Neuropilin 1

Neuropilin-1 is a protein that in humans is encoded by the NRP1 gene.[5][6][7] In humans, the neuropilin 1 gene is located at 10p11.22. This is one of two human neuropilins.

NRP1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1KEX, 2QQI, 2QQM, 2QQN, 3I97, 4DEQ, 4RN5, 5C7G
Identifiers
Aliases	NRP1, BDCA4, CD304, NP1, NRP, VEGF165R, Neuropilin 1
External IDs	OMIM: 602069 MGI: 106206 HomoloGene: 2876 GeneCards: NRP1
Gene location (Human) Chr. Chromosome 10 (human)[1] Band 10p11.22 Start 33,177,492 bp[1] End 33,336,262 bp[1]
Gene location (Mouse) Chr. Chromosome 8 (mouse)[2] Band 8 E2|8 75.78 cM Start 128,358,604 bp[2] End 128,503,363 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • heparin binding • vascular endothelial growth factor binding • cytokine binding • semaphorin receptor activity • coreceptor activity • metal ion binding • vascular endothelial growth factor-activated receptor activity • growth factor binding • GO:0001948 protein binding • GO:0005097, GO:0005099, GO:0005100 GTPase activator activity • protein kinase binding Cellular component • cytosol • membrane • extracellular region • semaphorin receptor complex • cell surface • sorting endosome • integral component of membrane • growth cone • receptor complex • cell membrane • axon • neuronal cell body • early endosome • neurofilament • cytoplasmic vesicle • extracellular • focal adhesion • neuron projection • glutamatergic synapse • integral component of postsynaptic membrane Biological process • negative regulation of neuron apoptotic process • facioacoustic ganglion development • vascular endothelial growth factor signaling pathway • VEGF-activated neuropilin signaling pathway involved in axon guidance • toxin transport • cell migration involved in sprouting angiogenesis • semaphorin-plexin signaling pathway involved in axon guidance • positive regulation of retinal ganglion cell axon guidance • positive regulation of smooth muscle cell migration • sympathetic neuron projection guidance • vascular endothelial growth factor receptor signaling pathway • sensory neuron axon guidance • angiogenesis • positive regulation of ERK1 and ERK2 cascade • animal organ morphogenesis • protein localization to early endosome • trigeminal nerve structural organization • regulation of axon extension involved in axon guidance • coronary artery morphogenesis • negative regulation of extrinsic apoptotic signaling pathway • neuron development • trigeminal nerve morphogenesis • angiogenesis involved in coronary vascular morphogenesis • commissural neuron axon guidance • negative regulation of axon extension involved in axon guidance • heart development • response to wounding • artery morphogenesis • positive regulation of peptidyl-tyrosine phosphorylation • branching involved in blood vessel morphogenesis • platelet-derived growth factor receptor signaling pathway • positive chemotaxis • facial nerve structural organization • hepatocyte growth factor receptor signaling pathway • axonal fasciculation • retina vasculature morphogenesis in camera-type eye • dorsal root ganglion morphogenesis • axon extension involved in axon guidance • sympathetic ganglion development • cell differentiation • semaphorin-plexin signaling pathway involved in neuron projection guidance • cellular response to hepatocyte growth factor stimulus • dendrite development • sprouting angiogenesis • neuron migration • nervous system development • regulation of retinal ganglion cell axon guidance • branchiomotor neuron axon guidance • gonadotrophin-releasing hormone neuronal migration to the hypothalamus • negative regulation of axon extension • retinal ganglion cell axon guidance • renal artery morphogenesis • ventral trunk neural crest cell migration • positive regulation of endothelial cell proliferation • sympathetic nervous system development • endothelial tip cell fate specification • cell-cell signaling • regulation of vesicle-mediated transport • trigeminal ganglion development • positive regulation of cytokine activity • positive regulation of axon extension involved in axon guidance • axon guidance • vestibulocochlear nerve structural organization • multicellular organism development • neural crest cell migration involved in autonomic nervous system development • endothelial cell chemotaxis • axonogenesis involved in innervation • dichotomous subdivision of terminal units involved in salivary gland branching • cellular response to vascular endothelial growth factor stimulus • motor neuron axon guidance • nerve development • cell migration • sympathetic neuron projection extension • semaphorin-plexin signaling pathway • signal transduction • otic placode development • motor neuron migration • outflow tract septum morphogenesis • substrate-dependent cell migration, cell extension • integrin-mediated signaling pathway • positive regulation of endothelial cell migration • actin cytoskeleton reorganization • regulation of Cdc42 protein signal transduction • substrate adhesion-dependent cell spreading • neuropilin signaling pathway • VEGF-activated neuropilin signaling pathway • positive regulation of phosphorylation • endothelial cell migration • GO:0032320, GO:0032321, GO:0032855, GO:0043089, GO:0032854 positive regulation of GTPase activity • positive regulation of angiogenesis • positive regulation of filopodium assembly • positive regulation of stress fiber assembly • positive regulation of focal adhesion assembly • positive regulation of cell migration involved in sprouting angiogenesis • positive regulation of substrate adhesion-dependent cell spreading • positive regulation of actin cytoskeleton reorganization • postsynapse organization • basal dendrite development • basal dendrite arborization Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	8829	18186
Ensembl	ENSG00000099250	ENSMUSG00000025810
UniProt	O14786	P97333
RefSeq (mRNA)	NM_001024628 NM_001024629 NM_001244972 NM_001244973 NM_003873 NM_001330068	NM_008737 NM_001358959 NM_001358960
RefSeq (protein)	NP_001019799 NP_001019800 NP_001231901 NP_001231902 NP_001316997 NP_003864	NP_032763 NP_001345888 NP_001345889
Location (UCSC)	Chr 10: 33.18 – 33.34 Mb	Chr 8: 128.36 – 128.5 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Function

NRP1 is a membrane-bound coreceptor to a tyrosine kinase receptor for both vascular endothelial growth factor (VEGF; MIM 192240) and semaphorin (see SEMA3A; MIM 603961) family members. NRP1 plays versatile roles in angiogenesis, axon guidance, cell survival, migration, and invasion.[supplied by OMIM][7]

Interactions

Neuropilin 1 has been shown to interact with Vascular endothelial growth factor A.[5][8]

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.[9][10][11][12][13][14]

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.[9] In vitro and in vivo mouse studies have shown membrane bound NRP1 to be proangiogenic and that NRP1 promotes the vascularization of prostate tumors.[15]

Elevated NRP1 expression is also correlated with the invasiveness of non-small cell lung cancer both in vitro and in vivo.[14]

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.[16] EG3287 has been shown to induce apoptosis in tumor cells with elevated NRP1 expression.[16] A patent for EG3287 was filed in 2002 and approved in 2003.[17] 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.[18]

References

1. GRCh38: Ensembl release 89: ENSG00000099250 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000025810 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Soker S, Takashima S, Miao HQ, Neufeld G, Klagsbrun M (March 1998). "Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor". Cell. 92 (6): 735–45. doi:10.1016/S0092-8674(00)81402-6. PMID 9529250.
6. Chen H, Chédotal A, He Z, Goodman CS, Tessier-Lavigne M (September 1997). "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. doi:10.1016/S0896-6273(00)80371-2. PMID 9331348.
7. "Entrez Gene: NRP1 neuropilin 1".
8. Mamluk R, Gechtman Z, Kutcher ME, Gasiunas N, Gallagher J, Klagsbrun M (July 2002). "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. doi:10.1074/jbc.M200730200. PMID 11986311.
9. 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 (January 2017). "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. doi:10.1038/onc.2016.482. PMC 5485179. PMID 28092670.
10. Fakhari M, Pullirsch D, Abraham D, Paya K, Hofbauer R, Holzfeind P, Hofmann M, Aharinejad S (January 2002). "Selective upregulation of vascular endothelial growth factor receptors neuropilin-1 and -2 in human neuroblastoma". Cancer. 94 (1): 258–63. doi:10.1002/cncr.10177. PMID 11815985.
11. Latil A, Bièche I, Pesche S, Valéri A, Fournier G, Cussenot O, Lidereau R (March 2000). "VEGF overexpression in clinically localized prostate tumors and neuropilin-1 overexpression in metastatic forms". International Journal of Cancer. 89 (2): 167–71. doi:10.1002/(SICI)1097-0215(20000320)89:2<167::AID-IJC11>3.0.CO;2-9. PMID 10754495.
12. Bachelder RE, Crago A, Chung J, Wendt MA, Shaw LM, Robinson G, Mercurio AM (August 2001). "Vascular endothelial growth factor is an autocrine survival factor for neuropilin-expressing breast carcinoma cells". Cancer Research. 61 (15): 5736–40. PMID 11479209.
13. Parikh AA, Fan F, Liu WB, Ahmad SA, Stoeltzing O, Reinmuth N, Bielenberg D, Bucana CD, Klagsbrun M, Ellis LM (June 2004). "Neuropilin-1 in human colon cancer: expression, regulation, and role in induction of angiogenesis". The American Journal of Pathology. 164 (6): 2139–51. doi:10.1016/s0002-9440(10)63772-8. PMC 1615754. PMID 15161648.
14. Hong TM, Chen YL, Wu YY, Yuan A, Chao YC, Chung YC, Wu MH, Yang SC, Pan SH, Shih JY, Chan WK, Yang PC (August 2007). "Targeting neuropilin 1 as an antitumor strategy in lung cancer". Clinical Cancer Research. 13 (16): 4759–68. doi:10.1158/1078-0432.CCR-07-0001. PMID 17699853.
15. Miao HQ, Lee P, Lin H, Soker S, Klagsbrun M (December 2000). "Neuropilin-1 expression by tumor cells promotes tumor angiogenesis and progression". FASEB Journal. 14 (15): 2532–9. doi:10.1096/fj.00-0250com. PMID 11099472.
16. Barr MP, Byrne AM, Duffy AM, Condron CM, Devocelle M, Harriott P, Bouchier-Hayes DJ, Harmey JH (January 2005). "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. doi:10.1038/sj.bjc.6602308. PMC 2361857. PMID 15655556.
17. "Vegf peptides and their use (WO 2003082918 A1)" (patent). Oct 9, 2003.
18. Gagnon ML, Bielenberg DR, Gechtman Z, Miao HQ, Takashima S, Soker S, Klagsbrun M (March 2000). "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. Bibcode:2000PNAS...97.2573G. doi:10.1073/pnas.040337597. PMC 15970. PMID 10688880.

Further reading

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