NRP1 - neuropilin 1 |Elisa - Clia - Antibody - Protein

Background

Neuropilin-1 (NRP1) is a multifunctional transmembrane glycoprotein that plays critical roles in multiple physiological processes, including vascular development, neural guidance, immune modulation, and cancer progression. First characterized as a receptor involved in the guidance of axons, NRP1 is now known to act as a co-receptor for various ligands, including vascular endothelial growth factor (VEGF) and semaphorin family proteins, which control angiogenesis and axonal guidance, respectively. NRP1 is widely expressed in endothelial cells, neurons, immune cells, and several tumor cell types. Its role in mediating signal transduction for multiple growth factors makes it highly significant in both normal developmental biology and pathologies, including cancer and cardiovascular diseases.

NRP1’s structure allows it to interact with a variety of ligands, facilitating its participation in different signaling pathways. Importantly, NRP1 lacks intrinsic kinase activity and instead functions by associating with other receptor complexes. This co-receptor capability is vital for its role in angiogenesis, where it enhances VEGF signaling by complexing with VEGF receptors (particularly VEGFR2), and in immune regulation, where it modulates T cell activity and antigen presentation. NRP1 has therefore become a target of interest for therapeutic intervention in diseases involving abnormal cell growth, such as cancer and chronic inflammatory conditions.

Protein Structure

Neuropilin-1 is a large, single-pass type I transmembrane protein that consists of several distinct extracellular domains, a transmembrane region, and a short cytoplasmic tail. The distinct structural domains of NRP1 enable it to interact with diverse ligands and participate in multiple signaling cascades.

Extracellular Domain:

• a1 and a2 Domains: The a1 and a2 domains of NRP1 form the CUB (complement subcomponents C1r/C1s, Uegf, and bone morphogenetic protein) domain. These domains are essential for binding to heparin and heparin-sulfate proteoglycans, which modulate ligand interactions and receptor localization on the cell surface.
• b1 and b2 Domains: These two domains form the coagulation factor V/VIII homology domains. They play a crucial role in binding to VEGF and semaphorins, which are important ligands for NRP1. The b1 domain, in particular, binds VEGF-A165, a key isoform involved in angiogenesis, through its interaction with the heparin-binding domain of VEGF-A.
• MAM Domain: The meprin, A-5 protein, and receptor protein-tyrosine phosphatase mu (MAM) domain is located near the transmembrane domain. It is involved in receptor dimerization and clustering, which are important for efficient signal transduction.

Transmembrane Domain:

• The transmembrane region of NRP1 anchors the receptor in the cell membrane and facilitates interaction with other co-receptors, such as VEGF receptors (VEGFRs) and plexins, to form multi-receptor signaling complexes. This domain’s structure is crucial for maintaining the receptor's spatial orientation, enabling the extracellular domain to interact with ligands and the intracellular domain to link with downstream signaling molecules.

Intracellular (Cytoplasmic) Tail:

• NRP1 has a short cytoplasmic domain that lacks intrinsic kinase activity but contains a PDZ-binding motif. This motif enables interaction with PDZ domain-containing proteins, which serve as adapter molecules connecting NRP1 to intracellular signaling pathways. The cytoplasmic tail also contributes to NRP1’s ability to influence receptor endocytosis and trafficking, thereby modulating the cellular response to ligands such as VEGF and semaphorins.

Classification and Subtypes

NRP1 belongs to the neuropilin family of receptors, which includes two main isoforms: neuropilin-1 (NRP1) and neuropilin-2 (NRP2). While NRP1 is expressed in a wide range of tissues, NRP2 has a more restricted expression pattern. These two receptors have overlapping but distinct ligand specificities; for example, NRP1 primarily binds VEGF-A isoforms and semaphorin-3A, whereas NRP2 binds VEGF-C/D and semaphorin-3F. Both receptors can heterodimerize, further expanding the range of signaling possibilities and allowing for fine-tuned regulation of cellular responses.

Function and Biological Significance

NRP1 has diverse functions due to its role as a co-receptor for different ligand-receptor complexes:

Angiogenesis:

• NRP1 is best known for its role in angiogenesis, the process by which new blood vessels form from pre-existing ones. NRP1 binds to VEGF-A165 and forms a complex with VEGFR2 on endothelial cells, enhancing VEGF signaling and promoting vascular permeability, endothelial cell migration, and proliferation. This function is essential for physiological processes like wound healing and tissue regeneration, as well as for pathological angiogenesis in cancer.

Axon Guidance and Neural Development:

• NRP1 is also a critical receptor in axon guidance during neural development. By interacting with semaphorin-3A, NRP1 regulates the direction of axonal growth, ensuring that neural circuits are correctly established. This role is crucial in the developing nervous system, where NRP1 assists in guiding axons to their appropriate targets.

Immune Modulation:

• NRP1 is expressed on regulatory T cells (Tregs) and other immune cells, where it modulates immune responses. NRP1’s role in Tregs involves aiding in the maintenance of immune tolerance and preventing excessive immune responses. It also influences dendritic cell function and can modulate antigen presentation and T cell activation, further highlighting its role in immune regulation.

Cancer and Tumor Progression:

• NRP1 expression is upregulated in several cancers, where it is associated with increased angiogenesis, tumor cell migration, and metastasis. By promoting angiogenesis through VEGF signaling and aiding in cell survival and invasion, NRP1 contributes to the tumor microenvironment and is often associated with a poor prognosis. This makes NRP1 an attractive target in cancer therapy, as inhibiting its function may reduce tumor growth and metastatic spread.

Cardiovascular Development:

• NRP1 is essential for cardiovascular development, specifically in the formation of the vascular system and heart. It is involved in the development of cardiac neural crest cells and contributes to vascular remodeling, which is vital for proper cardiovascular function.

Clinical Issues

NRP1 has significant clinical relevance in a range of diseases, particularly in cancer, vascular diseases, and immune-related conditions:

Cancer Therapy:

• Given its role in tumor angiogenesis and metastasis, NRP1 is a target for anticancer therapies. Blocking NRP1-VEGF interactions can potentially inhibit tumor growth by reducing blood supply to the tumor and limiting cancer cell migration. Anti-NRP1 antibodies and small molecule inhibitors are currently being explored in preclinical and clinical settings for various cancers.

Vascular and Cardiovascular Diseases:

• Abnormal NRP1 signaling has been implicated in vascular diseases, including diabetic retinopathy and atherosclerosis. Therapeutic modulation of NRP1 may help in managing these conditions by altering angiogenesis and vascular remodeling processes.

Immune Dysregulation and Autoimmunity:

• NRP1’s role in immune cell regulation has implications for autoimmune diseases. Dysregulated NRP1 expression on Tregs or dendritic cells may contribute to autoimmune pathology. Targeting NRP1 could therefore help restore immune balance in autoimmune diseases like rheumatoid arthritis and lupus.

Neurological Disorders:

• Abnormal NRP1 activity in the nervous system can affect axonal pathfinding and neural circuit formation. Research is ongoing to determine if targeting NRP1 could provide therapeutic benefits in neurodegenerative diseases or neurodevelopmental disorders where axon guidance and neuronal connectivity are compromised.

Summary

Neuropilin-1 (NRP1) is a versatile receptor that plays essential roles in angiogenesis, neural development, immune regulation, and cancer progression. Structurally, NRP1 is a type I transmembrane protein featuring an extracellular domain with ligand-binding motifs (CUB, coagulation factor homology, and MAM domains), a transmembrane region, and a short cytoplasmic tail with a PDZ-binding motif. This structure enables it to function as a co-receptor for a variety of ligands, including VEGF and semaphorins, allowing it to modulate several signaling pathways despite lacking intrinsic kinase activity.

NRP1’s roles in health and disease are varied. In normal physiology, it contributes to the development and maintenance of vascular and neural structures and plays a role in immune tolerance. In pathology, particularly cancer, NRP1 is associated with enhanced tumor angiogenesis, invasion, and metastasis. Its relevance extends to cardiovascular diseases and immune-related conditions, where dysregulated NRP1 activity contributes to disease progression.

Therapeutically, NRP1 is an attractive target. Blocking NRP1 interactions could inhibit tumor growth, reduce inflammation, and restore vascular integrity in diseases. Research continues to uncover the full spectrum of NRP1’s functions and potential as a therapeutic target in cancer, vascular diseases, and immune modulation.