Structural and Functional Relation of Neuropilins

Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 515)


Neuropilin is a type I transmembrane protein and the molecular mass is 120 kDa. Two homologues, Neuropilin-1 and -2, are identified. The primary structure of Neuropilin-1 and Neuropilin-2 is well conserved and is divided into four domains, CUB (a1/a2) domain, FV/FVIII (b1/62) domain, MAM (c) domain, and (d) domain that contains a transmembrane and a short cytoplasmic region. Both Neuropilin-1 and Neuropilin-2 have truncated and secreted form of splice variants. Neuropilins act as a receptor for two different extracellular ligands, class 3 semaphorins and specific isoforms of vascular endothelial growth factor. In both cases, neuropilin requires an additional transmembrane molecule to exhibit biological activity. PlexinA is essential for class 3 semaphorin signaling. Vascular endothelial cell growth factor (VEGF) receptor is the major receptor for VEGF and neuropilin acts as isoform specific co-receptor for VEGF. The CUB and FV/FVIII domains of Neuropilin are the binding sites of semaphorin and VEGF. The MAM domain mediates semaphorin signaling to Plexin-A. Cross talk between semaphorin and VEGF on neuropilin suggests that class 3 semaphorins and the secreted forms of neuropilin act as antagonists to VEGF and its related growth factors.


Vascular Endothelial Growth Factor Carboxyl Terminus Vascular Endothelial Cell Growth Factor Porcine Aortic Endothelial Cell Growth Cone Collapse 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Takagi S, Hirata T, Agata K et al. The A5 antigen, a candidate for the neuronal recognition molecule, has homologies to complement components and coagulation factors. Neuron 1991; 7(2):295–307.PubMedCrossRefGoogle Scholar
  2. 2.
    Takagi S, Kasuya Y, Shimizu M et al. Expression of a cell adhesion molecule, neuropilin, in the developing chick nervous system. Dev Biol 1995; 170(1):207–222.PubMedCrossRefGoogle Scholar
  3. 3.
    Kawakami A, Kitsukawa T, Takagi S et al. Developmentally regulated expression of a cell surface protein, neuropilin, in the mouse nervous system. J Neurobiol 1996; 29(1):1–17.PubMedCrossRefGoogle Scholar
  4. 4.
    He Z, Tessier-Lavigne M. Neuropilin is a receptor for the axonal chemorepellent Semaphorin III. Cell 1997; 90(4):739–751.PubMedCrossRefGoogle Scholar
  5. 5.
    Kolodkin AL, Levengood DV, Rowe EG et al. Neuropilin is a semaphorin III receptor. Cell 1997; 90(4):753–762.PubMedCrossRefGoogle Scholar
  6. 6.
    Semaphorin Nomenclature Committee. Unified nomenclature for the semaphorins/collapsins. Semaphorin Nomenclature Committee. Cell 1999; 97(5):551–552.CrossRefGoogle Scholar
  7. 7.
    Kitsukawa T, Shimizu M, Sanbo M et al. Neuropilin-semaphorin III/D-mediated chemorepulsive signals play a crucial role in peripheral nerve projection in mice. Neuron 1997; 19(5):995–1005.PubMedCrossRefGoogle Scholar
  8. 8.
    Taniguchi M, Yuasa S, Fujisawa H et al. Disruption of semaphorin III/D gene causes severe abnormality in peripheral nerve projection. Neuron 1997; 19(3):519–530.PubMedCrossRefGoogle Scholar
  9. 9.
    Soker S, Takashima S, Miao HQ et al. Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell 1998; 92(6):735–745.PubMedCrossRefGoogle Scholar
  10. 10.
    Klagsbrun M, D’Amore PA. Vascular endothelial growth factor and its receptors. Cytokine Growth Factor Rev 1996; 7(3):259–270.Google Scholar
  11. 11.
    Risau W. Mechanisms of angiogcnesis. Nature 1997; 386(6626):671–674.PubMedCrossRefGoogle Scholar
  12. 12.
    Kawasaki T, Kitsukawa T, Bekku Y et al. A requirement for neuropilin-1 in embryonic vessel formation. Development 1999; 126(21):4895–4902.PubMedGoogle Scholar
  13. 13.
    Kitsukawa T, Shimono A, Kawakami A et al. Overexpression of a membrane protein, neuropilin, in chimeric mice causes anomalies in the cardiovascular system, nervous system and limbs. Development 1995; 121(12):4309–4318.PubMedGoogle Scholar
  14. 14.
    Takahashi T, Fournier A, Nakamura F et al. Plexin-neuropilin-1 complexes form functional semaphorin-3A receptors. Cell 1999; 99(1):59–69.PubMedCrossRefGoogle Scholar
  15. 15.
    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 2000; 70(2):211–222.PubMedCrossRefGoogle Scholar
  16. 16.
    Chen H, Chedotal A, He Z et al. 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 1997; I9(3):547–559.Google Scholar
  17. 17.
    Cai H, Reed RR. Cloning and characterization of neuropilin-l-interacting protein: a PSD95/Dlg/ZO-1 domain-containing protein that interacts with the cytoplasmic domain of neuropilin-1. J Neurosci 1999; 19(15):6519–6527.PubMedGoogle Scholar
  18. 18.
    International Human Genome Sequencing Consortium. Initial sequencing and analysis of the human genome. Nature 2001; 409(6822):860–921.CrossRefGoogle Scholar
  19. 19.
    Gagnon ML, Bielenberg DR, Gechtman Z et al. Identification of a natural soluble neuropilin1 that binds vascular endothelial growth factor: In vivo expression and antitumor activity. Proc Natl Acad Sci USA 2000; 97(6):2573–2578.PubMedCrossRefGoogle Scholar
  20. 20.
    Tamagnone L, Artigiani S, Chen H et al. Plexins are a large family of receptors for trans-membrane, secreted, and GPI-anchored semaphorins in vertebrates. Cell 1999; 99(1):71–80.PubMedCrossRefGoogle Scholar
  21. 21.
    Kumanogoh A, Watanabe C, Lee I et al. Identification of CD72 as a lymphocyte receptor for the class IV semaphorin CD100: A novel mechanism for regulating B cell signaling. Immunity 2000; 13(5):621–631.PubMedCrossRefGoogle Scholar
  22. 22.
    Winberg ML, Noordermeer JN, Tamagnone L et al. Plexin A is a neuronal semaphorin receptor that controls axon guidance. Cell 1998; 95(7):903–916.PubMedCrossRefGoogle Scholar
  23. 23.
    Comeau MR, Johnson R, DuBose RF et al. A poxvirus-encoded semaphorin induces cytokine production from monocytes and binds to a novel cellular semaphorin receptor, VESPR. Immunity 1998; 8(4):473–482.PubMedCrossRefGoogle Scholar
  24. 24.
    Klostermann A, Lohrum M, Adams RH et al. The chemorepulsive activity of the axonal guidance signal semaphorin D requires dimerization. J Biol Chem 1998; 273(13):7326–7331.PubMedCrossRefGoogle Scholar
  25. 25.
    Nakamura F, Kalb RG, Strittmatter SM. Molecular basis of semaphorin-mediated axon guidance. J Neurobiol 2000; 44(2):219–229.PubMedCrossRefGoogle Scholar
  26. 26.
    Takahashi T, Nakamura F, Jin Z et al. Semaphorins A and E act as antagonists of neuropilin1 and agonists of neuropilin-2 receptors. Nat Neurosci 1998; 1(6):487–493.PubMedCrossRefGoogle Scholar
  27. 27.
    Chen H, He Z, Bagri A et al. Semaphorin-neuropilin interactions underlying sympathetic axon responses to class III semaphorins. Neuron 1998; 21(6):1283–1290.PubMedCrossRefGoogle Scholar
  28. 28.
    Eickholt BJ, Morrow R, Walsh FS et al. Structural features of collapsin required for biological activity and distribution of binding sites in the developing chick. Mol Cell Neurosci 1997; 9(5–6):358–371.PubMedCrossRefGoogle Scholar
  29. 29.
    Feiner L, Koppel AM, Kobayashi H et al. Secreted chick semaphorins bind recombinant neuropilin with similar affinities but bind different subsets of neurons in situ. Neuron 1997; 19(3):539–545.PubMedCrossRefGoogle Scholar
  30. 30.
    Nakamura F, Tanaka M, Takahashi T et al. Neuropilin-1 extracellular domains mediate semaphorin D/III-induced growth cone collapse. Neuron 1998; 21(5):1093–1100.PubMedCrossRefGoogle Scholar
  31. 31.
    Giger RJ, Urquhart ER, Gillespie SK et al. Neuropilin-2 is a receptor for semaphorin IV: Insight into the structural basis of receptor function and specificity. Neuron 1998; 21(5):1079–1092.PubMedCrossRefGoogle Scholar
  32. 32.
    Renzi MJ, Feiner L, Koppel AM et al. A dominant negative receptor for specific secreted semaphorins is generated by deleting an extracellular domain from neuropilin-1. J Neurosci 1999; 19(18):7870–7880.PubMedGoogle Scholar
  33. 33.
    Shimizu M, Murakami Y, Suto F et al. Determination of cell adhesion sites of neuropilin-I. J Cell Biol 2000; 148(6):1283–1293.PubMedCrossRefGoogle Scholar
  34. 34.
    De Vries L, Lou X, Zhao G et al. A PDZ domain containing protein, interacts specifically with the C terminus of RGS-GAIP. Proc Natl Acad Sci USA 1998; 95(21):12340–12345.PubMedCrossRefGoogle Scholar
  35. 35.
    Wang LH, Kalb RG, Strittmatter SM. A PDZ protein regulates the distribution of the trans-membrane semaphorin, M-SemF.JBiol Chem 1999; 274(20):14137–14146.PubMedCrossRefGoogle Scholar
  36. 36.
    Takahashi T, Strittmatter SM. PlexinAl autoinhibition by the plexin sema domain. Neuron 2001; 29(2):429–439.PubMedCrossRefGoogle Scholar
  37. 37.
    Cheng HJ, Bagri A, Yaron A et al. Plexin-a3 mediates semaphorin signaling and regulates the development of hippocampal axonal projections. Neuron 2001; 32(2):249–263.PubMedCrossRefGoogle Scholar
  38. 38.
    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). J Biol Chem 2001; 276(27):25520–25531.PubMedCrossRefGoogle Scholar
  39. 39.
    Gluzman-Poltorak Z, Cohen T, Shibuya M et al. Vascular endothelial growth factor receptor-1 and neuropilin-2 form complexes. J Biol Chem 2001; 276(22):18688–18694.PubMedCrossRefGoogle Scholar
  40. 40.
    Kagoshima M, Ito T, Kitamura H et al. Diverse gene expression and function of semaphorins in developing lung: positive and negative regulatory roles of semaphorins in lung branching morphogenesis. Genes Cells 2001; 6(6):559–571.PubMedCrossRefGoogle Scholar
  41. 41.
    Sekido Y, Bader S, Latif F et al. Human semaphorins A(V) and IV reside in the 3p21.3 small cell lung cancer deletion region and demonstrate distinct expression patterns. Proc Natl Acad Sci USA 1996; 93(9):4120–4125.CrossRefGoogle Scholar
  42. 42.
    Bagnard D, Vaillant C, Khuth ST et al. Semaphorin 3A-vascular endothelial growth factor-165 balance mediates migration and apoptosis of neural progenitor cells by the recruitment of shared receptor. J Neurosci 2001; 21(10):3332–334I.PubMedGoogle Scholar
  43. 43.
    Castellani V, Chedotal A, Schachner M et al. Analysis of the LI-deficient mouse phenotype reveals cross-talk between Sema3A and LI signaling pathways in axonal guidance. Neuron 2000; 27(2):237–249.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2002

Authors and Affiliations

  1. 1.Department of Molecular Pharmacology and NeurobiologyYokohama City University School of MedicineYokohama, KanagawaJapan
  2. 2.CRESTJapan Science and Technology Corporation(JST)Japan

Personalised recommendations