GTPases in Semaphorin Signaling

  • Andreas W. Püschel
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 600)


Ahallmark of semaphorin receptors is their interaction with multiple GTPases. Plexins, the signal transducing component of semaphorin receptors, directly associate with several GTPases. In addition, they not only recruit guaninine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs) but also are the only known integral membrane proteins that show a catalytic activity as GAPs for small GTPases. GTPases function upstream of semaphorin receptors and regulate the activity of plexins through an interaction with the cytoplasmic domain. The association of Plexin-A1 (Sema3A receptor) or Plexin-B1 (Sema4D receptor) with the GTPase Rnd1 and ligand-dependent receptor clustering are required for their activity as R-Ras GAPs. The GTPases R-Ras and Rho function downstream of plexins and are required for the repulsive effects of semaphorins. In this review, I will focus on the role of GTPases in signaling by two plexins that have been analyzed in most detail, Plexin-A1 and Plexin-B1


Growth Cone Cytoplasmic Domain Growth Cone Collapse Intracellular Signaling Mechanism Axonal Growth Cone 
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.


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  1. 1.
    Fiore R, Püschel AW. The function of semaphorins during nervous system development. Front Biosci 2003; 8:484–499.CrossRefGoogle Scholar
  2. 2.
    He Z, Tessier-Lavigne M. Neuropilin is a receptor for the axonal chemorepellent Semaphorin III. Cell 1997, 90(4):739–751.PubMedCrossRefGoogle Scholar
  3. 3.
    Kolodkin AL, Levengood DV, Rowe EG et al. Neuropilin is a semaphorin III receptor. Cell 1997; 90(4):753–762.PubMedCrossRefGoogle Scholar
  4. 4.
    Rohm B, Ottemeyer A, Lohrum M et al. Plexin/neuropilin complexes mediate repulsion by the axonal guidance signal semaphorin 3A. Mech Dev. 2000; 93(1–2):95–104.PubMedCrossRefGoogle Scholar
  5. 5.
    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
  6. 6.
    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.PubMedCrossRefGoogle Scholar
  7. 7.
    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.PubMedCrossRefGoogle Scholar
  8. 8.
    Artigiani S, Conrotto P, Fazzari P et al. Plexin-B3 is a functional receptor for semaphorin 5A. EMBO Rep 2004; 5(7):710–714.PubMedCrossRefGoogle Scholar
  9. 9.
    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.PubMedCrossRefGoogle Scholar
  10. 10.
    Fan J, Mansfield SG, Redmond T et al. The organization of F-actin and microtubules in growth cones exposed to a brain-derived collapsing factor. J Cell Biol 1993; 121(4): 867–878.PubMedCrossRefGoogle Scholar
  11. 11.
    Fan J, Raper JA. Localized collapsing cues can steer growth cones without inducing their full collapse. Neuron 1995; 14(2):263–274.PubMedCrossRefGoogle Scholar
  12. 12.
    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
  13. 13.
    Serini G, Valdembri D, Zanivan S et al. Class 3 semaphorins control vascular morphogenesis by inhibiting integrin function. Nature 2003; 424(694):391–397.PubMedCrossRefGoogle Scholar
  14. 14.
    Castellani V, Falk J, Rougon G. Semaphorin3A-induced receptor endocytosis during axon guidance responses is mediated by L1 CAM. Mol Cell Neurosci 2004; 26(1):89–100.PubMedCrossRefGoogle Scholar
  15. 15.
    Jurney WM, Gallo G, Letourneau PC et al. Rac1-mediated endocytosis during ephrin-A2-and semaphorin 3A-induced growth cone collapse. J Neurosci 2002; 22(14):6019–6028.PubMedGoogle Scholar
  16. 16.
    Fournier AE, Nakamura F, Kawamoto S et al. Semaphorin3A enhances endocytosis at sites of receptor-F-actin colocalization during growth cone collapse. J Cell Biol 2000; 149(2):411–422.PubMedCrossRefGoogle Scholar
  17. 17.
    Bagnard D, Sainturet N, Meyronet D et al. Differential MAP kinases activation during semaphorin3A-induced repulsion or apoptosis of neural progenitor cells. Mol Cell Neurosci 2004; 25(4):722–731.PubMedCrossRefGoogle Scholar
  18. 18.
    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.PubMedCrossRefGoogle Scholar
  19. 19.
    Brown M, Jacobs T, Eickholt B et al. Alpha2-chimaerin, cyclin-dependent Kinase 5/p53, and its target collapsin response mediator protein-2 are essential components in semaphorin 3A-induced growth-cone collapse. J Neurosci 2004; 24(41):8994–9004.PubMedCrossRefGoogle Scholar
  20. 20.
    Campbell DS, Holt CE. Apoptotic pathway and MAPKs differentially regulate chemotropic responses of retinal growth cones. Neuron 2003; 37(6):939–952.PubMedCrossRefGoogle Scholar
  21. 21.
    Eickholt BJ, Walsh FS, Doherty P. An inactive pool of GSK-3 at the leading edge of growth cones is implicated in Semaphorin 3A signaling. J Cell Biol 2002; 157(2):211–217.PubMedCrossRefGoogle Scholar
  22. 22.
    Fujioka S, Masuda K, Toguchi M et al. Neurotrophic effect of Semaphorin 4D in PC12 cells. Biochem Biophys Res Commun 2003; 301(2):304–310.PubMedCrossRefGoogle Scholar
  23. 23.
    Mitsui N, Inatome R, Takahashi S et al. Involvement of Fes/Fps tyrosine kinase in semaphorin3A signaling. EMBO J 2002; 21:3274–3285.PubMedCrossRefGoogle Scholar
  24. 24.
    Pasterkamp PJ, Peschon JJ, Spriggs MK et al. Semaphorin 7A promotes axon outgrowth through integrins and MAPKs. Nature 2003; 424(6947):398–405.PubMedCrossRefGoogle Scholar
  25. 25.
    Sasaki Y, Cheng C, Uchida Y et al. Fyn and Cdk5 mediate semaphorin-3A signaling, which is involved in regulation of dendrite orientation in cerebral cortex. Neuron 2002; 35(5):907–920.PubMedCrossRefGoogle Scholar
  26. 26.
    Schwamborn JC, Fiore R, Bagnard D et al. Semaphorin 3A stimulates neurite extension and regulates gene expression in PC12 cells. J Biol Chem 2004; 279(30):30923–30926.PubMedCrossRefGoogle Scholar
  27. 27.
    Uchida Y, Ohshima T, Sasaki Y et al. Semaphorin3A signaling is mediated via sequential Cdk5 and GSK3beta phosphorylation of CRMP2: Implication of common phosphorylating mechanism underlying axon guidance and Alzheimer’ disease. Genes Cells 2005; 10(2):165–179.PubMedCrossRefGoogle Scholar
  28. 28.
    Takahashi T, Strittmatter SM. PlexinA1 autoinhibition by the plexin sema domain. Neuron 2001; 29(2):429–439.PubMedCrossRefGoogle Scholar
  29. 29.
    Oinuma I, Katoh H, Negishi M. Molecular dissection of the semaphorin 4D receptor plexin-B1-stimulated R-Ras GTPase-activating protein activity and neurite remodeling in hippocampal neurons. J Neurosci 2004; 24(50):11473–11480.PubMedCrossRefGoogle Scholar
  30. 30.
    Antipenko A, Himanen JP, van Leyen K et al. Structure of the semaphorin-3A receptor binding module. Neuron 2003; 39(4):589–598.PubMedCrossRefGoogle Scholar
  31. 31.
    Campbell ID, Ginsberg MH. The talin-tail interaction places integrin activation on FERM ground. Trends Biochem Sci 2004; 29(8):429–435.PubMedCrossRefGoogle Scholar
  32. 32.
    Kim M, Carman CV, Springer TA Bidirectional transmembrane signaling by cytoplasmic domain separation in integrins. Science 2003; 301(5640):1720–1725.PubMedCrossRefGoogle Scholar
  33. 33.
    Takagi J, Petre BM, Walz T et al. Global conformational rearrangements in integrin extracellular domains in outside-in and inside-out signaling. Cell 2002; 110(5):599–611.PubMedCrossRefGoogle Scholar
  34. 34.
    Wennerberg K, Rossman KL, Der CJ. The Ras superfamily at a glance. J Cell Sci 2005; 118(5):843–846.PubMedCrossRefGoogle Scholar
  35. 35.
    Wennerberg K, Der CJ. Rho-family GTPases: It’s not only Rac and Rho (and I like it). J Cell Sci 2004; 117(8):1301–1312.PubMedCrossRefGoogle Scholar
  36. 36.
    Nobes CD, Lauritzen I, Mattei MG et al. A new member of the Rho family, Rnd1, promotes disassembly of actin filament structures and loss of cell adhesion. J Cell Biol 1998; 141(1):187–197.PubMedCrossRefGoogle Scholar
  37. 37.
    Govek EE, Newey SE, Van Aelst L. The role of the Rho GTPases in neuronal development. Genes Dev 2005; 19(1):1–49.PubMedCrossRefGoogle Scholar
  38. 38.
    Chiarugi P, Cirri P. Redox regulation of protein tyrosine phosphatases during receptor tyrosine kinase signal transduction. Trends Biochem Sci 2003; 28(9):509–514.PubMedCrossRefGoogle Scholar
  39. 39.
    Jalink K, van Corven EJ, Hengeveld T et al. Inhibition of lysophosphatidate-and thrombin-induced neurite retraction and neuronal cell rounding by ADP ribosylation of the small GTP-binding protein Rho. J Cell Biol 1994; 126(3):801–810.PubMedCrossRefGoogle Scholar
  40. 40.
    Wahl S, Barth H, Ciossek T et al. Ephrin-A5 induces collapse of growth cones by activating Rho and Rho kinase. J Cell Biol 2000; 149(2):263–270.PubMedCrossRefGoogle Scholar
  41. 41.
    Aurandt J, Vikis HG, Gutkind 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 2002; 99(19):12085–12090.PubMedCrossRefGoogle Scholar
  42. 42.
    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 2002; 297(1):32–37.PubMedCrossRefGoogle Scholar
  43. 43.
    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.PubMedCrossRefGoogle Scholar
  44. 44.
    Swiercz JM, Kuner R, Behrens J et al. Plexin-B1 directly interacts with PDZ-RhoGEF/LARG to regulate RhoA and growth cone morphology. Neuron 2002; 35(1):51–63.PubMedCrossRefGoogle Scholar
  45. 45.
    Jin Z, Strittmatter SM. Rac1 mediates collapsin-1-induced growth cone collapse. J Neurosci 1997; 15(17):6256–6563.Google Scholar
  46. 46.
    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
  47. 47.
    Västrik 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.PubMedCrossRefGoogle Scholar
  48. 48.
    Luo Y, Raible D, Raper JA. Collapsin: A protein in brain that induces the collapse and paralysis of neuronal growth cones. Cell 1993; 75(2):217–227.PubMedCrossRefGoogle Scholar
  49. 49.
    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.PubMedCrossRefGoogle Scholar
  50. 50.
    Toyofuku T, Yoshida J, Sugimoto T et al. FARP2 triggers signals for Sema3A-mediated axonal repulsion. Nat Neurosci 2005; 8(12):1712–1719.PubMedCrossRefGoogle Scholar
  51. 51.
    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.PubMedCrossRefGoogle Scholar
  52. 52.
    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.PubMedCrossRefGoogle Scholar
  53. 53.
    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.PubMedCrossRefGoogle Scholar
  54. 54.
    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
  55. 55.
    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.PubMedCrossRefGoogle Scholar
  56. 56.
    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.PubMedCrossRefGoogle Scholar
  57. 57.
    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.PubMedCrossRefGoogle Scholar
  58. 58.
    Scheffzek K, Ahmadian MR, Kabsch W et al. The Ras-RasGAP complex: Structural basis for GTPase activation and its loss in oncogenic Ras mutants. Science 1997; 277(5324):333–338.PubMedCrossRefGoogle Scholar
  59. 59.
    Scheffzek K, Ahmadian MR, Wiesmuller L et al. Structural analysis of the GAP-related domain from neurofibromin and its implications. EMBO J 1998; 17(15):4313–4327.PubMedCrossRefGoogle Scholar
  60. 60.
    Scheffzek K, Ahmadian MR, Wittinghofer A. GTPase-activating proteins: Helping hands to complement an active site. Trends Biochem Sci 1998; 23(7):257–262.PubMedCrossRefGoogle Scholar
  61. 61.
    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
  62. 62.
    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
  63. 63.
    Ling K, Doughman RL, Firestone AJ et al. Type I gamma phosphatidylinositol phosphate kinase targets and regulates focal adhesions. Nature 2002; 420(6911):89–93.PubMedCrossRefGoogle Scholar
  64. 64.
    Di Paolo G, Pellegrini L, Letinic K et al. Recruitment and regulation of phosphatidylinositol phosphate kinase type 1 gamma by the FERM domain of talin. Nature 2002; 420(6911):85–89.PubMedCrossRefGoogle Scholar
  65. 65.
    Aizawa H, Wakatsuki S, Ishii A et al. Phosphorylation of cofilin by LIM-kinase is necessary for semaphorin 3A-induced growth cone collapse. Nat Neurosci 2001; 4(4):367–373.PubMedCrossRefGoogle Scholar
  66. 66.
    Pollard TD, Borisy GG. Cellular motility driven by assembly and disassembly of actin filaments. Cell 2003; 112(4):453–465.PubMedCrossRefGoogle Scholar
  67. 67.
    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.PubMedCrossRefGoogle Scholar
  68. 68.
    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(20):4689–4700.PubMedCrossRefGoogle Scholar
  69. 69.
    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.PubMedCrossRefGoogle Scholar
  70. 70.
    Swiercz JM, Kuner R, Offermanns S. Plexin-B1/RhoGEF-mediated RhoA activation involves the receptor tyrosine kinase ErbB-2. J Cell Biol 2004; 165(6):869–880.PubMedCrossRefGoogle Scholar
  71. 71.
    Dalpe G, Zhang LW, Zheng H et al. Conversion of cell movement responses to Semaphorin-1 and Plexin-1 from attraction to repulsion by lowered levels of specific RAC GTPases in C. elegans. Development 2004; 131(9):2073–2088.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2007

Authors and Affiliations

  • Andreas W. Püschel
    • 1
  1. 1.Abteilung Molekularbiologie, Institut für Allgemeine Zoologie und GenetikWestfälische Wilhelms-UniversitätMünsterGermany

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