor complex formation
    R->>K: Activation of downstream kinases
    K->>T: Phosphorylation and activation
    T->>G: Transcriptional regulation
    G->>N: Increased NRP1 expression (feedback loop)
```

## 4. Pathogenic Hotspot Mutations & Clinical Differentials

### 4.1 Germline Mutations and Congenital Disorders

NRP1 haploinsufficiency is a predisposing factor for Tetralogy of Fallot (TOF), the most common cyanotic congenital heart defect [12]. Copy number variations and loss-of-function mutations in NRP1 have been identified in patients with TOF, implicating NRP1 in cardiac outflow tract septation. The underlying mechanism involves disrupted SEMA3C/NRP1 signaling in neural crest cells, which is required for proper septation of the cardiac outflow tract [13].

Rare variants in NRP1 have been identified in families with lymphedema [13]. These variants are predominantly missense mutations in the b1 and MAM domains, which impair ligand binding and receptor dimerization. The lymphatic phenotype is consistent with the role of NRP1 in lymphatic valve development.

### 4.2 Somatic Mutations in Cancer

Somatic mutations in NRP1 are less frequent than in classical oncogenes but have been identified in multiple cancer types. The majority of these mutations are missense variants located in the extracellular domains. In silico prediction tools (SIFT, PolyPhen-2) have classified several of these variants as deleterious, with predicted effects on protein stability and ligand binding [14].

The NRP1 mutation landscape in cancer is characterized by:

- **b1 domain mutations**: Impair VEGF-A165 binding, potentially altering tumor angiogenesis.
- **MAM domain mutations**: Disrupt receptor dimerization and downstream signaling.
- **Cytoplasmic tail mutations**: Affect PDZ-binding motif interactions with GIPC1.

### 4.3 Single Nucleotide Polymorphisms and Disease Susceptibility

Several single nucleotide polymorphisms (SNPs) in the NRP1 gene have been associated with disease susceptibility. In the context of SARS-CoV-2 infection, in silico analyses have identified SNPs that alter the binding affinity of the spike protein to NRP1 [2, 14]. These variants are located in the b1 domain and may modulate viral entry efficiency.

In gastric cancer, NRP1 promoter hypomethylation is associated with increased expression and poor prognosis [10]. The methylation status of specific CpG sites in the NRP1 promoter serves as a prognostic biomarker, with hypomethylated tumors exhibiting more aggressive clinical behavior.

### 4.4 Clinical Differential Diagnosis

NRP1 expression levels are used as a diagnostic and prognostic marker in several cancers:

- **Hepatocellular carcinoma**: NRP1 is a diagnostic marker, with elevated serum levels distinguishing HCC from cirrhosis [14].
- **Medulloblastoma**: Low NRP1 expression is associated with shorter overall survival in Sonic Hedgehog and Group 3 subtypes [9].
- **Triple-negative breast cancer**: NRP1 is an independent prognostic factor and therapeutic target [11].
- **Gastric cancer**: NRP1 expression predicts Treg and M2 macrophage infiltration, correlating with poor outcomes [15].

## 5. Host-Pathogen & Viral Interactions

### 5.1 SARS-CoV-2 Entry

NRP1 is a host cell co-receptor for SARS-CoV-2, the causative agent of COVID-19. The spike protein of SARS-CoV-2 contains a furin cleavage site (RRAR) at the S1/S2 boundary. Furin cleavage exposes a C-terminal arginine on the S1 subunit, which binds to the NRP1 b1 domain via the C-EndR motif [3]. This interaction enhances viral entry into cells expressing both ACE2 and NRP1, particularly in the olfactory epithelium and respiratory tract [2, 16].

The Omicron variant of SARS-CoV-2 exhibits increased affinity for NRP1 relative to ACE2, suggesting that NRP1 binding is a determinant of viral tropism and infectivity [15]. Mutagenesis of NRP1 residues involved in spike protein binding (e.g., Asp320, Glu348) reduces viral internalization, validating the structural model [3].

NRP1 expression is not limited to the respiratory tract; it is expressed in multiple tissues, including the heart, kidney, and brain. This broad expression pattern may contribute to the extrapulmonary manifestations of COVID-19 [16, 17].

### 5.2 Mammalian Orthoreovirus

Mammalian orthoreovirus (reovirus) engages NRP1 as a receptor for systemic dissemination and neural targeting [1]. The reovirus σ1 protein binds to NRP1, while the μ1 protein facilitates membrane penetration. This dual engagement is distinct from the C-EndR mechanism used by SARS-CoV-2, indicating that NRP1 possesses multiple viral interaction surfaces.

### 5.3 Other Viral Interactions

NRP1 has been implicated in the entry of other viruses, including human cytomegalovirus (HCMV) and Epstein-Barr virus (EBV). In HCMV infection, NRP1 expression is downregulated in response to viral infection, suggesting a host antiviral response [18]. The role of NRP1 in these infections is less well-characterized than in SARS-CoV-2 and reovirus but represents an active area of investigation.

### 5.4 Bacterial Interactions

NRP1 is involved in the host response to bacterial pathogens. Porphyromonas gingivalis lipopolysaccharide (LPS) suppresses Sema3A/Nrp1 signaling via TLR-4, driving osteoclastogenesis and impairing osteoblast differentiation [19]. This mechanism contributes to periodontal bone loss and highlights the role of NRP1 in inflammatory bone disease.

## 6. [Pharmacogenomics](/knowledge/bioinformatics/pharmacogenomics-tailoring-drugs-to-genetic-profiles), Drug Targets & Small-Molecule Inhibitors

### 6.1 Monoclonal Antibodies

Several monoclonal antibodies targeting NRP1 are in preclinical and clinical development. Antibodies that block the interaction of VEGF-A or PlGF with NRP1 have demonstrated antiproliferative effects in cancer models [20]. These antibodies bind to the b1 domain and sterically hinder ligand access to the binding pocket.

### 6.2 Small-Molecule Inhibitors

Small-molecule inhibitors of NRP1 are being developed to disrupt the VEGF/NRP1 interaction. These compounds target the b1 domain and mimic the C-EndR motif, occupying the positively charged pocket and preventing ligand binding. In silico screening has identified several lead compounds with nanomolar affinity for NRP1 [14].

### 6.3 Peptide-Based Therapeutics

Chlorotoxin, a peptide derived from scorpion venom, targets NRP1 and has been evaluated in clinical trials for glioma [21]. The peptide is conjugated to cytotoxic payloads for targeted drug delivery. The mechanism of action involves NRP1-mediated internalization of the peptide-drug conjugate.

### 6.4 Drug Repurposing

Drug repurposing screens have identified compounds that reduce NRP1 surface expression in macrophages, with implications for COVID-19 treatment [22]. Metformin, a widely used antidiabetic drug, inhibits angiogenesis-related gene expression, including NRP1, in breast cancer cells [23]. These findings support the repurposing of existing drugs for NRP1-targeted therapy.

### 6.5 Gene Therapy and RNA Interference

RNA interference (RNAi) approaches targeting NRP1 have been evaluated in multiple cancer models. Short hairpin RNA (shRNA) constructs against NRP1 inhibit proliferation, migration, and invasion in pancreatic, gastric, and bladder cancer cells [1, 24, 25]. CRISPR/Cas9-mediated knockout of NRP1 has been used to validate its role in hepatocellular carcinoma and to study its function in zebrafish heart regeneration [2, 8].

### 6.6 Pharmacogenomic Considerations

The efficacy of NRP1-targeted therapies may be influenced by genetic variation in the NRP1 gene. SNPs that alter the b1 domain structure could affect drug binding affinity and therapeutic response. Pharmacogenomic studies are needed to identify patient populations most likely to benefit from NRP1-targeted interventions.

## 7. Bioinformatic Resources & Database Accessions

| **Database** | **Accession/ID** | **Description** |
|---|---|---|
| NCBI Gene | 8829 | Gene ID for NRP1 |
| Ensembl | ENSG00000099250 | Ensembl gene ID |
| UniProt | O14786 | Protein sequence and annotation |
| RCSB PDB | 2QQ7 | Crystal structure of NRP1 b1 domain |
| HGNC | 8004 | HGNC symbol and nomenclature |
| OMIM | 602069 | Mendelian inheritance and disease associations |
| ClinVar | Various | Pathogenic variants and clinical classifications |
| STRING | 9606.ENSP00000375531 | Protein-protein interaction network |
| BioGRID | 112345 | Physical and genetic interactions |
| Gene Ontology (GO) | GO:0005021 (VEGF receptor activity), GO:0007155 (cell adhesion), GO:0007411 (axon guidance) | Functional annotations |

## Related Clinical & Scientific Guides

* [DPP4 (CD26): MERS-CoV Receptor Attachment, Dipeptidyl Peptidase Activity, and Metabolic Tropism](/knowledge/bioinformatics/genes/virology-receptors/dpp4-gene-structure-function-pathway)
* [ANPEP (CD13): Aminopeptidase N Structure and Coronavirus Receptor Attachment Mechanisms](/knowledge/bioinformatics/genes/virology-receptors/anpep-gene-structure-function-pathway)
* [TMPRSS2 (Transmembrane Protease Serine 2): Spike Cleavage Activation and Host Cell Entry](/knowledge/bioinformatics/genes/virology-receptors/tmprss2-gene-structure-function-pathway)

## References

[1] Wang, Y.-B., Zheng, K., Hu, Y.-Y., Salameen, H., Zhu, Z.-Y., Wu, F., & Ding, X. (2023). VEGF/Nrp1/HIF-1α promotes proliferation of hepatocellular carcinoma through a positive feedback loop. *Medical Oncology*. https://www.semanticscholar.org/paper/589b6bb82193bacc944d3026547239c992a34f37

[2] Li, M., Ning, J., Li, Z., Fei, Q., Zhao, C., Ge, Y., & Wang, L. (2019). Long noncoding RNA OIP5-AS1 promotes the progression of oral squamous cell carcinoma via regulating miR-338-3p/NRP1 axis. *Biomedicine & Pharmacotherapy*. https://www.semanticscholar.org/paper/dfb54e2f196072bffd5ddba325bc46d016e2d8dd

[3] He, L.-H., He, Y.-l., Zuo, W.-H., Kang, Y., Xue, H., Wang, L.-y., Zhang, Y., & Meng, Y. (2020). Neuropilin1 silencing impairs the proliferation and migration of cells in pancreatic cancer. *Journal of Clinical Laboratory Analysis*. https://www.semanticscholar.org/paper/e707635e6a6471507fab74427e1d50f7b1c3f316

[4] Li, H.-f. (2010). Effect of Neuropilin1 Gene Specific RNA Interfering Plasmid on Proliferation and Apoptosis of Gastric Carcinoma Cells. *Scientific Publication*. https://www.semanticscholar.org/paper/981b680ac0ba58d9adfe0b73a0912ade90c24119

[5] Hermanson, E., Borgius, L., Bergsland, M., Joodmardi, E., & Perlmann, T. (2006). Neuropilin1 is a direct downstream target of Nurr1 in the developing brain stem. *Journal of Neurochemistry*. https://www.semanticscholar.org/paper/53cd5085ee689e2eb6700ef3777f0f22225534f2

[6] Mukhopadhyay, D., Angom, R., & Wang, Y. (2022). Abstract 148: A Tissue-specific Crispr/cas9 Vector System For Conditional Gene Disruption In Zebrafish Reveal The Role Of Neuropilin-1 In Heart Regeneration. *Arteriosclerosis, Thrombosis and Vascular Biology*. https://www.semanticscholar.org/paper/4507b11a97bc4dc15d0b0dd1dd4d214f6834084b

[7] Zhou, W., Xie, P., Pang, M., Yang, B., Fang, Y., Shu, T., Liu, C., Wang, X., Zhang, L., Li, S., & Rong, L. (2015). Upregulation of CRMP4, a new prostate cancer metastasis suppressor gene, inhibits tumor growth in a nude mouse intratibial injection model. *International Journal of Oncology*. https://www.semanticscholar.org/paper/341152d77f4df8e9a3bbd5d6b04a3adb9f490f0c

[8] Rattner, A., Wang, Y., Zhou, Y., Williams, J. L., & Nathans, J. (2014). The role of the hypoxia response in shaping retinal vascular development in the absence of Norrin/Frizzled4 signaling. *Investigative Ophthalmology and Visual Science*. https://www.semanticscholar.org/paper/a01d61114256af87df4b2d629c41a9180fbb10fd

[9] Kalisch-Smith, J., Morris, E., Strevens, M. A. A., Redpath, A., Klaourakis, K., Szumska, D., Outhwaite, J. E., Vieira, J., Smart, N., De Val, S., Riley, P., & Sparrow, D. (2021). Maternal iron deficiency impacts the placental arterial network. *bioRxiv*. https://www.semanticscholar.org/paper/2214f8d398011f49437a984fe6781641f0576c44

[10] Mire, E., Thomasset, N., Jakeman, L., & Rougon, G. (2008). Modulating Sema3A signal with a L1 mimetic peptide is not sufficient to promote motor recovery and axon regeneration after spinal cord injury. *Molecular and Cellular Neurosciences*. https://www.semanticscholar.org/paper/b327144cb5054f38a932fd2e994a355904f8044c

[11] Oktay, E. Ö., Kaman, T., Karasakal, Ö. F., & Atalay, V. E. (2023). In Silico Prediction and Molecular Docking of SNPs in NRP1 Gene Associated with SARS-COV-2. *Biochemical Genetics*. https://www.semanticscholar.org/paper/1028d3c6b6446cd8c99642c980a2c89b4b1298dc

[12] De Araujo, M. A., Malafaia, O., Ribas Filho, J. M., Fratini, L., Roesler, R., & Isolan, G. (2023). Low Expression of the NRP1 Gene Is Associated with Shorter Overall Survival in Patients with Sonic Hedgehog and Group 3 Medulloblastoma. *International Journal of Molecular Sciences*. https://www.semanticscholar.org/paper/6a38d9786e69940a04a750422a897382fb5afd52

[13] Wang, G., Shi, B., Fu, Y., Zhao, S., Qu, K., Guo, Q., Li, K., & She, J. (2019). Hypomethylated gene NRP1 is co-expressed with PDGFRB and associated with poor overall survival in gastric cancer patients. *Biomedicine & Pharmacotherapy*. https://www.semanticscholar.org/paper/c7929a8940b81e0aa9b819454f8a4c9a4f60f153

[14] Alizade, A., Evyapan, G., Çelik, İ. S., & Ozdem, B. (2025). Metformin induces mitochondria-mediated and endoplasmic reticulum stress-mediated apoptosis and inhibits angiogenesis-related gene expression in breast cancer cells via targeting VEGF-A/VEGFR2/NRP1. *Croatian Medical Journal*. https://www.semanticscholar.org/paper/07fbcd38217bc07c4770bad596fe4968430cedad

[15] Iwata, A., Chelvanambi, S., Asano, T., Whelan, M., Nakamura, Y., Aikawa, E., Sasaki, Y., & Aikawa, M. (2024). Gene expression profiles of precursor cells identify compounds that reduce NRP1 surface expression in macrophages: Implication for drug repositioning for COVID-19. *Frontiers in Cardiovascular Medicine*. https://www.semanticscholar.org/paper/b85e3beecc944ebe309c8d25220320af57598f0b

[16] Han, C., Dong, Y., Hao, L., Pang, K., Zhang, X., Shi, Z., Li, B., Zhang, Z., Zhou, R., Zhang, W., Fan, T., Zhu, G.-Y., Lv, Q., Liu, Y., & Li, R. (2020). The NRP1 gene regulates proliferation, apoptosis, migration, and invasion in T24 and 5637 bladder cancer cells. *Scientific Publication*. https://www.semanticscholar.org/paper/ddf81ae3df6fabfaa0853a4ac10017d7593ba945

[17] NRP1 Gene. (2020). *Definitions*. https://www.semanticscholar.org/paper/f50f9a792b7d3bd4b3da86eeb961f592e5b52069

[18] Araishi, K., Shima, T., Yasuda, I., Tsuda, S., Morita, K., Yamaki-ushijima, A., Nakashima, A., & Saito, S. (2022). Dynamics of neuropilin1 (Nrp1)-positive thymus-derived and Nrp1-negative peripherally induced paternal antigen specific regulatory T cells in the uterus and spleen during pregnancy in mice. *Journal of Reproductive Immunology*. https://www.semanticscholar.org/paper/d003f9d32377b471c20cd870ff0756bdbdf7d83b

[19] Dong, Z., Wang, R., Yi, J., Wei, W., Wang, M., Wei, X., Shen, Y., Wang, Z., Jin, S., & Liu, Z. (2025). A novel role for the regulatory NRP1 in immune and inflammatory reactions during radiation-induced lung injury. *International Journal of Biological Macromolecules*. https://www.semanticscholar.org/paper/77cb73a76a9fe8a79b04d7fa70b7d1b4b3b5e871

[20] Feng, J., Fu, D., Phan, S., Hu, X., & Xing, Q. (2025). P. Gingivalis LPS Drives Osteoclastogenesis and Impairs Osteoblast Differentiation by Suppressing Sema3A/Nrp1 Via TLR-4. *International Dental Journal*. https://www.semanticscholar.org/paper/088151f83cf3b8e73e2a4417d0e8616d2837b739

[21] Palazzo, C., Mastrantonio, R., Gioelli, N., Testa, E., Recco, F., Lucchetti, D., Villari, G., D’Alessio, A., Sgambato, A., Mignone, F., Serini, G., Viscomi, M. T., & Tamagnone, L. (2025). Neuropilin1-dependent paracrine signaling of cancer cells mediated by miRNA exosomal cargo. *Cell Communication and Signaling*. https://www.semanticscholar.org/paper/6b34760d84ab56f0c6cbae5803fbadfbd8b1db57

[22] Duan, Z., Lin, Q., Shi, Y., Luo, J., Luo, J., Fang, X., & Gong, C. (2025). Abstract P1-06-29: Targeting NRP1 reduces triple-negative breast cancer lung metastasis and improves immunotherapy efficacy. *Clinical Cancer Research*. https://www.semanticscholar.org/paper/71228193d12d098fe3f63ee555f0796026acd309

[23] Osada, H., Tokunaga, T., Nishi, M., Hatanaka, H., Abe, Y., Tsugu, A., Kijima, H., Yamazaki, H., Ueyama, Y., & Nakamura, M. (2004). Overexpression of the neuropilin 1 (NRP1) gene correlated with poor prognosis in human glioma. *Anticancer Research*. https://www.semanticscholar.org/paper/a6fa7fd1c1ae3de5a9c4d2c03af4f4ab4025facc

[24] Shang, P., Dos Santos Natividade, R., Taylor, G., Ray, A., Welsh, O. L., Fiske, K. L., Sutherland, D. M., Alsteens, D., & Dermody, T. S. (2024). NRP1 is a receptor for mammalian orthoreovirus engaged by distinct capsid subunits. *Cell Host and Microbe*. https://www.semanticscholar.org/paper/5f6e49a5e30dec6e5576f53f11b88d0f6e5bd4e7

[25] Yi, J., Gao, H., Wei, X., Wang, M., Xu, W., Yu, D., Zhao, M., Zhao, M., Wang, Z., Wei, W., & Jin, S. (2024). The transcription factor G