- Neuropilin-1 (NRP-1) is a multifunctional, non-tyrosine kinase transmembrane glycoprotein that acts as a co-receptor for various signaling molecules.
- It was initially identified as a receptor involved in axonal guidance within the nervous system, but subsequent research has shown that it also plays a critical role in angiogenesis, immune regulation, and tumor biology.
- Unlike VEGF receptors, NRP-1 does not have intrinsic kinase activity; instead, it modulates the signaling of its partner receptors, amplifying or fine-tuning biological responses.
- Structurally, NRP-1 has a large extracellular domain with multiple binding sites, a single transmembrane domain, and a short cytoplasmic tail lacking enzymatic activity. Its extracellular domains allow it to interact with a broad spectrum of ligands, including members of the vascular endothelial growth factor (VEGF) family, class 3 semaphorins (key molecules in axon guidance), transforming growth factor-beta (TGF-β), and various integrins. Among its most studied interactions, NRP-1 binds VEGF-A165, a major isoform of VEGF-A, and forms complexes with VEGFR-2, greatly enhancing VEGF-mediated angiogenic signaling. This makes NRP-1 an important modulator of vascular development and permeability.
- In the nervous system, NRP-1 functions primarily as a receptor for semaphorin 3A (Sema3A), guiding axonal growth and neuronal patterning during embryonic development. In the vascular system, NRP-1 works in concert with VEGFR-2 to promote endothelial cell proliferation, migration, and new vessel sprouting. It also contributes to vascular permeability and vessel stabilization. Beyond these functions, NRP-1 is expressed on immune cells, such as regulatory T cells (Tregs), where it influences immune tolerance and suppression. This highlights its broader role as a signaling hub that bridges neural, vascular, and immune biology.
- Pathologically, NRP-1 is strongly implicated in cancer progression. Many tumors overexpress NRP-1, which enhances VEGF-driven angiogenesis, creating abnormal blood vessels that nourish tumor growth. NRP-1 also interacts with growth factor pathways like platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF), further supporting tumor cell survival and metastasis. Moreover, its expression on tumor-associated macrophages and Tregs contributes to an immunosuppressive microenvironment, allowing tumors to evade immune surveillance. High levels of NRP-1 are often associated with aggressive tumor behavior and poor prognosis in cancers such as breast, lung, pancreatic, and prostate cancers.
- Clinically, NRP-1 is an attractive therapeutic target. Strategies to inhibit its function include blocking antibodies, peptides that interfere with VEGF-NRP-1 binding, and small molecules designed to disrupt receptor interactions. These approaches are being explored in oncology to suppress tumor angiogenesis and immune evasion. At the same time, NRP-1’s role in neurovascular development and immune regulation suggests potential therapeutic applications in neurological disorders, cardiovascular disease, and autoimmune conditions.
