The CRMP Family of Proteins and Their Role in Sema3A Signaling

  • Eric F. Schmidt
  • Stephen M. Strittmatter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 600)


The CRMP proteins were originally identified as mediators of Sema3A signaling and neuronal differentiation. Much has been learned about the mechanism by which CRMPs regulate cellular responses to Sema3A. In this review, the evidence for CRMP as a component of the Sema3A signaling cascade and the modulation of CRMP by plexin and phosphorylation are considered. In addition, current knowledge of the function of CRMP in a variety of cellular processes, including regulation of the cytoskeleton and endocytosis, is discussed in relationship to the mechanisms of axonal growth cone Sema3A response

The secreted protein Sema3A (collapsin-1) was the first identified vertebrate semaphorin. Sema3A acts primarily as a repulsive axon guidance cue, and can cause a dramatic collapse of the growth cone lamellipodium. This process results from the redistribution of the F-actin cytoskeleton1,2 and endocytosis of the growth cone cell membrane.2, 3, 4 Neuropilin-1 (NP1) and members of the class A plexins (PlexA) form a Sema3A receptor complex, with NP1 serving as a high-affinity ligand binding partner, and PlexA transducing the signal into the cell via its large intracellular domain. Although the effect of Sema3A on growth cones was first described nearly 15 years ago, the intracellular signaling pathways that lead to the cellular effects have only recently begun to be understood. Monomeric G-proteins, various kinases, the redox protein, MICAL, and protein turnover have all been implicated in PlexA transduction. In addition, the collapsin-response-mediator protein (CRMP), family of cytosolic phosphoproteins plays a crucial role in Sema3A/NP1/PlexA signal transduction. Current knowledge regarding CRMP functions are reviewed here


Growth Cone Optic Neuritis Paraneoplastic Neurological Syndrome Nonneuronal 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.


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  1. 1.
    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; 121:867–878.PubMedCrossRefGoogle Scholar
  2. 2.
    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; 149:411–422.PubMedCrossRefGoogle Scholar
  3. 3.
    Castellani V, Falk J, Rougon G. Semaphorin3A-induced receptor endocytosis during axon guidance responses is mediated by L1 CAM. Mol Cell Neurosci 2004; 26:89–100.PubMedCrossRefGoogle Scholar
  4. 4.
    Jurney WM, Gallo G, Letourneau PC et al. Rac1-mediated endocytosis during ephrin-A2-and semaphorin 3A-induced growth cone collapse. J Neurosci 2002; 22:6019–6028.PubMedGoogle Scholar
  5. 5.
    Minturn JE, Fryer HJ, Geschwind DH et al. TOAD-64, a gene expressed early in neuronal differentiation in the rat, is related to unc-33, a C. elegans gene involved in axon outgrowth. J Neurosci 1995; 15:6757–6766.PubMedGoogle Scholar
  6. 6.
    Hamajima N, Matsuda K, Sakata S et al. A novel gene family defined by human dihydropyrimidinase and three related proteins with differential tissue distribution. Gene 1996; 180:157–163.PubMedCrossRefGoogle Scholar
  7. 7.
    Byk T, Dobransky T, Cifuentes-Diaz C et al. Identification and molecular characterization of Unc-33-like phosphoprotein (Ulip), a putative mammalian homolog of the axonal guidance-associated unc-33 gene product. J Neurosci 1996; 16:688–701.PubMedGoogle Scholar
  8. 8.
    Quinn CC, Gray GE, Hockfield S. A family of proteins implicated in axon guidance and out-growth J Neurobiol 1999; 41:158–164.PubMedCrossRefGoogle Scholar
  9. 9.
    Gaetano C, Matsuo T, Thiele CJ. Identification and characterization of a retinoic acid-regulated human homologue of the unc-33-like phosphoprotein gene (hUlip) from neuroblastoma cells. J Biol Chem 1997; 272:12195–12201.PubMedCrossRefGoogle Scholar
  10. 10.
    Goshima Y, Nakamura F, Strittmatter P et al. Collapsin-induced growth cone collapse mediated by an intracellular protein related to UNC-33. Nature 1995; 376:509–514.PubMedCrossRefGoogle Scholar
  11. 11.
    Takemoto T, Sasaki Y, Hamajima N et al. Cloning and characterization of the Caenorhabditis elegans CeCRMP/DHP-1 and-2; common ancestors of CRMP and dihydropyrimidinase?. Gene 2000; 261:259–267.PubMedCrossRefGoogle Scholar
  12. 12.
    Leung T, Ng Y, Cheong A et al. p80 ROKalpha binding protein is a novel splice variant of CRMP-1 which associates with CRMP-2 and modulates RhoA-induced neuronal morphology. FEBS Lett 2002; 532:445–449.PubMedCrossRefGoogle Scholar
  13. 13.
    Quinn CC, Chen E, Kinjo TG et al. TUC-4b, a novel TUC family variant, regulates neurite outgrowth and associates with vesicles in the growth cone. J Neurosci 2003; 23:2815–2823.PubMedGoogle Scholar
  14. 14.
    Wang LH, Strittmatter SM. Brain CRMP forms heterotetramers similar to liver dihydropyrimidinase. J Neurochem 1997; 69:2261–2269.PubMedCrossRefGoogle Scholar
  15. 15.
    Deo RC, Schmidt EF, Elhabazi A et al. Structural bases for CRMP function in plexin-dependent semaphorin3A signaling. Embo J 2004; 23:9–22.PubMedCrossRefGoogle Scholar
  16. 16.
    Kamata T, Daar IO, Subleski M et al. Xenopus CRMP-2 is an early response gene to neural induction. Brain Res Mol Brain Res 1998; 57:201–210.PubMedCrossRefGoogle Scholar
  17. 17.
    Kodama Y, Murakumo Y, Ichihara M et al. Induction of CRMP-2 by GDNF and analysis of the CRMP-2 promoter region. Biochem Biophys Res Commun 2004; 320:108–115.PubMedCrossRefGoogle Scholar
  18. 18.
    Tateossian H, Powles N, Dickinson R et al. Determination of downstream targets of FGF signaling using gene trap and cDNA subtractive approaches. Exp Cell Res 2004; 292:101–114.PubMedCrossRefGoogle Scholar
  19. 19.
    Wang LH, Strittmatter SM. A family of rat CRMP genes is differentially expressed in the nervous system. J Neurosci 1996; 16:6197–6207.PubMedGoogle Scholar
  20. 20.
    Veyrac A, Giannetti N, Charrier E et al. Expression of collapsin response mediator proteins 1, 2 and 5 is differentially regulated in newly generated and mature neurons of the adult olfactory system. Eur J Neurosci 2005; 21:2635–2648.PubMedCrossRefGoogle Scholar
  21. 21.
    Doetsch F, Hen R. Young and excitable: The function of new neurons in the adult mammalian brain. Curr Opin Neurobiol 2005; 15:121–128.PubMedCrossRefGoogle Scholar
  22. 22.
    Fukada M, Watakabe I, Yuasa-Kawada J et al. Molecular characterization of CRMP5, a novel member of the collapsin response mediator protein family. J Biol Chem 2000; 275:37957–37965.PubMedCrossRefGoogle Scholar
  23. 23.
    Li W, Herman RK, Shaw JE. Analysis of the Caenorhabditis elegans axonal guidance and out-growth gene unc-33. Genetics 1992; 132:675–689.PubMedGoogle Scholar
  24. 24.
    Hotta A, Inatome R, Yuasa-Kawada J et al. Critical role of collapsin response mediator protein-associated molecule CRAM for filopodia and growth cone development in neurons. Mol Biol Cell 2005; 16:32–39.PubMedCrossRefGoogle Scholar
  25. 25.
    Inagaki N, Chihara K, Arimura N et al. CRMP-2 induces axons in cultured hippocampal neurons. Nat Neurosci 2001; 4:781–782.PubMedCrossRefGoogle Scholar
  26. 26.
    Rosslenbroich V, Dai L, Franken S et al. Subcellular localization of collapsin response mediator proteins to lipid rafts. Biochem Biophys Res Commun 2003; 305:392–399.PubMedCrossRefGoogle Scholar
  27. 27.
    Pasterkamp RJ, De Winter F, Holtmaat AJ et al. Evidence for a role of, the chemorepellent semaphorin III and its receptor neuropilin-1 in the regeneration of primary olfactory axons. J Neurosci 1998; 18:9962–9976.PubMedGoogle Scholar
  28. 28.
    Suzuki Y, Nakagomi S, Namikawa K et al. Collapsin response mediator protein-2 accelerates axon regeneration of nerve-injured motor neurons of rat. J Neurochem 2003; 86:1042–1050.PubMedCrossRefGoogle Scholar
  29. 29.
    Takahashi T, Fournier A, Nakamura F et al. Plexin-neuropilin-1 complexes form functional semaphorin-3A receptors. Cell 1999; 99:59–69.PubMedCrossRefGoogle Scholar
  30. 30.
    Suto F, Ito K, Uemura M et al. Plexin-a4 mediates axon-repulsive activities of both secreted and transmembrane semaphorins and plays roles in nerve fiber guidance. J Neurosci 2005; 25:3628–3637.PubMedCrossRefGoogle Scholar
  31. 31.
    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; 4:367–373.PubMedCrossRefGoogle Scholar
  32. 32.
    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; 157:211–217.PubMedCrossRefGoogle Scholar
  33. 33.
    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
  34. 34.
    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; 35:907–920.PubMedCrossRefGoogle Scholar
  35. 35.
    Brown M, Jacobs T, Eickholt B et al. Alpha2-chimaerin, cyclin-dependent Kinase 5/p35, and its target collapsin response mediator protein-2 are essential components in semaphorin 3A-induced growth-cone collapse. J Neurosci 2004; 24:8994–9004.PubMedCrossRefGoogle Scholar
  36. 36.
    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’s disease. Genes Cells 2005; 10:165–179.PubMedCrossRefGoogle Scholar
  37. 37.
    Cole AR, Knebel A, Morrice NA et al. GSK-3 phosphorylation of the Alzheimer epitope within collapsin response mediator proteins regulates axon elongation in primary neurons J Biol Chem 2004; 279:50176–50180.PubMedCrossRefGoogle Scholar
  38. 38.
    Yoshimura T, Kawano Y, Arimura N et al. GSK-3beta regulates phosphorylation of CRMP-2 and neuronal polarity. Cell 2005; 120:137–149.PubMedCrossRefGoogle Scholar
  39. 39.
    Gu Y, Hamajima N, Ihara Y. Neurofibrillary tangle-associated collapsin response mediator protein-2 (CRMP-2) is highly phosphorylated on Thr-509, Ser-518, and Ser-522. Biochemistry 2000; 39:4267–4275.PubMedCrossRefGoogle Scholar
  40. 40.
    Ryan KA, Pimplikar SW. Activation of GSK-3 and phosphorylation of CRMP2 in transgenic mice expressing APP intracellular domain. J Cell Biol 2005; 171:327–335.PubMedCrossRefGoogle Scholar
  41. 41.
    Arimura N, Inagaki N, Chihara K et al. Phosphorylation of collapsin response mediator protein-2 by Rho-kinase. Evidence for two separate signaling pathways for growth cone collapse. J Biol Chem 2000; 275:23973–23980.PubMedCrossRefGoogle Scholar
  42. 42.
    Arimura N, Menager C, Kawano Y et al. Phosphorylation by Rho kinase regulates CRMP-2 activity in growth cones. Mol Cell Biol 2005; 25:9973–9984.PubMedCrossRefGoogle Scholar
  43. 43.
    Amano M, Fukata Y, Kaibuchi K. Regulation and functions of Rho-associated kinase. Exp Cell Res 2000; 261:44–51.PubMedCrossRefGoogle Scholar
  44. 44.
    Fukata Y, Itoh TJ, Kimura T et al. CRMP-2 binds to tubulin heterodimers to promote microtubule assembly. Nat Cell Biol 2002; 4:583–591.PubMedGoogle Scholar
  45. 45.
    Gu Y, Ihara Y. Evidence that collapsin response mediator protein-2 is involved in the dynamics of microtubules. J Biol Chem 2000; 275:17917–17920.PubMedCrossRefGoogle Scholar
  46. 46.
    Yuasa-Kawada J, Suzuki R, Kano F et al. Axonal morphogenesis controlled by antagonistic roles of two CRMP subtypes in microtubule organization. Eur J Neurosci 2003; 17:2329–2343.PubMedCrossRefGoogle Scholar
  47. 47.
    Gordon-Weeks PR. Microtubules and growth cone function. J Neurobiol 2004; 58:70–83.PubMedCrossRefGoogle Scholar
  48. 48.
    Rosslenbroich V, Dai L, Baader SL et al. Collapsin response mediator protein-4 regulates F-actin bundling. Exp Cell Res 2005; 310:434–444.PubMedCrossRefGoogle Scholar
  49. 49.
    Liu BP, Strittmatter SM. Semaphorin-mediated axonal guidance via Rho-related G proteins. Curr Opin Cell Biol 2001; 13:619–626.PubMedCrossRefGoogle Scholar
  50. 50.
    Jin Z, Strittmatter SM. Rac1 mediates collapsin-1-induced growth cone collapse. J Neurosci 1997; 17:6256–6263.PubMedGoogle Scholar
  51. 51.
    Toyofuku T, Yoshida J, Sugimoto T et al. FARP2 triggers signals for Sema3A-mediated axonal repulsion. Nat Neurosci 2005; 8:1712–1719.PubMedCrossRefGoogle Scholar
  52. 52.
    Turner LJ, Nicholls S, Hall A. The activity of the plexin-A1 receptor is regulated by Rac. J Biol Chem 2004; 279:33199–33205.PubMedCrossRefGoogle Scholar
  53. 53.
    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; 22:471–477.PubMedGoogle Scholar
  54. 54.
    Hall C, Brown M, Jacobs T et al. Collapsin response mediator protein switches RhoA and Rac1 morphology in N1E-115 neuroblastoma cells and is regulated by Rho kinase. J. Biol Chem 2001; 276:43482–43486.PubMedCrossRefGoogle Scholar
  55. 55.
    Kobayashi K, Kuroda S, Fukata M et al. p140Sra-1 (specifically Rac1-associated protein) is a novel specific target for Rac1 small GTPase. J Biol Chem 1998; 273:291–295.PubMedCrossRefGoogle Scholar
  56. 56.
    Kawano Y, Yoshimura T, Tsuboi D et al. CRMP-2 is involved in kinesin-1-dependent transport of the Sra-1/WAVE1 complex and axon formation. Mol Cell Biol 2005; 25:9920–9935.PubMedCrossRefGoogle Scholar
  57. 57.
    Symons M, Settleman J. Rho family GTPases: More than simple switches. Trends Cell Biol 2000; 10:415–419.PubMedCrossRefGoogle Scholar
  58. 58.
    Hussain NK, Jenna S, Glogauer M et al. Endocytic protein intersectin-1 regulates actin assembly via Cdc42 and N-WASP. Nat Cell Biol 2001; 3:927–932.PubMedCrossRefGoogle Scholar
  59. 59.
    Hussain NK, Yamabhai M, Ramjaun AR et al. Splice variants of intersectin are components of the endocytic machinery in neurons and nonneuronal cells. J Biol Chem 1999; 274:15671–15677.PubMedCrossRefGoogle Scholar
  60. 60.
    Santolini E, Puri C, Salcini AE et al. Numb is an endocytic protein. J Cell Biol 2000; 151:1345–1352.PubMedCrossRefGoogle Scholar
  61. 61.
    Nishimura T, Fukata Y, Kato K et al. CRMP-2 regulates polarized Numb-mediated endocytosis for axon growth. Nat Cell Biol 2003; 5:819–826.PubMedCrossRefGoogle Scholar
  62. 62.
    Lee S, Kim JH, Lee CS et al. Collapsin response mediator protein-2 inhibits neuronal phospholipase D(2) activity by direct interaction. J Biol Chem 2002; 277:6542–6549.PubMedCrossRefGoogle Scholar
  63. 63.
    McDermott M, Wakelam MJ, Morris AJ. Phospholipase D. Biochem Cell Biol 2004; 82:225–253.PubMedCrossRefGoogle Scholar
  64. 64.
    Shen Y, Xu L, Foster DA. Role for phospholipase D in receptor-mediated endocytosis. Mol Cell Biol 2001; 21:595–602.PubMedCrossRefGoogle Scholar
  65. 65.
    Terman JR, Mao T, Pasterkamp RJ et al. MICALs, a family of conserved flavoprotein oxidoreductases, function in plexin-mediated axonal repulsion. Cell 2002; 109:887–900.PubMedCrossRefGoogle Scholar
  66. 66.
    Pasterkamp RJ, Dai HN, Terman JR et al. MICAL flavoprotein monooxygenases: Expression during neural development and following spinal cord injuries in the rat. Mol Cell Neurosci 2005.Google Scholar
  67. 67.
    Siebold C, Berrow N, Walter TS et al. High-resolution structure of the catalytic region of MICAL (molecule interacting with CasL), a multidomain flavoenzyme-signaling molecule. Proc Natl Acad Sci USA 2005; 102:16836–16841.PubMedCrossRefGoogle Scholar
  68. 68.
    Yoshida H, Watanabe A, Ihara Y. Collapsin response mediator protein-2 is associated with neurofibrillary tangles in Alzheimer’s disease. J Biol Chem 1998; 273:9761–9768.PubMedCrossRefGoogle Scholar
  69. 69.
    Good PF, Alapat D, Hsu A et al. A role for semaphorin 3A signaling in the degeneration of hippocampal neurons during Alzheimer’s disease. J Neurochem 2004; 91:716–736.PubMedCrossRefGoogle Scholar
  70. 70.
    Honnorat J, Byk T, Kusters I et al. Ulip/CRMP proteins are recognized by autoantibodies in paraneoplastic neurological syndromes. Eur J Neurosci 1999; 11:4226–4232.PubMedCrossRefGoogle Scholar
  71. 71.
    Yu Z, Kryzer TJ, Griesmann GE et al. CRMP-5 neuronal autoantibody: Marker of lung cancer and thymoma-related autoimmunity. Ann Neurol 2001; 49:146–154.PubMedCrossRefGoogle Scholar
  72. 72.
    Cross SA, Salomao DR, Parisi JE et al. Paraneoplastic autoimmune optic neuritis with retinitis defined by CRMP-5-IgG. Ann Neurol 2003; 54:38–50.PubMedCrossRefGoogle Scholar
  73. 73.
    Honnorat J, Antoine JC, Derrington E et al. Antibodies to a subpopulation of glial cells and a 66 kDa developmental protein in patients with paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry 1996; 61:270–278.PubMedCrossRefGoogle Scholar
  74. 74.
    Shih JY, Yang SC, Hong TM et al. Collapsin response mediator protein-1 and the invasion and metastasis of cancer cells. J Natl Cancer Inst 2001; 93:1392–1400.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2007

Authors and Affiliations

  • Eric F. Schmidt
  • Stephen M. Strittmatter
    • 1
  1. 1.Stephen M. Strittmatter—Department of NeurologyYale University School of MedicineNew HavenUSA

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