Neuropilin 1 Explained

Neuropilin-1 is a protein that in humans is encoded by the NRP1 gene.^{[1] [2] [3]} In humans, the neuropilin 1 gene is located at 10p11.22. This is one of two human neuropilins.

Function

NRP1 is a membrane-bound coreceptor to a tyrosine kinase receptor for both vascular endothelial growth factor (for example, VEGFA) and semaphorin (for example, SEMA3A) family members. NRP1 plays versatile roles in angiogenesis, axon guidance, cell survival, migration, and invasion.[supplied by OMIM]^[3]

Interactions

Neuropilin 1 has been shown to interact with Vascular endothelial growth factor A.^{[1] [4]}

Role in COVID-19

Research has shown that neuropilin 1 facilitates entry of SARS-CoV-2 into cells, making it a possible target for future antiviral drugs.^{[5] [6]}

Implication in cancer

Neuropilin 1 has been implicated in the vascularization and progression of cancers. NRP1 expression has been shown to be elevated in a number of human patient tumor samples, including brain, prostate, breast, colon, and lung cancers and NRP1 levels are positively correlated with metastasis.^{[7] [8] [9] [10] [11] [12]}

In prostate cancer NRP1 has been demonstrated to be an androgen-suppressed gene, upregulated during the adaptive response of prostate tumors to androgen-targeted therapies and a prognostic biomarker of clinical metastasis and lethal PCa.^[7] In vitro and in vivo mouse studies have shown membrane bound NRP1 to be proangiogenic and that NRP1 promotes the vascularization of prostate tumors.^[13]

Elevated NRP1 expression is also correlated with the invasiveness of non-small cell lung cancer both in vitro and in vivo.

Target for cancer therapies

As a co-receptor for VEGF, NRP1 is a potential target for cancer therapies. A synthetic peptide, EG3287, was generated in 2005 and has been shown to block NRP1 activity.^[14] EG3287 has been shown to induce apoptosis in tumor cells with elevated NRP1 expression. A patent for EG3287 was filed in 2002 and approved in 2003.^[15] As of 2015 there were no clinical trials ongoing or completed for EG3287 as a human cancer therapy.

Soluble NRP1 has the opposite effect of membrane bound NRP1 and has anti-VEGF activity. In vivo mouse studies have shown that injections of sNRP-1 inhibits progression of acute myeloid leukemia in mice.^[16]

Further reading

• Zachary I, Gliki G . Signaling transduction mechanisms mediating biological actions of the vascular endothelial growth factor family . Cardiovascular Research . 49 . 3 . 568–81 . February 2001 . 11166270 . 10.1016/S0008-6363(00)00268-6 . free .
• He Z, Tessier-Lavigne M . Neuropilin is a receptor for the axonal chemorepellent Semaphorin III . Cell . 90 . 4 . 739–51 . August 1997 . 9288753 . 10.1016/S0092-8674(00)80534-6 . 9720408 . free .
• Giger RJ, Urquhart ER, Gillespie SK, Levengood DV, Ginty DD, Kolodkin AL . Neuropilin-2 is a receptor for semaphorin IV: insight into the structural basis of receptor function and specificity . Neuron . 21 . 5 . 1079–92 . November 1998 . 9856463 . 10.1016/S0896-6273(00)80625-X . 18445456 . free .
• Chen H, He Z, Bagri A, Tessier-Lavigne M . Semaphorin-neuropilin interactions underlying sympathetic axon responses to class III semaphorins . Neuron . 21 . 6 . 1283–90 . December 1998 . 9883722 . 10.1016/S0896-6273(00)80648-0 . free .
• Takahashi T, Nakamura F, Jin Z, Kalb RG, Strittmatter SM . Semaphorins A and E act as antagonists of neuropilin-1 and agonists of neuropilin-2 receptors . Nature Neuroscience . 1 . 6 . 487–93 . October 1998 . 10196546 . 10.1038/2203 . 38320889 .
• Rossignol M, Beggs AH, Pierce EA, Klagsbrun M . Human neuropilin-1 and neuropilin-2 map to 10p12 and 2q34, respectively . Genomics . 57 . 3 . 459–60 . May 1999 . 10329017 . 10.1006/geno.1999.5790 .
• Makinen T, Olofsson B, Karpanen T, Hellman U, Soker S, Klagsbrun M, Eriksson U, Alitalo K . Differential binding of vascular endothelial growth factor B splice and proteolytic isoforms to neuropilin-1 . The Journal of Biological Chemistry . 274 . 30 . 21217–22 . July 1999 . 10409677 . 10.1074/jbc.274.30.21217 . free .
• Cai H, Reed RR . Cloning and characterization of neuropilin-1-interacting protein: a PSD-95/Dlg/ZO-1 domain-containing protein that interacts with the cytoplasmic domain of neuropilin-1 . The Journal of Neuroscience . 19 . 15 . 6519–27 . August 1999 . 10414980 . 6782790 . 10.1523/JNEUROSCI.19-15-06519.1999.
• Takahashi T, Fournier A, Nakamura F, Wang LH, Murakami Y, Kalb RG, Fujisawa H, Strittmatter SM . Plexin-neuropilin-1 complexes form functional semaphorin-3A receptors . Cell . 99 . 1 . 59–69 . October 1999 . 10520994 . 10.1016/S0092-8674(00)80062-8 . 18167425 . free .
• Tamagnone L, Artigiani S, Chen H, He Z, Ming GI, Song H, Chedotal A, Winberg ML, Goodman CS, Poo M, Tessier-Lavigne M, Comoglio PM . Plexins are a large family of receptors for transmembrane, secreted, and GPI-anchored semaphorins in vertebrates . Cell . 99 . 1 . 71–80 . October 1999 . 10520995 . 10.1016/S0092-8674(00)80063-X . 17386412 . free .
• Gagnon ML, Bielenberg DR, Gechtman Z, Miao HQ, Takashima S, Soker S, Klagsbrun M . Identification of a natural soluble neuropilin-1 that binds vascular endothelial growth factor: In vivo expression and antitumor activity . Proceedings of the National Academy of Sciences of the United States of America . 97 . 6 . 2573–8 . March 2000 . 10688880 . 15970 . 10.1073/pnas.040337597 . 2000PNAS...97.2573G . free .
• Gluzman-Poltorak Z, Cohen T, Herzog Y, Neufeld G . Neuropilin-2 is a receptor for the vascular endothelial growth factor (VEGF) forms VEGF-145 and VEGF-165 [corrected] . The Journal of Biological Chemistry . 275 . 24 . 18040–5 . June 2000 . 10748121 . 10.1074/jbc.M909259199 . free .
• Fuh G, Garcia KC, de Vos AM . The interaction of neuropilin-1 with vascular endothelial growth factor and its receptor flt-1 . The Journal of Biological Chemistry . 275 . 35 . 26690–5 . September 2000 . 10842181 . 10.1074/jbc.M003955200 . free.
• Rossignol M, Gagnon ML, Klagsbrun M . Genomic organization of human neuropilin-1 and neuropilin-2 genes: identification and distribution of splice variants and soluble isoforms . Genomics . 70 . 2 . 211–22 . December 2000 . 11112349 . 10.1006/geno.2000.6381 .
• Simpson JC, Wellenreuther R, Poustka A, Pepperkok R, Wiemann S . Systematic subcellular localization of novel proteins identified by large-scale cDNA sequencing . EMBO Reports . 1 . 3 . 287–92 . September 2000 . 11256614 . 1083732 . 10.1093/embo-reports/kvd058 .
• Whitaker GB, Limberg BJ, Rosenbaum JS . Vascular endothelial growth factor receptor-2 and neuropilin-1 form a receptor complex that is responsible for the differential signaling potency of VEGF(165) and VEGF(121) . The Journal of Biological Chemistry . 276 . 27 . 25520–31 . July 2001 . 11333271 . 10.1074/jbc.M102315200 . free .
• Walter JW, North PE, Waner M, Mizeracki A, Blei F, Walker JW, Reinisch JF, Marchuk DA . Somatic mutation of vascular endothelial growth factor receptors in juvenile hemangioma . Genes, Chromosomes & Cancer . 33 . 3 . 295–303 . March 2002 . 11807987 . 10.1002/gcc.10028 . 33428561 .

Notes and References

1. Soker S, Takashima S, Miao HQ, Neufeld G, Klagsbrun M . Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor . Cell . 92 . 6 . 735–45 . March 1998 . 9529250 . 10.1016/S0092-8674(00)81402-6 . 547080 . free .
2. Chen H, Chédotal A, He Z, Goodman CS, Tessier-Lavigne M . Neuropilin-2, a novel member of the neuropilin family, is a high affinity receptor for the semaphorins Sema E and Sema IV but not Sema III . Neuron . 19 . 3 . 547–59 . September 1997 . 9331348 . 10.1016/S0896-6273(00)80371-2 . 17985062 . free .
3. Web site: Entrez Gene: NRP1 neuropilin 1.
4. Mamluk R, Gechtman Z, Kutcher ME, Gasiunas N, Gallagher J, Klagsbrun M . Neuropilin-1 binds vascular endothelial growth factor 165, placenta growth factor-2, and heparin via its b1b2 domain . The Journal of Biological Chemistry . 277 . 27 . 24818–25 . July 2002 . 11986311 . 10.1074/jbc.M200730200 . free .
5. Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity. Science. 13 November 2020. Cantuti-Castelvetri. Ludovico. Ojha. Ravi. Pedro. Liliana D.. Djannatian. Minou. Franz. Jonas. Kuivanen. Suvi. Meer. Franziska van der. Kallio. Katri. Kaya. Tuğberk. Anastasina. Maria. Smura. Teemu. Levanov. Lev. Szirovicza. Leonora. Tobi. Allan. Kallio-Kokko. Hannimari. Österlund. Pamela. Joensuu. Merja. Meunier. Frédéric A.. Butcher. Sarah J.. Winkler. Martin Sebastian. Mollenhauer. Brit. Helenius. Ari. Gokce. Ozgun. Teesalu. Tambet. Hepojoki. Jussi. Vapalahti. Olli. Stadelmann. Christine. Balistreri. Giuseppe. Simons. Mikael. 370. 6518. 856–860. 10.1126/science.abd2985. 33082293. 7857391. 2020Sci...370..856C .
6. News: Neuropilin-1 drives SARS-CoV-2 infectivity, finds breakthrough study. MedicalXpress.
7. Tse BW, Volpert M, Ratther E, Stylianou N, Nouri M, McGowan K, Lehman ML, McPherson SJ, Roshan-Moniri M, Butler MS, Caradec J, Gregory-Evans CY, McGovern J, Das R, Takhar M, Erho N, Alshalafa M, Davicioni E, Schaeffer EM, Jenkins RB, Ross AE, Karnes RJ, Den RB, Fazli L, Gregory PA, Gleave ME, Williams ED, Rennie PS, Buttyan R, Gunter JH, Selth LA, Russell PJ, Nelson CC, Hollier BG . Neuropilin-1 is upregulated in the adaptive response of prostate tumors to androgen-targeted therapies and is prognostic of metastatic progression and patient mortality . Oncogene . 36 . 24 . 3417–3427 . January 2017 . 28092670 . 5485179 . 10.1038/onc.2016.482 .
8. Fakhari M, Pullirsch D, Abraham D, Paya K, Hofbauer R, Holzfeind P, Hofmann M, Aharinejad S . Selective upregulation of vascular endothelial growth factor receptors neuropilin-1 and -2 in human neuroblastoma . Cancer . 94 . 1 . 258–63 . January 2002 . 11815985 . 10.1002/cncr.10177 . 45773136 . free .
9. Latil A, Bièche I, Pesche S, Valéri A, Fournier G, Cussenot O, Lidereau R . VEGF overexpression in clinically localized prostate tumors and neuropilin-1 overexpression in metastatic forms . International Journal of Cancer . 89 . 2 . 167–71 . March 2000 . 10754495 . 10.1002/(SICI)1097-0215(20000320)89:2<167::AID-IJC11>3.0.CO;2-9 . 7393385 . free .
10. Bachelder RE, Crago A, Chung J, Wendt MA, Shaw LM, Robinson G, Mercurio AM . Vascular endothelial growth factor is an autocrine survival factor for neuropilin-expressing breast carcinoma cells . Cancer Research . 61 . 15 . 5736–40 . August 2001 . 11479209 .
11. Parikh AA, Fan F, Liu WB, Ahmad SA, Stoeltzing O, Reinmuth N, Bielenberg D, Bucana CD, Klagsbrun M, Ellis LM . Neuropilin-1 in human colon cancer: expression, regulation, and role in induction of angiogenesis . The American Journal of Pathology . 164 . 6 . 2139–51 . June 2004 . 15161648 . 10.1016/s0002-9440(10)63772-8 . 1615754.
12. Hong TM, Chen YL, Wu YY, Yuan A, Chao YC, Chung YC, Wu MH, Yang SC, Pan SH, Shih JY, Chan WK, Yang PC . Targeting neuropilin 1 as an antitumor strategy in lung cancer . Clinical Cancer Research . 13 . 16 . 4759–68 . August 2007 . 17699853. 10.1158/1078-0432.CCR-07-0001 . free .
13. Miao HQ, Lee P, Lin H, Soker S, Klagsbrun M . Neuropilin-1 expression by tumor cells promotes tumor angiogenesis and progression . FASEB Journal . 14 . 15 . 2532–9 . December 2000 . 11099472 . 10.1096/fj.00-0250com . free . 2370002 .
14. Barr MP, Byrne AM, Duffy AM, Condron CM, Devocelle M, Harriott P, Bouchier-Hayes DJ, Harmey JH . A peptide corresponding to the neuropilin-1-binding site on VEGF(165) induces apoptosis of neuropilin-1-expressing breast tumour cells . British Journal of Cancer . 92 . 2 . 328–33 . January 2005 . 15655556. 10.1038/sj.bjc.6602308 . 2361857.
15. Web site: Vegf peptides and their use (WO 2003082918 A1) . Oct 9, 2003. patent.
16. Gagnon ML, Bielenberg DR, Gechtman Z, Miao HQ, Takashima S, Soker S, Klagsbrun M . Identification of a natural soluble neuropilin-1 that binds vascular endothelial growth factor: In vivo expression and antitumor activity . Proceedings of the National Academy of Sciences of the United States of America . 97 . 6 . 2573–8 . March 2000 . 10688880 . 15970 . 10.1073/pnas.040337597 . 2000PNAS...97.2573G . free .