NRP1

Official Full Name

neuropilin 1

Organism

Homo sapiens

GeneID

8829

Background

This gene encodes one of two neuropilins, which contain specific protein domains which allow them to participate in several different types of signaling pathways that control cell migration. Neuropilins contain a large N-terminal extracellular domain, made up of complement-binding, coagulation factor V/VIII, and meprin domains. These proteins also contains a short membrane-spanning domain and a small cytoplasmic domain. Neuropilins bind many ligands and various types of co-receptors; they affect cell survival, migration, and attraction. Some of the ligands and co-receptors bound by neuropilins are vascular endothelial growth factor (VEGF) and semaphorin family members. This protein has also been determined to act as a co-receptor for SARS-CoV-2 (which causes COVID-19) to infect host cells. [provided by RefSeq, Nov 2020]

Synonyms

NP1; NRP; BDCA4; CD304; VEGF165R;

Bio Chemical Class

Neuropilin and tolloid-like

Protein Sequence

MERGLPLLCAVLALVLAPAGAFRNDKCGDTIKIESPGYLTSPGYPHSYHPSEKCEWLIQAPDPYQRIMINFNPHFDLEDRDCKYDYVEVFDGENENGHFRGKFCGKIAPPPVVSSGPFLFIKFVSDYETHGAGFSIRYEIFKRGPECSQNYTTPSGVIKSPGFPEKYPNSLECTYIVFVPKMSEIILEFESFDLEPDSNPPGGMFCRYDRLEIWDGFPDVGPHIGRYCGQKTPGRIRSSSGILSMVFYTDSAIAKEGFSANYSVLQSSVSEDFKCMEALGMESGEIHSDQITASSQYSTNWSAERSRLNYPENGWTPGEDSYREWIQVDLGLLRFVTAVGTQGAISKETKKKYYVKTYKIDVSSNGEDWITIKEGNKPVLFQGNTNPTDVVVAVFPKPLITRFVRIKPATWETGISMRFEVYGCKITDYPCSGMLGMVSGLISDSQITSSNQGDRNWMPENIRLVTSRSGWALPPAPHSYINEWLQIDLGEEKIVRGIIIQGGKHRENKVFMRKFKIGYSNNGSDWKMIMDDSKRKAKSFEGNNNYDTPELRTFPALSTRFIRIYPERATHGGLGLRMELLGCEVEAPTAGPTTPNGNLVDECDDDQANCHSGTGDDFQLTGGTTVLATEKPTVIDSTIQSEFPTYGFNCEFGWGSHKTFCHWEHDNHVQLKWSVLTSKTGPIQDHTGDGNFIYSQADENQKGKVARLVSPVVYSQNSAHCMTFWYHMSGSHVGTLRVKLRYQKPEEYDQLVWMAIGHQGDHWKEGRVLLHKSLKLYQVIFEGEIGKGNLGGIAVDDISINNHISQEDCAKPADLDKKNPEIKIDETGSTPGYEGEGEGDKNISRKPGNVLKTLDPILITIIAMSALGVLLGAVCGVVLYCACWHNGMSERNLSALENYNFELVDGVKLKKDKLNTQSTYSEA

Open

Disease

Retinopathy, Solid tumour/cancer

Approved Drug

1 +

Clinical Trial Drug

2 +

Discontinued Drug

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Detailed Information

Neuropilin 1, NRP1 is an important member of the NRP family and plays an important role in neurodevelopment, angiogenesis, tumor invasion, metastasis and immunity. As a co-receptor of tyrosine kinase, NRP1 participates in various signaling pathways, and these signaling pathways participate in the process of angiogenesis, which is essential for the biological function of blood vessels.

Nrp1 Figure 1. NRP1 structure and strategies to target its functions. (Graziani, G., et al. 2015)

The Features of NRP1

When NRP1 is used as a co-receptor for the vascular endothelial growth factor (VEGF) family, it can play the role of binding or regulating other extracellular ligands, such as Semaphorin 3 (Sema3), fibroblast growth factor (FGF). NRP1 was first discovered in neurons of the central nervous system, especially in developing embryos. In addition, it was found that NRP1 can be expressed in blood vessels of different tissues, especially arterial blood vessels. As individuals continue to develop, NRP1 is expressed in arterial endothelial cells and tumor vasculature, but not on the veins or lymphatic endothelial cells. The role of NRP1 as a VEGF165 co-receptor is well known. In endothelial cells, NRP mainly enhances signal transmission by ensuring the optimal presentation of VEGF and stabilizing the VEGF/VEGFR (VEGF receptor) pathway. Therefore, the stable binding of VEGF165 to VEGFR-2 and the complete activation of VEGFR-2 require the interaction of VEGF165 and NRP1 to achieve.

Studies have shown that NRP1 can also mediate the migration of vascular smooth muscle cells through platelet derived growth factor (PDGF), thereby promoting angiogenesis. Since the abnormal expression of NRP1 in a variety of tumor cells plays a pathological role in promoting tumorigenesis and development, NRP1 is crucial for tumorigenesis and development. NRP1 has been determined to be highly expressed in various malignant tumors in humans, but is relatively low in the corresponding normal tissue structure. The growth viability of various tumor cells is closely related to the expression of NRP1. The abundant expression of NRP1 in various advanced tumors can prove this theory.

NRP1 and Tumor

Semaphorins are a family of proteins, Sema3 is a secreted protein, and NRP1 can serve as its receptor. Hypoxic conditions can induce Sema3A to act as an attractant for tumor-associated macrophages (TAMS), through NRP1 and plex-in-A1/plexin-A4 to form a complex receptor, triggering VEGFR-1 phosphorylation. When the NRP1 gene in macrophages is deleted, TAMS still exerts its function of weakening angiogenesis and immunosuppression in the area of normal oxidized tumors, thereby inhibiting tumor growth and metastasis. This shows that the heterogeneity of TAMS depends on its environment and is strictly controlled by the Sema3A/NRP1 signal. NRP1 is a marker of pro-angiogenic M2 macrophages under physiological conditions. Although NRP1 is not directly involved in the recruitment of TAMS, it may be involved in the entry of TAMS into the hypoxic area, and the absence of NRP1 can cause the redistribution of TAMS, thereby blocking the occurrence of in situ and spontaneous tumors. In addition, Sema3A mainly attracts macrophages in the NRP1-dependent manner, and at the same time, when the expression level of NRP1 is down-regulated in the same cell, Sema3A will show the effect of inhibiting the migration of macrophages. These results indicate that Sema3A derived from tumor cells is mainly responsible for TAMS entering the hypoxic area through the NRP1 signal. Consistent with Sema3A-mediated attraction or rejection of macrophages, Sema3A expression is associated with tumor progression and tumor suppression. This reveals the role of the Sema3A/NRP1 signal pathway in guiding macrophages into hypoxic areas and their ability to evade anti-tumor immunity and promote angiogenesis.

References:

Graziani, G., & Lacal, P. M. (2015). Neuropilin-1 as Therapeutic Target for Malignant Melanoma. Frontiers in Oncology, 125-125.
Amadio, M. , Govoni, S. , & Pascale, A. . (2016). Targeting vegf in eye neovascularization: whats new? Pharmacological Research, 103, 253-269.
Kwiatkowski, S. C. , Guerrero, P. A. , Shinya, H. , Zhihua, C. , Morales, J. E. , & Manish, A. , et al. (2017). Neuropilin-1 modulates tgfβ signaling to drive glioblastoma growth and recurrence after anti-angiogenic therapy. Plos One, 12(9), e0185065.

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