Semaphorin Signals in Cell Adhesion and Cell Migration: Functional Role and Molecular Mechanisms

  • Andrea Casazza
  • Pietro Fazzari
  • Luca Tamagnone
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 600)


Cell migration is pivotal in embryo development and in the adult. During development a wide range of progenitor cells travel over long distances before undergoing terminal differentiation. Moreover, the morphogenesis of epithelial tissues and of the cardiovascular system involves remodelling compact cell layers and sprouting of new tubular branches. In the adult, cell migration is essential for leucocytes involved in immune response. Furthermore, invasive and metastatic cancer cells have the distinctive ability to overcome normal tissue boundaries, travel in and out of blood vessels, and settle down in heterologous tissues. Cell migration normally follows strict guidance cues, either attractive, or inhibitory and repulsive. Semaphorins are a wide family of signals guiding cell migration during development and in the adult. Recent findings have established that semaphorin receptors, the plexins, govern cell migration by regulating integrin-based cell substrate adhesion and actin cytoskeleton dynamics, via specific monomeric GTPases. Plexins furthermore recruit tyrosine kinases in receptor complexes, which allows switching between multiple signaling pathways and functional outcomes. In this article, we will review the functional role of semaphorins in cell migration and the implicated molecular mechanisms controlling cell adhesion


Cell Migration Neural Crest Cell Axon Guidance Integrin Activation External Granular Layer 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Tamagnone L, Artigiani S, Chen H et al. Plexins are a large family of receptors for transmembrane, secreted, and GPI-anchored semaphorins in vertebrates. Cell 1999; 99(1):71–80.PubMedGoogle Scholar
  2. 2.
    Artigiani S, Comoglio PM, Tamagnone L. Plexins, semaphorins, and scatter factor receptors: a common root for cell guidance signals? IUBMB Life 1999; 48(5):477–482.PubMedGoogle Scholar
  3. 3.
    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.PubMedGoogle Scholar
  4. 4.
    Antipenko A, Himanen JP, van Leyen K et al. Structure of the semaphorin-3A receptor binding module. Neuron 2003; 39(4):589–598.PubMedGoogle Scholar
  5. 5.
    Love CA, Harlos K, Mavaddat N et al. The ligand-binding face of the semaphorins revealed by the high-resolution crystal structure of SEMA4D. Nat Struct Biol 2003; 10(10):843–848.PubMedGoogle Scholar
  6. 6.
    Gherardi E, Youles ME, Miguel RN et al. Functional map and domain structure of MET, the product of the c-met protooncogene and receptor for hepatocyte growth factor/scatter factor. Proc Natl Acad Sci USA 2003; 100(21):12039–12044.PubMedGoogle Scholar
  7. 7.
    Oinuma I, Ishikawa Y, Katoh H et al. The Semaphorin 4D receptor Plexin-B1 is a GTPase activating protein for R-Ras. Science 2004; 305(5685):862–865.PubMedGoogle Scholar
  8. 8.
    Tamagnone L, Comoglio PM. To move or not to move? Semaphorin signaling in cell migration. EMBO Rep 2004; 5(4):356–361.PubMedGoogle Scholar
  9. 9.
    Takahashi T, Fournier A, Nakamura F et al. Plexin-neuropilin-1 complexes form functional semaphorin-3A receptors. Cell 1999; 99(1):59–69.PubMedGoogle Scholar
  10. 10.
    Wang L, Zeng H, Wang P et al. Neuropilin-1-mediated vascular permeability factor/vascular endothelial growth factor-dependent endothelial cell migration. J Biol Chem 2003; 278(49):48848–48860.PubMedGoogle Scholar
  11. 11.
    Godenschwege TA, Hu H, Shan-Crofts X et al. Bi-directional signaling by Semaphorin 1a during central synapse formation in Drosophila. Nat Neurosci 2002; 5(12):1294–1301.PubMedGoogle Scholar
  12. 12.
    Toyofuku T, Zhang H, Kumanogoh A et al. Guidance of myocardial patterning in cardiac development by Sema6D reverse signaling. Nat Cell Biol 2004; 6(12):1204–1211.PubMedGoogle Scholar
  13. 13.
    Comoglio PM, Tamagnone L, Giordano S. Invasive growth: a two-way street for semaphorin signaling. Nat Cell Biol 2004; 6(12):1155–1157.PubMedGoogle Scholar
  14. 14.
    Elhabazi A, Delaire S, Bensussan A et al. Biological activity of soluble CD100. I. The extracellular region of CD100 is released from the surface of T lymphocytes by regulated proteolysis. J Immunol 2001; 166(7):4341–4347.PubMedGoogle Scholar
  15. 15.
    Wang X, Kumanogoh A, Watanabe C et al. Functional soluble CD100/Sema4D released from activated lymphocytes: possible role in normal and pathologic immune responses. Blood 2001; 97(11):3498–3504.PubMedGoogle Scholar
  16. 16.
    Serini G, Valdembri D, Zanivan S et al. Class 3 semaphorins control vascular morphogenesis by inhibiting integrin function. Nature 2003; 424(6947):391–397.PubMedGoogle Scholar
  17. 17.
    Ridley AJ, Schwartz MA, Burridge K et al. Cell migration: integrating signals from front to back. Science 2003; 302(5651):1704–1709.PubMedGoogle Scholar
  18. 18.
    Ivankovic-Dikic I, Gronroos E, Blaukat A et al. Pyk2 and FAK regulate neurite outgrowth induced by growth factors and integrins. Nat Cell Biol 2000; 2(9):574–581.PubMedGoogle Scholar
  19. 19.
    Turney SG, Bridgman PC. Laminin stimulates and guides axonal outgrowth via growth cone myosin II activity. Nat Neurosci 2005; 8(6):717–719.PubMedGoogle Scholar
  20. 20.
    Nakamoto T, Kain KH, Ginsberg MH. Neurobiology: New connections between integrins and axon guidance. Curr Biol 2004; 14(3):R121–R123.PubMedGoogle Scholar
  21. 21.
    Pasterkamp RJ, Peschon JJ, Spriggs MK et al. Semaphorin 7A promotes axon outgrowth through integrins and MAPKs. Nature 2003; 424(6947):398–405.PubMedGoogle Scholar
  22. 22.
    Julien F, Bechara A, Fiore R et al. Dual functional activity of semaphorin 3B is required for positioning the anterior commissure. Neuron 2005; 48(1):63–75.PubMedGoogle Scholar
  23. 23.
    Matthes DJ, Sink H, Kolodkin AL et al. Semaphorin II can function as a selective inhibitor of specific synaptic arborizations. Cell 1995; 81(4):631–639.PubMedGoogle Scholar
  24. 24.
    Liu XB, Low LK, Jones EG et al. Stereotyped axon pruning via plexin signaling is associated with synaptic complex elimination in the hippocampus. J Neurosci 2005; 25(40):9124–9134.PubMedGoogle Scholar
  25. 25.
    Marin O, Yaron A, Bagri A et al. Sorting of striatal and cortical interneurons regulated by semaphorin-neuropilin interactions. Science 2001; 293(5531):872–875.PubMedGoogle Scholar
  26. 26.
    Tamamaki N, Nakamura K, Kaneko T. Cell migration from the corticostriatal angle to the basal telencephalon in rat embryos. Neuroreport 2001; 12(4):775–780.PubMedGoogle Scholar
  27. 27.
    Kerjan G, Dolan J, Haumaitre C et al. The transmembrane semaphorin Sema6A controls cerebellar granule cell migration. Nat Neurosci 2005; 8(11):1516–1524.PubMedGoogle Scholar
  28. 28.
    Eickholt BJ, Mackenzie SL, Graham A et al. Evidence for collapsin-1 functioning in the control of neural crest migration in both trunk and hindbrain regions. Development 1999; 126(10):2181–2189.PubMedGoogle Scholar
  29. 29.
    Osborne NJ, Begbie J, Chilton JK et al. Semaphorin/neuropilin signaling influences the positioning of migratory neural crest cells within the hindbrain region of the chick. Dev Dyn 2005; 232(4):939–949.PubMedGoogle Scholar
  30. 30.
    Kawasaki T, Bekku Y, Suto F et al. Requirement of neuropilin 1-mediated Sema3A signals in patterning of the sympathetic nervous system. Development 2002; 129(3):671–680.PubMedGoogle Scholar
  31. 31.
    Gammill LS, Gonzalez C, Gu C et al. Guidance of trunk neural crest migration requires neuropilin 2/semaphorin 3F signaling. Development 2006; 133(1):99–106.PubMedGoogle Scholar
  32. 32.
    Yu HH, Moens CB. Semaphorin signaling guides cranial neural crest cell migration in zebrafish. Dev Biol 2005; 280(2):373–385.PubMedGoogle Scholar
  33. 33.
    Brown CB, Feiner L, Lu MM et al. PlexinA2 and semaphorin signaling during cardiac neural crest development. Development 2001; 128(16): 3071–3080.PubMedGoogle Scholar
  34. 34.
    Feiner L, Webber AL, Brown CB et al. Targeted disruption of semaphorin 3C leads to persistent truncus arteriosus and aortic arch interruption. Development 2001; 128(16): 3061–3070.PubMedGoogle Scholar
  35. 35.
    Cohen RI, Rottkamp DM, Maric D et al. A role for semaphorins and neuropilins in oligodendrocyte guidance. J Neurochem 2003; 85(5): 1262–1278.PubMedGoogle Scholar
  36. 36.
    Spassky N, de Castro F, Le Bras B et al. Directional guidance of oligodendroglial migration by class 3 semaphorins and netrin-1. J Neurosci 2002; 22(14): 5992–6004.PubMedGoogle Scholar
  37. 37.
    Goldberg JL, Vargas ME, Wang JT et al. An oligodendrocyte lineage-specific semaphorin, Sema5A, inhibits axon growth by retinal ganglion cells. J Neurosci 2004; 24(21): 4989–4999.PubMedGoogle Scholar
  38. 38.
    Moreau-Fauvarque C, Kumanogoh A, Camand E et al. The transmembrane semaphorin Sema4D/CD100, an inhibitor of axonal growth, is expressed on oligodendrocytes and upregulated after CNS lesion. J Neurosci 2003; 23(27): 9229–9239.PubMedGoogle Scholar
  39. 39.
    Neufeld G, Lange T, Varshavsky A, Kessler O. Semaphorin signaling in vascular and tumor biology. In: Pasterkamp RJ, ed. Semaphorins: Receptor and Intracellular Signaling Mechanisms. Georgetown: Landes Bioscience, 2006.Google Scholar
  40. 40.
    Miao HQ, Soker S, Feiner L et al. Neuropilin-1 mediates collapsin-1/semaphorin III inhibition of endothelial cell motility: functional competition of collapsin-1 and vascular endothelial growth factor-165. J Cell Biol 1999; 146(1): 233–242.PubMedGoogle Scholar
  41. 41.
    Gu C, Yoshida Y, Livet J et al. Semaphorin 3E and plexin-D1 control vascular pattern independently of neuropilins. Science 2005; 307(5707): 265–268.PubMedGoogle Scholar
  42. 42.
    Kessler O, Shraga-Heled N, Lange T et al. Semaphorin-3F is an inhibitor of tumor angiogenesis. Cancer Res 2004; 64(3): 1008–1015.PubMedGoogle Scholar
  43. 43.
    Bielenberg DR, Hida Y, Shimizu A et al. Semaphorin 3F, a chemorepulsant for endothelial cells, induces a poorly vascularized, encapsulated, nonmetastatic tumor phenotype. J Clin Invest 2004; 114(9): 1260–1271.PubMedGoogle Scholar
  44. 44.
    Dhanabal M, Wu F, Alvarez E et al. Recombinant semaphorin 6A-1 ectodomain inhibits in vivo growth factor and tumor cell line-induced angiogenesis. Cancer Biol Ther 2005; 4(6): 659–668.PubMedGoogle Scholar
  45. 45.
    Basile JR, Barac A, Zhu T et al. Class IV semaphorins promote angiogenesis by stimulating Rho-initiated pathways through plexin-B. Cancer Res 2004; 64(15): 5212–5224.PubMedGoogle Scholar
  46. 46.
    Conrotto P, Valdembri D, Corso S et al. Sema4D induces angiogenesis through Met recruitment by Plexin B1. Blood 2005; 105(11): 4321–4329.PubMedGoogle Scholar
  47. 47.
    Behar O, Golden JA, Mashimo H et al. Semaphorin III is needed for normal patterning and growth of nerves, bones and heart. Nature 1996; 383(6600): 525–528.PubMedGoogle Scholar
  48. 48.
    Toyofuku T, Zhang H, Kumanogoh A et al. Dual roles of Sema6D in cardiac morphogenesis through region-specific association of its receptor, Plexin-A1, with off-track and vascular endothelial growth factor receptor type 2. Genes Dev 2004; 18(4): 435–447.PubMedGoogle Scholar
  49. 49.
    Kikutani H. Semaphorin signaling during cardiac development. In: Pasterkamp RJ, ed. Semaphorins: Receptor and Intracellular Signaling Mechanisms. Georgetown: Landes Bioscience, 2006.Google Scholar
  50. 50.
    Ito T, Kagoshima M, Sasaki Y et al. Repulsive axon guidance molecule Sema3A inhibits branching morphogenesis of fetal mouse Lung. Mech Dev 2000; 97(1–2): 35–45.PubMedGoogle Scholar
  51. 51.
    Kagoshima M, Ito T. 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.PubMedGoogle Scholar
  52. 52.
    Roy PJ, Zheng H, Warren CE et al. mab-20 encodes Semaphorin-2a and is required to prevent ectopic cell contacts during epidermal morphogenesis in Caenorhabditis elegans. Development 2000 Feb; 127(4): 755–67 2000; 127(4): 755–767.PubMedGoogle Scholar
  53. 53.
    Ginzburg VE, Roy PJ, Culotti JG. Semaphorin 1a and semaphorin 1b are required for correct epidermal cell positioning and adhesion during morphogenesis in C. elegans. Development 2002; 129(9): 2065–2078.PubMedGoogle Scholar
  54. 54.
    Fujii T, Nakao F, Shibata Y et al. Caenorhabditis elegans PlexinA, PLX-1, interacts with transmembrane semaphorins and regulates epidermal morphogenesis. Development 2002; 129(9): 2053–2063.PubMedGoogle Scholar
  55. 55.
    Liu Z, Fujii T, Nukazuka A et al. C. elegans PlexinA PLX-1 mediates a cell contact-dependent stop signal in vulval precursor cells. Dev Biol 2005; 282(1): 138–151.PubMedGoogle Scholar
  56. 56.
    Dalpe G, Brown L, Culotti JG. Vulva morphogenesis involves attraction of plexin 1-expressing primordial vulva cells to semaphorin 1a sequentially expressed at the vulva midline. Development 2005; 132(6): 1387–1400.PubMedGoogle Scholar
  57. 57.
    Holmes S, Downs AM, Fosberry A et al. Sema7A is a potent monocyte stimulator. Scand J Immunol 2002; 56(3): 270–275.PubMedGoogle Scholar
  58. 58.
    Chabbert-de Ponnat I, Marie-Cardine A, Pasterkamp RJ et al. Soluble CD100 functions on human monocytes and immature dendritic cells require plexin C1 and plexin B1, respectively. Int Immunol 2005; 17(4): 439–447.PubMedGoogle Scholar
  59. 59.
    Walzer T, Galibert L, De Smedt T. Dendritic cell function in mice lacking Plexin C1. Int Immunol 2005; 17(7): 943–950.PubMedGoogle Scholar
  60. 60.
    Shi W, Kumanogoh A, Watanabe C et al. The class IV semaphorin CD100 plays nonredundant roles in the immune system: defective B and T cell activation in CD100-deficient mice. Immunity 2000; 13(5): 633–642.PubMedGoogle Scholar
  61. 61.
    Kumanogoh A, Shikina T, Suzuki K et al. Nonredundant roles of Sema4A in the immune system: defective T cell priming and Th1/Th2 regulation in Sema4A-deficient mice. Immunity 2005; 22(3): 305–316.PubMedGoogle Scholar
  62. 62.
    Wong AW, Brickey WJ, Taxman DJ et al. CIITA-regulated plexin-A1 affects T-cell-dendritic cell interactions. Nat Immunol 2003; 4(9): 891–898.PubMedGoogle Scholar
  63. 63.
    Potiron V, Nasarre P, Roche J, Healy C, Boumsell L. Semaphorin signaling in the immune system. In: Pasterkamp RJ, ed. Semaphorins: Receptor and Intracellular Signaling Mechanisms. Georgetown: Landes Bioscience, 2006.Google Scholar
  64. 64.
    Christensen CR, Klingelhofer J, Tarabykina S et al. Transcription of a novel mouse semaphorin gene, M-semaH, correlates with the metastatic ability of mouse tumor cell lines. Cancer Res 1998; 58(6): 1238–1244.PubMedGoogle Scholar
  65. 65.
    Kuroki T, Trapasso F, Yendamuri S et al. Allelic loss on chromosome 3p21.3 and promoter hypermethylation of semaphorin 3B in non-small cell lung cancer. Cancer Res 2003; 63(12): 3352–3355.PubMedGoogle Scholar
  66. 66.
    Miao HQ, Lee P, Lin H et al. Neuropilin-1 expression by tumor cells promotes tumor angiogenesis and progression. FASEB J 2000; 14(15): 2532–2539.PubMedGoogle Scholar
  67. 67.
    Christensen C, Ambartsumian N, Gilestro G et al. Proteolytic processing converts the repelling signal Sema3E into an inducer of invasive growth and lung metastasis. Cancer Res 2005; 65(14): 6167–6177.PubMedGoogle Scholar
  68. 68.
    Barberis D, Artigiani S, Casazza A et al. Plexin signaling hampers integrin-based adhesion, leading to Rho-kinase independent cell rounding, and inhibiting lamellipodia extension and cell motility. FASEB J 2004; 18(3): 592–594.PubMedGoogle Scholar
  69. 69.
    Conrotto P, Corso S, Gamberini S et al. Interplay between scatter factor receptors and B plexins controls invasive growth. Oncogene 2004; 23(30): 5131–5137.PubMedGoogle Scholar
  70. 70.
    Giordano S, Corso S, Conrotto P et al. The semaphorin 4D receptor controls invasive growth by coupling with Met. Nat Cell Biol 2002; 4(9): 720–724.PubMedGoogle Scholar
  71. 71.
    Kusy S, Nasarre P, Chan D et al. Selective suppression of in vivo tumorigenicity by semaphorin SEMA3F in lung cancer cells. Neoplasia 2005; 7(5): 457–465.PubMedGoogle Scholar
  72. 72.
    Maestrini E, Tamagnone T, Longati P et al. A family of transmembrane proteins with homology to the MET-hepatocyte growth factor receptor. Proc Natl Acad Sci USA 1996; 93: 674–678.PubMedGoogle Scholar
  73. 73.
    Rohm B, Rahim B, Kleiber B et al. The semaphorin 3A receptor may directly regulate the activity of small GTPases. FEBS Lett 2000; 486(1): 68–72.PubMedGoogle Scholar
  74. 74.
    Pasterkamp RJ, Kolodkin AL. Semaphorin junction: making tracks toward neural connectivity. Curr Opin Neurobiol 2003; 13(1): 79–89.PubMedGoogle Scholar
  75. 75.
    Puschel AW. GTPases in semaphorin signaling. In: Pasterkamp RJ, ed. Semaphorins: Receptor and Intracellular Signaling Mechanisms. Georgetown: Landes Bioscience, 2006.Google Scholar
  76. 76.
    Driessens MH, Hu H, Nobes CD et al. Plexin-B semaphorin receptors interact directly with active Rac and regulate the actin cytoskeleton by activating Rho. Curr Biol 2001; 11(5): 339–344.PubMedGoogle Scholar
  77. 77.
    Vikis HG, Li W, He Z et al. The semaphorin receptor plexin-B1 specifically interacts with active Rac in a ligand-dependent manner. Proc Natl Acad Sci USA 2000; 97(23): 12457–12462.PubMedGoogle Scholar
  78. 78.
    Turner LJ, Nicholls S, Hall A. The activity of the plexin-A1 receptor is regulated by Rac. J Biol Chem 2004; 279(32): 33199–33205.PubMedGoogle Scholar
  79. 79.
    Jin Z, Strittmatter SM. Rac1 mediates collapsin-1-induced growth cone collapse. J Neurosci 1997; 17(16): 6256–6263.PubMedGoogle Scholar
  80. 80.
    Kuhn TB, Brown MD, Wilcox CL et al. Myelin and collapsin-1 induce motor neuron growth cone collapse through different pathways: inhibition of collapse by opposing mutants of rac1. J Neurosci 1999; 19(6): 1965–1975.PubMedGoogle Scholar
  81. 81.
    Vastrik I, Eickholt BJ, Walsh FS et al. Sema3A-induced growth-cone collapse is mediated by Rac1 amino acids 17–32. Curr Biol 1999; 9(18): 991–998.PubMedGoogle Scholar
  82. 82.
    Jurney WM, Gallo G, Letourneau PG et al. Rac1-mediated endocytosis during ephrin-A2-and semaphorin 3A-induced growth cone collapse. J Neurosci 2002; 22(14): 6019–6028.PubMedGoogle Scholar
  83. 83.
    Hu H, Marton TF, Goodman CS. Plexin B mediates axon, guidance in Drosophila by simultaneously inhibiting active Rac and enhancing RhoA signaling. Neuron 2001; 32(1):39–51.PubMedGoogle Scholar
  84. 84.
    Vikis HG, Li W, Guan KL. The plexin-B1/Rac interaction inhibits PAK activation and enhances Sema4D ligand binding. Genes Dev 2002; 16(7):836–845.PubMedGoogle Scholar
  85. 85.
    Artigiani S, Barberis D, Fazzari P et al. Functional regulation of semaphorin receptors by proprotein convertases. J Biol Chem 2003; 278(12):10094–10101.PubMedGoogle Scholar
  86. 86.
    Zanata SM, Hovatta I, Rohm B et al. Antagonistic effects of Rnd1 and RhoD GTPases regulate receptor activity in Semaphorin 3A-induced cytoskeletal collapse. J Neurosci 2002; 22(2):471–477.PubMedGoogle Scholar
  87. 87.
    Oinuma I, Katoh H, Harada A et al. Direct interaction of Rnd1 with Plexin-B1 regulates PDZ-RhoGEF-mediated Rho activation by Plexin-B1 and induces cell contraction in COS-7 cells. J Biol Chem 2003; 278(28):25671–25677.PubMedGoogle Scholar
  88. 88.
    Castellani V, De Angelis E, Kenwrick S et al. Cis and trans interactions of L1 with neuropilin-1 control axonal responses to semaphorin 3A. EMBO J 2002; 21(23):6348–6357.PubMedGoogle Scholar
  89. 89.
    Kantor DB, Chivatakarn O, Peer KL et al. Semaphorin 5A is a bifunctional axon guidance cue regulated by heparan and chondroitin sulfate proteoglycans. Neuron 2004; 44(6):961–975.PubMedGoogle Scholar
  90. 90.
    Song H, Ming G, He Z et al. Conversion of neuronal growth cone responses from repulsion to attraction by cyclic nucleotides [see comments]. Science 1998; 281(5382):1515–1518.PubMedGoogle Scholar
  91. 91.
    Basile JR, Afkhami T, Gutkind JS. Semaphorin 4D/plexin-B1 induces endothelial cell migration through the activation of PYK2, Src, and the phosphatidylinositol 3-kinase-Akt pathway. Mol Cell Biol 2005; 25(16):6889–6898.PubMedGoogle Scholar
  92. 92.
    Zhang Z, Vuori K, Wang H et al. Integrin activation, by R-ras. Cell 1996; 85(1):61–69.PubMedGoogle Scholar
  93. 93.
    Wozniak MA, Kwong L, Chodniewicz D et al. R-Ras controls membrane protrusion and cell migration through the spatial regulation of Rac and Rho. Mol Cell Biol 2005; 16(1):84–96.Google Scholar
  94. 94.
    Kinbara K, Goldfinger LE, Hansen M et al. Ras GTPases: integrins’ friends or foes? nat Rev Mol Cell Biol 2003; 4(10):767–776.PubMedGoogle Scholar
  95. 95.
    Marte BM, Rodriguez-Viciana P, Wennstrom S et al. R-Ras can activate, the phosphoinositide 3-kinase but not the MAP kinase arm of the Ras effector pathways. Curr Biol 1997; 7(1):63–70.PubMedGoogle Scholar
  96. 96.
    Berrier AL, Mastrangelo AM, Downward J et al. Activated R-ras, Rac1, PI 3-kinase and PKCepsilon can each restore cell spreading inhibited by isolated integrin betal cytoplasmic domains. J Cell Biol 2000; 151(7):1549–1560.PubMedGoogle Scholar
  97. 97.
    Jeong HW, Nam JO, Kim IS. The COOH-terminal end of R-Ras alters the motility and morphology of breast epithelial cells through Rho/Rho-kinase. Cancer Res 2005; 65(2):507–515.PubMedGoogle Scholar
  98. 98.
    Arthur WT, Burridge K. RhoA inactivation by, p190RhoGAP regulates cell spreading and migration by promoting membrane protrusion and polarity. Mol Biol Cell 2001; 12(9):2711–2720.PubMedGoogle Scholar
  99. 99.
    Barberis D, Casazza A, Sordella R et al. p190 Rho-GTPase activating protein associates with plexins and it is required for semaphorin signaling. J Cell Sci 2005; 118(Pt 20):4689–4700.PubMedGoogle Scholar
  100. 100.
    Ridley AJ, Hall A. The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors. Cell 1992; 70(3):389–399.PubMedGoogle Scholar
  101. 101.
    Raftopoulou M, Hall A. Cell migration: Rho GTPases lead the way. Dev Biol 2004; 265(1):23–32.PubMedGoogle Scholar
  102. 102.
    Komatsu M, Ruoslahti E. R-Ras is a global regulator of vascular regeneration that suppresses intimal hyperplasia and tumor angiogenesis. Nat Med 2005.Google Scholar
  103. 103.
    Driessens MH, Olivo C, Nagata K et al. B plexins activate Rho through PDZ-RhoGEF. FEBS Lett 2002; 529(2–3):168–172.PubMedGoogle Scholar
  104. 104.
    Hirotani M, Ohoka Y, Yamamoto T et al. Interaction of plexin-B1 with PDZ domain-containing Rho guanine nucleotide exchange factors. Biochem Biophys Res Commun 2002l 297(1):32–37.PubMedGoogle Scholar
  105. 105.
    Perrot V, Vazquez-Prado J, Gutkind JS. Plexin B Regulates Rho through the Guanine Nucleotide Exchange Factors Leukemia-associated Rho GEF (LARG) and PDZ-RhoGEF. J Biol Chem 2002; 277(45):43115–43120.PubMedGoogle Scholar
  106. 106.
    Swiercz JM, Kuner R, Behrens J et al. Plexin-B1 directly interacts with PDZ-Rho GEF/LARG to regulate RhoA and growth cone morphology. Neuron 2002; 35(1):51–63.PubMedGoogle Scholar
  107. 107.
    Aurandt J, Vikis HG, Gutkin JS et al. The semaphorin receptor plexin-B1 signals through a direct interaction with the Rho-specific nucleotide exchange factor, LARG. Proc Natl Acad Sci USA 2002; 99(19):12085–12090.PubMedGoogle Scholar
  108. 108.
    Swiercz JM, Kuner R, Offermanns S. Plexin-B1/Rho GEF-mediated RhoA activation involves the receptor tyrosine kinase ErbB-2. J Cell Biol 2004; 165(6):869–880.PubMedGoogle Scholar
  109. 109.
    Banerjee J, Wedegaertner PB. Identification of a novel sequence in PDZ-RhoGEF that mediates interaction with the actin cytoskeleton. Mol Biol Cell 2004; 15(4):1760–1775.PubMedGoogle Scholar
  110. 110.
    Toyofuku T, Yoshida J, Sugimoto T et al. FARP2 triggers signals for Sema3A-mediated axonal repulsion. Nat Neurosci 2005; 8(12):1712–1719.PubMedGoogle Scholar
  111. 111.
    van Horck FP, Lavazais E, Eickholt BJ et al. Essential role of type I(alpha) phosphatidylinositol 4-phosphate, 5-kinase in neurite remodeling. Curr Biol 2002; 12(3):241–245.PubMedGoogle Scholar
  112. 112.
    Eickholt BJ. Protein kinases in semaphorin signaling. In: Pasterkamp RJ, ed. Semaphorins: Receptor and Intracellular Signaling Mechanisms. Georgetown: Landes Bioscience, 2006.Google Scholar
  113. 113.
    Artigiani S, Conrotto P, Fazzari P et al. Plexin-B3 is a functional receptor for semaphorin 5A. EMBO Rep 2004; 5(7):710–714.PubMedGoogle Scholar
  114. 114.
    Winberg ML, Tamagnone L, Bai J et al. The transmembrane protein Off-track associates with Plexins and functions downstream of Semaphorin signaling during axon guidance. Neuron 2001; 32(1):53–62.PubMedGoogle Scholar
  115. 115.
    Atwal JK, Singh KK, Tessier-Lavigne M et al. Semaphorin 3F antagonizes neurotrophin-induced phosphatidylinositol 3-kinase and mitogen-activated protein kinase kinase signaling: a mechanism for growth cone collapse. J Neurosci 2003; 23(20):7602–7609.PubMedGoogle Scholar
  116. 116.
    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.PubMedGoogle Scholar
  117. 117.
    Ohta K, Mizutani A, Kawakami A et al. Plexin: a novel neuronal, cell surface molecule that mediates cell adhesion via a homophilic binding mechanism in the presence of calcium ions. Neuron 1995; 14(6):1189–1199.PubMedGoogle Scholar
  118. 118.
    Hartwig C, Veske A, Krejcova S et al. Plexin B3 promotes neurite outgrowth, interacts homophilically, and interacts with Rin. BMC Neurosci 2005; 6:53.PubMedGoogle Scholar
  119. 119.
    Shimizu M, Murakami Y, Suto F et al. Determination of cell adhesion sites of neuropilin-1. J Cell Biol 2000; 148(6):1283–1293.PubMedGoogle Scholar
  120. 120.
    Carmeliet P, Tessier-Lavigne M. Common mechanisms of nerve and blood vessel wiring. Nature 2005; 436(7048):193–200.PubMedGoogle Scholar
  121. 121.
    Kurschat P, Bielenberg D, Rossignol M et al. Neuron restrictive silencer factor NRSF/REST is a transcriptional repressor of neuropilin-1 and diminishes the ability of semaphorin 3A to inhibit keratinocyte migration. J Biol Chem 2005; 281(5):2721–2729.PubMedGoogle Scholar
  122. 122.
    Mikule K, Gatlin JC, de la Houssaye BA et al. Growth cone collapse induced by semaphorin 3A requires 12/15-lipoxygenase. J Neurosci 2002; 22(12):4932–4941.PubMedGoogle Scholar
  123. 123.
    Kashiwagi H, Shiraga M, Kato H et al. Negative regulation of platelet function by a secreted cell repulsive protein, semaphorin 3A. Blood 2005; 106(3):913–921.PubMedGoogle Scholar
  124. 124.
    Delaire S, Billard C, Tordjman R et al. Biological activity of soluble CD100. II. Soluble CD100, similarly to H-SemaIII, inhibits immune cell migration. J Immunol 2001; 166(7):4348–4354.PubMedGoogle Scholar
  125. 125.
    Bachelder RE, Lipscomb EA, Lin X et al. Competing autocrine pathways involving alternative neuropilin-1 ligands regulate chemotaxis of carcinoma cells. Cancer Res 2003; 63(17):5230–5233.PubMedGoogle Scholar
  126. 126.
    Nasarre P, Constantin B, Rouhaud L et al. Semaphorin SEMA3F and VEGF have opposing effects on cell attachment and spreading. Neoplasia 2003; 5(1):83–92.PubMedGoogle Scholar
  127. 127.
    Nasarre P, Kusy S, Constantin B et al. Semaphorin SEMA3F has a repulsing activity on breast cancer cells and inhibits E-cadherin-mediated cell adhesion. Neoplasia 2005; 7(2):180–190.PubMedGoogle Scholar
  128. 128.
    Delorme G, Saltel F, Bonnelye E et al. Expression, and function of semaphorin 7A in bone cells. Biol Cell 2005; 97(7):589–597.PubMedGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2007

Authors and Affiliations

  • Andrea Casazza
  • Pietro Fazzari
  • Luca Tamagnone
    • 1
  1. 1.Institute for Cancer Research and Treatment (RCC)University of Turin Medical SchoolCandiolo (Torino)Italy

Personalised recommendations