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Dysregulation of CRMP2 Post-Translational Modifications Drive Its Pathological Functions

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Abstract

Collapsin response mediator proteins (CRMPs) are a family of ubiquitously expressed, homologous phosphoproteins best known for coordinating cytoskeletal formation and regulating cellular division, migration, polarity, and synaptic connection. CRMP2, the most studied of the five family members, is best known for its affinity for tubulin heterodimers and function in regulating the microtubule network. These functions are tightly regulated by post-translational modifications including phosphorylation, SUMOylation, oxidation, and O-GlcNAcylation. While CRMP2’s physiological functions rely mostly on its non-phosphorylated state, dysregulation of CRMP2 phosphorylation and SUMOylation has been reported to be involved in the pathophysiology of multiple diseases including cancer, chronic pain, spinal cord injury, neurofibromatosis type 1, and others. Here, we provide a consolidated update on what is known about CRMP2 signaling and function, first focusing on axonal growth and neuronal polarity, then illustrating the link between dysregulated CRMP2 post-translational modifications and diseases. We additionally discuss the roles of CRMP2 in non-neuronal cells, both in the CNS and regions of the periphery. Finally, we offer thoughts on the therapeutic implications of modulating CRMP2 function in a variety of diseases.

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References

  1. Wang LH, Strittmatter SM (1996) A family of rat CRMP genes is differentially expressed in the nervous system. J Neurosci 16(19):6197–6207

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Tan F, Thiele CJ, Li Z (2014) Collapsin response mediator proteins: Potential diagnostic and prognostic biomarkers in cancers (review). Oncol Lett 7(5):1333–1340. https://doi.org/10.3892/ol.2014.1909

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Ip JP, Fu AK, Ip NY (2014) CRMP2: Functional roles in neural development and therapeutic potential in neurological diseases. Neuroscientist 20(6):589–598. https://doi.org/10.1177/1073858413514278

    Article  CAS  PubMed  Google Scholar 

  4. Makihara H, Nakai S, Ohkubo W, Yamashita N, Nakamura F, Kiyonari H, Shioi G, Jitsuki-Takahashi A et al (2016) CRMP1 and CRMP2 have synergistic but distinct roles in dendritic development. Genes Cells : devoted to molecular & cellular mechanisms 21(9):994–1005. https://doi.org/10.1111/gtc.12399

    Article  CAS  Google Scholar 

  5. Fukata Y, Itoh TJ, Kimura T, Menager C, Nishimura T, Shiromizu T, Watanabe H, Inagaki N et al (2002) CRMP-2 binds to tubulin heterodimers to promote microtubule assembly. Nat Cell Biol 4(8):583–591. https://doi.org/10.1038/ncb825

    Article  CAS  PubMed  Google Scholar 

  6. Yamashita N, Ohshima T, Nakamura F, Kolattukudy P, Honnorat J, Mikoshiba K, Goshima Y (2012) Phosphorylation of CRMP2 (collapsin response mediator protein 2) is involved in proper dendritic field organization. J Neurosci 32(4):1360–1365. https://doi.org/10.1523/JNEUROSCI.5563-11.2012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Crews L, Ruf R, Patrick C, Dumaop W, Trejo-Morales M, Achim CL, Rockenstein E, Masliah E (2011) Phosphorylation of collapsin response mediator protein-2 disrupts neuronal maturation in a model of adult neurogenesis: Implications for neurodegenerative disorders. Mol Neurodegener 6:67. https://doi.org/10.1186/1750-1326-6-67

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Nagai J, Takaya R, Piao W, Goshima Y, Ohshima T (2016) Deletion of Crmp4 attenuates CSPG-induced inhibition of axonal growth and induces nociceptive recovery after spinal cord injury. Mol Cell Neurosci 74:42–48. https://doi.org/10.1016/j.mcn.2016.03.006

    Article  CAS  PubMed  Google Scholar 

  9. Yoshida H, Watanabe A, Ihara Y (1998) Collapsin response mediator protein-2 is associated with neurofibrillary tangles in Alzheimer’s disease. J Biol Chem 273(16):9761–9768

    Article  CAS  PubMed  Google Scholar 

  10. Moutal A, Cai S, Luo S, Voisin R, Khanna R (2018) CRMP2 is necessary for Neurofibromatosis type 1 related pain. Channels 12(1):47–50. https://doi.org/10.1080/19336950.2017.1370524

    Article  PubMed  Google Scholar 

  11. Moutal A, Yang X, Li W, Gilbraith KB, Luo S, Cai S, Francois-Moutal L, Chew LA et al (2017) CRISPR/Cas9 editing of Nf1 gene identifies CRMP2 as a therapeutic target in neurofibromatosis type 1-related pain that is reversed by (S)-Lacosamide. Pain 158(12):2301–2319. https://doi.org/10.1097/j.pain.0000000000001002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Moutal A, Dustrude ET, Largent-Milnes TM, Vanderah TW, Khanna M, Khanna R (2017) Blocking CRMP2 SUMOylation reverses neuropathic pain. Mol Psychiatry 23(11):2119–2121. https://doi.org/10.1038/mp.2017.117

    Article  CAS  Google Scholar 

  13. Moutal A, Luo S, Largent-Milnes TM, Vanderah TW, Khanna R (2018) Cdk5-mediated CRMP2 phosphorylation is necessary and sufficient for peripheral neuropathic pain. Neurobiol Pain doi:https://doi.org/10.1016/j.ynpai.2018.07.003

  14. Charrier E, Reibel S, Rogemond V, Aguera M, Thomasset N, Honnorat J (2003) Collapsin response mediator proteins (CRMPs): Involvement in nervous system development and adult neurodegenerative disorders. Mol Neurobiol 28(1):51–64. https://doi.org/10.1385/MN:28:1:51

    Article  CAS  PubMed  Google Scholar 

  15. Benedict JW, Getty AL, Wishart TM, Gillingwater TH, Pearce DA (2009) Protein product of CLN6 gene responsible for variant late-onset infantile neuronal ceroid lipofuscinosis interacts with CRMP-2. J Neurosci Res 87(9):2157–2166. https://doi.org/10.1002/jnr.22032

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Duplan L, Bernard N, Casseron W, Dudley K, Thouvenot E, Honnorat J, Rogemond V, De Bovis B et al (2010) Collapsin response mediator protein 4a (CRMP4a) is upregulated in motoneurons of mutant SOD1 mice and can trigger motoneuron axonal degeneration and cell death. J Neurosci 30(2):785–796. https://doi.org/10.1523/JNEUROSCI.5411-09.2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lim NK, Hung LW, Pang TY, McLean CA, Liddell JR, Hilton JB, Li QX, White AR et al (2014) Localized changes to glycogen synthase kinase-3 and collapsin response mediator protein-2 in the Huntington’s disease affected brain. Hum Mol Genet 23(15):4051–4063. https://doi.org/10.1093/hmg/ddu119

    Article  CAS  PubMed  Google Scholar 

  18. Togashi K, Hasegawa M, Nagai J, Tonouchi A, Masukawa D, Hensley K, Goshima Y, Ohshima T (2018) Genetic suppression of CRMP2 phosphorylation improves outcome in MPTP-induced Parkinson's model mice. Genes Cells : devoted to molecular & cellular mechanisms. https://doi.org/10.1111/gtc.12651

  19. Petratos S, Ozturk E, Azari MF, Kenny R, Lee JY, Magee KA, Harvey AR, McDonald C et al (2012) Limiting multiple sclerosis related axonopathy by blocking Nogo receptor and CRMP-2 phosphorylation. Brain J Neurol 135(Pt 6):1794–1818. https://doi.org/10.1093/brain/aws100

    Article  Google Scholar 

  20. Tabares-Seisdedos R, Rubenstein JL (2009) Chromosome 8p as a potential hub for developmental neuropsychiatric disorders: Implications for schizophrenia, autism and cancer. Mol Psychiatry 14(6):563–589. https://doi.org/10.1038/mp.2009.2

    Article  CAS  PubMed  Google Scholar 

  21. Pham X, Song G, Lao S, Goff L, Zhu H, Valle D, Avramopoulos D (2016) The DPYSL2 gene connects mTOR and schizophrenia. Transl Psychiatry 6(11):e933. https://doi.org/10.1038/tp.2016.204

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Tobe BTD, Crain AM, Winquist AM, Calabrese B, Makihara H, Zhao WN, Lalonde J, Nakamura H et al (2017) Probing the lithium-response pathway in hiPSCs implicates the phosphoregulatory set-point for a cytoskeletal modulator in bipolar pathogenesis. Proc Natl Acad Sci U S A 114(22):E4462–E4471. https://doi.org/10.1073/pnas.1700111114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Shimada K, Ishikawa T, Nakamura F, Shimizu D, Chishima T, Ichikawa Y, Sasaki T, Endo I et al (2014) Collapsin response mediator protein 2 is involved in regulating breast cancer progression. Breast Cancer 21(6):715–723. https://doi.org/10.1007/s12282-013-0447-5

    Article  PubMed  Google Scholar 

  24. Meyronet D, Massoma P, Thivolet F, Chalabreysse L, Rogemond V, Schlama A, Honnorat J, Thomasset N (2008) Extensive expression of collapsin response mediator protein 5 (CRMP5) is a specific marker of high-grade lung neuroendocrine carcinoma. Am J Surg Pathol 32(11):1699–1708. https://doi.org/10.1097/PAS.0b013e31817dc37c

    Article  PubMed  Google Scholar 

  25. Shih JY, Yang SC, Hong TM, Yuan A, Chen JJ, Yu CJ, Chang YL, Lee YC et al (2001) Collapsin response mediator protein-1 and the invasion and metastasis of cancer cells. J Natl Cancer Inst 93(18):1392–1400

    Article  CAS  PubMed  Google Scholar 

  26. Gao X, Pang J, Li LY, Liu WP, Di JM, Sun QP, Fang YQ, Liu XP et al (2010) Expression profiling identifies new function of collapsin response mediator protein 4 as a metastasis-suppressor in prostate cancer. Oncogene 29(32):4555–4566. https://doi.org/10.1038/onc.2010.213

    Article  CAS  PubMed  Google Scholar 

  27. Moutal A, Villa LS, Yeon SK, Householder KT, Park KD, Sirianni RW, Khanna R (2018) CRMP2 phosphorylation drives glioblastoma cell proliferation. Mol Neurobiol 55(5):4403–4416. https://doi.org/10.1007/s12035-017-0653-9

    Article  CAS  PubMed  Google Scholar 

  28. Moutal A, Honnorat J, Massoma P, Desormeaux P, Bertrand C, Malleval C, Watrin C, Chounlamountri N et al (2015) CRMP5 controls glioblastoma cell proliferation and survival through notch-dependent signaling. Cancer Res 75(17):3519–3528. https://doi.org/10.1158/0008-5472.CAN-14-0631

    Article  CAS  PubMed  Google Scholar 

  29. Khanna R, Wilson SM, Brittain JM, Weimer J, Sultana R, Butterfield A, Hensley K (2012) Opening Pandora's jar: A primer on the putative roles of CRMP2 in a panoply of neurodegenerative, sensory and motor neuron, and central disorders. Future Neurol 7(6):749–771. https://doi.org/10.2217/fnl.12.68

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Brot S, Rogemond V, Perrot V, Chounlamountri N, Auger C, Honnorat J, Moradi-Ameli M (2010) CRMP5 interacts with tubulin to inhibit neurite outgrowth, thereby modulating the function of CRMP2. J Neurosci 30(32):10639–10654. https://doi.org/10.1523/JNEUROSCI.0059-10.2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Quach TT, Wilson SM, Rogemond V, Chounlamountri N, Kolattukudy PE, Martinez S, Khanna M, Belin MF et al (2013) Mapping CRMP3 domains involved in dendrite morphogenesis and voltage-gated calcium channel regulation. J Cell Sci 126(Pt 18):4262–4273. https://doi.org/10.1242/jcs.131409

    Article  CAS  PubMed  Google Scholar 

  32. Tan M, Cha C, Ye Y, Zhang J, Li S, Wu F, Gong S, Guo G (2015) CRMP4 and CRMP2 interact to coordinate cytoskeleton dynamics, regulating growth cone development and axon elongation. Neural Plast 2015:947423. https://doi.org/10.1155/2015/947423

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Ponnusamy R, Lohkamp B (2013) Insights into the oligomerization of CRMPs: Crystal structure of human collapsin response mediator protein 5. J Neurochem 125(6):855–868. https://doi.org/10.1111/jnc.12188

    Article  CAS  PubMed  Google Scholar 

  34. Hedgecock EM, Culotti JG, Thomson JN, Perkins LA (1985) Axonal guidance mutants of Caenorhabditis elegans identified by filling sensory neurons with fluorescein dyes. Dev Biol 111(1):158–170

    Article  CAS  PubMed  Google Scholar 

  35. Li W, Herman RK, Shaw JE (1992) Analysis of the Caenorhabditis elegans axonal guidance and outgrowth gene unc-33. Genetics 132(3):675–689

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Goshima Y, Nakamura F, Strittmatter P, Strittmatter SM (1995) Collapsin-induced growth cone collapse mediated by an intracellular protein related to UNC-33. Nature 376(6540):509–514. https://doi.org/10.1038/376509a0

    Article  CAS  PubMed  Google Scholar 

  37. Minturn JE, Fryer HJ, Geschwind DH, Hockfield S (1995) 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 15(10):6757–6766

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Hamajima N, Matsuda K, Sakata S, Tamaki N, Sasaki M, Nonaka M (1996) A novel gene family defined by human dihydropyrimidinase and three related proteins with differential tissue distribution. Gene 180(1–2):157–163

    Article  CAS  PubMed  Google Scholar 

  39. Byk T, Dobransky T, Cifuentes-Diaz C, Sobel A (1996) 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 16(2):688–701

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Yuasa-Kawada J, Suzuki R, Kano F, Ohkawara T, Murata M, Noda M (2003) Axonal morphogenesis controlled by antagonistic roles of two CRMP subtypes in microtubule organization. Eur J Neurosci 17(11):2329–2343

    Article  PubMed  Google Scholar 

  41. Balastik M, Zhou XZ, Alberich-Jorda M, Weissova R, Ziak J, Pazyra-Murphy MF, Cosker KE, Machonova O et al (2015) Prolyl isomerase Pin1 regulates axon guidance by stabilizing CRMP2A selectively in distal axons. Cell Rep 13(4):812–828. https://doi.org/10.1016/j.celrep.2015.09.026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Zhang Y, Chen K, Sloan SA, Bennett ML, Scholze AR, O'Keeffe S, Phatnani HP, Guarnieri P et al (2014) An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci 34(36):11929–11947. https://doi.org/10.1523/JNEUROSCI.1860-14.2014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Bretin S, Reibel S, Charrier E, Maus-Moatti M, Auvergnon N, Thevenoux A, Glowinski J, Rogemond V et al (2005) Differential expression of CRMP1, CRMP2A, CRMP2B, and CRMP5 in axons or dendrites of distinct neurons in the mouse brain. J Comp Neurol 486(1):1–17. https://doi.org/10.1002/cne.20465

    Article  CAS  PubMed  Google Scholar 

  44. Francois-Moutal L, Dustrude ET, Wang Y, Brustovetsky T, Dorame A, Ju W, Moutal A, Perez-Miller S et al (2018) Inhibition of the Ubc9 E2 SUMO-conjugating enzyme-CRMP2 interaction decreases NaV1.7 currents and reverses experimental neuropathic pain. Pain 159(10):2115–2127. https://doi.org/10.1097/j.pain.0000000000001294

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Dustrude ET, Perez-Miller S, Francois-Moutal L, Moutal A, Khanna M, Khanna R (2017) A single structurally conserved SUMOylation site in CRMP2 controls NaV1.7 function. Channels 11(4):316–328. https://doi.org/10.1080/19336950.2017.1299838

    Article  PubMed  PubMed Central  Google Scholar 

  46. Dustrude ET, Moutal A, Yang X, Wang Y, Khanna M, Khanna R (2016) Hierarchical CRMP2 posttranslational modifications control NaV1.7 function. Proc Natl Acad Sci U S A 113(52):E8443–E8452. https://doi.org/10.1073/pnas.1610531113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Dustrude ET, Wilson SM, Ju W, Xiao Y, Khanna R (2013) CRMP2 protein SUMOylation modulates NaV1.7 channel trafficking. J Biol Chem 288(34):24316–24331. https://doi.org/10.1074/jbc.M113.474924

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Myllykoski M, Baumann A, Hensley K, Kursula P (2017) Collapsin response mediator protein 2: High-resolution crystal structure sheds light on small-molecule binding, post-translational modifications, and conformational flexibility. Amino Acids 49(4):747–759. https://doi.org/10.1007/s00726-016-2376-z

    Article  CAS  PubMed  Google Scholar 

  49. Lawal M, Olotu FA, Soliman MES (2018) Across the blood-brain barrier: Neurotherapeutic screening and characterization of naringenin as a novel CRMP-2 inhibitor in the treatment of Alzheimer's disease using bioinformatics and computational tools. Comput Biol Med 98:168–177. https://doi.org/10.1016/j.compbiomed.2018.05.012

    Article  CAS  PubMed  Google Scholar 

  50. Olguin-Albuerne M, Moran J (2018) Redox signaling mechanisms in nervous system development. Antioxid Redox Signal 28(18):1603–1625. https://doi.org/10.1089/ars.2017.7284

    Article  CAS  PubMed  Google Scholar 

  51. Chew LA, Khanna R (2018) CRMP2 and voltage-gated ion channels: Potential roles in neuropathic pain. Neuronal Signal 2(1). https://doi.org/10.1042/NS20170220

  52. Leney AC, El Atmioui D, Wu W, Ovaa H, Heck AJR (2017) Elucidating crosstalk mechanisms between phosphorylation and O-GlcNAcylation. Proc Natl Acad Sci U S A 114(35):E7255–E7261. https://doi.org/10.1073/pnas.1620529114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Cole RN, Hart GW (2001) Cytosolic O-glycosylation is abundant in nerve terminals. J Neurochem 79(5):1080–1089

    Article  CAS  PubMed  Google Scholar 

  54. Cnops L, Van de Plas B, Arckens L (2004) Age-dependent expression of collapsin response mediator proteins (CRMPs) in cat visual cortex. Eur J Neurosci 19(8):2345–2351. https://doi.org/10.1111/j.0953-816X.2004.03330.x

    Article  PubMed  Google Scholar 

  55. Cnops L, Hu TT, Burnat K, Van der Gucht E, Arckens L (2006) Age-dependent alterations in CRMP2 and CRMP4 protein expression profiles in cat visual cortex. Brain Res 1088(1):109–119. https://doi.org/10.1016/j.brainres.2006.03.028

    Article  CAS  PubMed  Google Scholar 

  56. Ricard D, Stankoff B, Bagnard D, Aguera M, Rogemond V, Antoine JC, Spassky N, Zalc B et al (2000) Differential expression of collapsin response mediator proteins (CRMP/ULIP) in subsets of oligodendrocytes in the postnatal rodent brain. Mol Cell Neurosci 16(4):324–337. https://doi.org/10.1006/mcne.2000.0888

    Article  CAS  PubMed  Google Scholar 

  57. Zeisel A, Hochgerner H, Lonnerberg P, Johnsson A, Memic F, van der Zwan J, Haring M, Braun E et al (2018) Molecular architecture of the mouse nervous system. Cell 174(4):999–1014 e1022. https://doi.org/10.1016/j.cell.2018.06.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Ricard D, Rogemond V, Charrier E, Aguera M, Bagnard D, Belin MF, Thomasset N, Honnorat J (2001) Isolation and expression pattern of human Unc-33-like phosphoprotein 6/collapsin response mediator protein 5 (Ulip6/CRMP5): Coexistence with Ulip2/CRMP2 in Sema3a- sensitive oligodendrocytes. J Neurosci 21(18):7203–7214

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Fernandez-Gamba A, Leal MC, Maarouf CL, Richter-Landsberg C, Wu T, Morelli L, Roher AE, Castano EM (2012) Collapsin response mediator protein-2 phosphorylation promotes the reversible retraction of oligodendrocyte processes in response to non-lethal oxidative stress. J Neurochem 121(6):985–995. https://doi.org/10.1111/j.1471-4159.2012.07742.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Syed YA, Abdulla SA, Kotter MR (2017) Studying the effects of semaphorins on oligodendrocyte lineage cells. Methods Mol Biol 1493:363–378. https://doi.org/10.1007/978-1-4939-6448-2_26

    Article  CAS  PubMed  Google Scholar 

  61. Syed YA, Hand E, Mobius W, Zhao C, Hofer M, Nave KA, Kotter MR (2011) Inhibition of CNS remyelination by the presence of semaphorin 3A. J Neurosci 31(10):3719–3728. https://doi.org/10.1523/jneurosci.4930-10.2011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Piaton G, Aigrot MS, Williams A, Moyon S, Tepavcevic V, Moutkine I, Gras J, Matho KS et al (2011) Class 3 semaphorins influence oligodendrocyte precursor recruitment and remyelination in adult central nervous system. Brain J Neurol 134(Pt 4):1156–1167. https://doi.org/10.1093/brain/awr022

    Article  Google Scholar 

  63. Zhang Y, Sloan SA, Clarke LE, Caneda C, Plaza CA, Blumenthal PD, Vogel H, Steinberg GK et al (2016) Purification and characterization of progenitor and mature human astrocytes reveals transcriptional and functional differences with mouse. Neuron 89(1):37–53. https://doi.org/10.1016/j.neuron.2015.11.013

    Article  CAS  PubMed  Google Scholar 

  64. Kamata T, Subleski M, Hara Y, Yuhki N, Kung H, Copeland NG, Jenkins NA, Yoshimura T et al (1998) Isolation and characterization of a bovine neural specific protein (CRMP-2) cDNA homologous to unc-33, a C. elegans gene implicated in axonal outgrowth and guidance. Brain Res Mol Brain Res 54(2):219–236

    Article  CAS  PubMed  Google Scholar 

  65. Bennett ML, Bennett FC, Liddelow SA, Ajami B, Zamanian JL, Fernhoff NB, Mulinyawe SB, Bohlen CJ et al (2016) New tools for studying microglia in the mouse and human CNS. Proc Natl Acad Sci U S A 113(12):E1738–E1746. https://doi.org/10.1073/pnas.1525528113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Hirbec H, Marmai C, Duroux-Richard I, Roubert C, Esclangon A, Croze S, Lachuer J, Peyroutou R et al (2018) The microglial reaction signature revealed by RNAseq from individual mice. Glia 66(5):971–986. https://doi.org/10.1002/glia.23295

    Article  PubMed  Google Scholar 

  67. Hensley K, Christov A, Kamat S, Zhang XC, Jackson KW, Snow S, Post J (2010) Proteomic identification of binding partners for the brain metabolite lanthionine ketimine (LK) and documentation of LK effects on microglia and motoneuron cell cultures. J Neurosci 30(8):2979–2988. https://doi.org/10.1523/JNEUROSCI.5247-09.2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Kotaka K, Nagai J, Hensley K, Ohshima T (2017) Lanthionine ketimine ester promotes locomotor recovery after spinal cord injury by reducing neuroinflammation and promoting axon growth. Biochem Biophys Res Commun 483(1):759–764. https://doi.org/10.1016/j.bbrc.2016.12.069

    Article  CAS  PubMed  Google Scholar 

  69. Hensley K, Gabbita SP, Venkova K, Hristov A, Johnson MF, Eslami P, Harris-White ME (2013) A derivative of the brain metabolite lanthionine ketimine improves cognition and diminishes pathology in the 3 x Tg-AD mouse model of Alzheimer disease. J Neuropathol Exp Neurol 72(10):955–969. https://doi.org/10.1097/NEN.0b013e3182a74372

    Article  CAS  PubMed  Google Scholar 

  70. Zhou LS, Zhao GL, Liu Q, Jiang SC, Wang Y, Zhang DM (2015) Silencing collapsin response mediator protein-2 reprograms macrophage phenotype and improves infarct healing in experimental myocardial infarction model. J Inflamm (London, England) 12:11. https://doi.org/10.1186/s12950-015-0053-8

    Article  CAS  Google Scholar 

  71. Bradke F, Dotti CG (2000) Establishment of neuronal polarity: Lessons from cultured hippocampal neurons. Curr Opin Neurobiol 10(5):574–581

    Article  CAS  PubMed  Google Scholar 

  72. Inagaki N, Chihara K, Arimura N, Menager C, Kawano Y, Matsuo N, Nishimura T, Amano M et al (2001) CRMP-2 induces axons in cultured hippocampal neurons. Nat Neurosci 4(8):781–782. https://doi.org/10.1038/90476

    Article  CAS  PubMed  Google Scholar 

  73. Yoshimura T, Kawano Y, Arimura N, Kawabata S, Kikuchi A, Kaibuchi K (2005) GSK-3beta regulates phosphorylation of CRMP-2 and neuronal polarity. Cell 120(1):137–149. https://doi.org/10.1016/j.cell.2004.11.012

    Article  CAS  PubMed  Google Scholar 

  74. Wang LH, Strittmatter SM (1997) Brain CRMP forms heterotetramers similar to liver dihydropyrimidinase. J Neurochem 69(6):2261–2269

    Article  CAS  PubMed  Google Scholar 

  75. Niwa S, Nakamura F, Tomabechi Y, Aoki M, Shigematsu H, Matsumoto T, Yamagata A, Fukai S et al (2017) Structural basis for CRMP2-induced axonal microtubule formation. Sci Rep 7(1):10681. https://doi.org/10.1038/s41598-017-11031-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Kimura T, Watanabe H, Iwamatsu A, Kaibuchi K (2005) Tubulin and CRMP-2 complex is transported via Kinesin-1. J Neurochem 93(6):1371–1382. https://doi.org/10.1111/j.1471-4159.2005.03063.x

    Article  CAS  PubMed  Google Scholar 

  77. Muller-Reichert T, Chretien D, Severin F, Hyman AA (1998) Structural changes at microtubule ends accompanying GTP hydrolysis: information from a slowly hydrolyzable analogue of GTP, guanylyl (alpha,beta)methylenediphosphonate. Proc Natl Acad Sci U S A 95(7):3661–3666

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Chae YC, Lee S, Heo K, Ha SH, Jung Y, Kim JH, Ihara Y, Suh PG et al (2009) Collapsin response mediator protein-2 regulates neurite formation by modulating tubulin GTPase activity. Cell Signal 21(12):1818–1826. https://doi.org/10.1016/j.cellsig.2009.07.017

    Article  CAS  PubMed  Google Scholar 

  79. Wilson SM, Khanna R (2015) Specific binding of lacosamide to collapsin response mediator protein 2 (CRMP2) and direct impairment of its canonical function: Implications for the therapeutic potential of lacosamide. Mol Neurobiol 51(2):599–609. https://doi.org/10.1007/s12035-014-8775-9

    Article  CAS  PubMed  Google Scholar 

  80. Wilson SM, Moutal A, Melemedjian OK, Wang Y, Ju W, Francois-Moutal L, Khanna M, Khanna R (2014) The functionalized amino acid (S)-Lacosamide subverts CRMP2-mediated tubulin polymerization to prevent constitutive and activity-dependent increase in neurite outgrowth. Front Cell Neurosci 8:196. https://doi.org/10.3389/fncel.2014.00196

    Article  PubMed  PubMed Central  Google Scholar 

  81. Wang Y, Brittain JM, Jarecki BW, Park KD, Wilson SM, Wang B, Hale R, Meroueh SO et al (2010) In silico docking and electrophysiological characterization of lacosamide binding sites on collapsin response mediator protein-2 identifies a pocket important in modulating sodium channel slow inactivation. J Biol Chem 285(33):25296–25307. https://doi.org/10.1074/jbc.M110.128801

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Sumi T, Imasaki T, Aoki M, Sakai N, Nitta E, Shirouzu M, Nitta R (2018) Structural insights into the altering function of CRMP2 by phosphorylation. Cell Struct Funct 43(1):15–23. https://doi.org/10.1247/csf.17025

    Article  CAS  PubMed  Google Scholar 

  83. Uchida Y, Ohshima T, Yamashita N, Ogawara M, Sasaki Y, Nakamura F, Goshima Y (2009) Semaphorin3A signaling mediated by Fyn-dependent tyrosine phosphorylation of collapsin response mediator protein 2 at tyrosine 32. J Biol Chem 284(40):27393–27401. https://doi.org/10.1074/jbc.M109.000240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Sasaki Y, Cheng C, Uchida Y, Nakajima O, Ohshima T, Yagi T, Taniguchi M, Nakayama T et al (2002) Fyn and Cdk5 mediate semaphorin-3A signaling, which is involved in regulation of dendrite orientation in cerebral cortex. Neuron 35(5):907–920

    Article  CAS  PubMed  Google Scholar 

  85. Varrin-Doyer M, Vincent P, Cavagna S, Auvergnon N, Noraz N, Rogemond V, Honnorat J, Moradi-Ameli M et al (2009) Phosphorylation of collapsin response mediator protein 2 on Tyr-479 regulates CXCL12-induced T lymphocyte migration. J Biol Chem 284(19):13265–13276. https://doi.org/10.1074/jbc.M807664200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Giraudon P, Nicolle A, Cavagna S, Benetollo C, Marignier R, Varrin-Doyer M (2013) Insight into the role of CRMP2 (collapsin response mediator protein 2) in T lymphocyte migration: The particular context of virus infection. Cell Adhes Migr 7(1):38–43. https://doi.org/10.4161/cam.22385

    Article  Google Scholar 

  87. Zheng Y, Sethi R, Mangala LS, Taylor C, Goldsmith J, Wang M, Masuda K, Karaminejadranjbar M et al (2018) Tuning microtubule dynamics to enhance cancer therapy by modulating FER-mediated CRMP2 phosphorylation. Nat Commun 9(1):476. https://doi.org/10.1038/s41467-017-02811-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Moutal A, Chew LA, Yang X, Wang Y, Yeon SK, Telemi E, Meroueh S, Park KD et al (2016) (S)-lacosamide inhibition of CRMP2 phosphorylation reduces postoperative and neuropathic pain behaviors through distinct classes of sensory neurons identified by constellation pharmacology. Pain 157(7):1448–1463. https://doi.org/10.1097/j.pain.0000000000000555

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Moutal A, Francois-Moutal L, Perez-Miller S, Cottier K, Chew LA, Yeon SK, Dai J, Park KD et al (2016) (S)-Lacosamide binding to collapsin response mediator protein 2 (CRMP2) regulates CaV2.2 activity by subverting its phosphorylation by Cdk5. Mol Neurobiol 53(3):1959–1976. https://doi.org/10.1007/s12035-015-9141-2

    Article  CAS  PubMed  Google Scholar 

  90. Sarhan AR, Szyroka J, Begum S, Tomlinson MG, Hotchin NA, Heath JK, Cunningham DL (2017) Quantitative phosphoproteomics reveals a role for collapsin response mediator protein 2 in PDGF-induced cell migration. Sci Rep 7(1):3970. https://doi.org/10.1038/s41598-017-04015-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Yang Z, Kuboyama T, Tohda C (2017) A systematic strategy for discovering a therapeutic drug for Alzheimer’s disease and its target molecule. Front Pharmacol 8:340. https://doi.org/10.3389/fphar.2017.00340

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Abe H, Jitsuki S, Nakajima W, Murata Y, Jitsuki-Takahashi A, Katsuno Y, Tada H, Sano A et al (2018) CRMP2-binding compound, edonerpic maleate, accelerates motor function recovery from brain damage. Science 360(6384):50–57. https://doi.org/10.1126/science.aao2300

    Article  CAS  PubMed  Google Scholar 

  93. Williamson R, van Aalten L, Mann DM, Platt B, Plattner F, Bedford L, Mayer J, Howlett D et al (2011) CRMP2 hyperphosphorylation is characteristic of Alzheimer’s disease and not a feature common to other neurodegenerative diseases. J Alzheimer's Dis : JAD 27(3):615–625. https://doi.org/10.3233/JAD-2011-110617

    Article  CAS  Google Scholar 

  94. Cole AR, Noble W, van Aalten L, Plattner F, Meimaridou R, Hogan D, Taylor M, LaFrancois J et al (2007) Collapsin response mediator protein-2 hyperphosphorylation is an early event in Alzheimer’s disease progression. J Neurochem 103(3):1132–1144. https://doi.org/10.1111/j.1471-4159.2007.04829.x

    Article  CAS  PubMed  Google Scholar 

  95. Isono T, Yamashita N, Obara M, Araki T, Nakamura F, Kamiya Y, Alkam T, Nitta A et al (2013) Amyloid-beta(2)(5)(-)(3)(5) induces impairment of cognitive function and long-term potentiation through phosphorylation of collapsin response mediator protein 2. Neurosci Res 77(3):180–185. https://doi.org/10.1016/j.neures.2013.08.005

    Article  CAS  PubMed  Google Scholar 

  96. Xing H, Lim YA, Chong JR, Lee JH, Aarsland D, Ballard CG, Francis PT, Chen CP et al (2016) Increased phosphorylation of collapsin response mediator protein-2 at Thr514 correlates with beta-amyloid burden and synaptic deficits in Lewy body dementias. Molecular Brain 9(1):84. https://doi.org/10.1186/s13041-016-0264-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Patrakitkomjorn S, Kobayashi D, Morikawa T, Wilson MM, Tsubota N, Irie A, Ozawa T, Aoki M et al (2008) Neurofibromatosis type 1 (NF1) tumor suppressor, neurofibromin, regulates the neuronal differentiation of PC12 cells via its associating protein, CRMP-2. J Biol Chem 283(14):9399–9413. https://doi.org/10.1074/jbc.M708206200

    Article  CAS  PubMed  Google Scholar 

  98. Moutal A, Dustrude ET, Khanna R (2017) Sensitization of ion channels contributes to central and peripheral dysfunction in neurofibromatosis type 1. Mol Neurobiol 54(5):3342–3349. https://doi.org/10.1007/s12035-016-9907-1

    Article  CAS  PubMed  Google Scholar 

  99. Moutal A, Sun L, Yang X, Li W, Cai S, Luo S, Khanna R (2018) CRMP2-neurofibromin interface drives NF1-related pain. Neuroscience 381:79–90. https://doi.org/10.1016/j.neuroscience.2018.04.002

    Article  CAS  PubMed  Google Scholar 

  100. Grant NJ, Coates PJ, Woods YL, Bray SE, Morrice NA, Hastie CJ, Lamont DJ, Carey FA et al (2015) Phosphorylation of a splice variant of collapsin response mediator protein 2 in the nucleus of tumour cells links cyclin dependent kinase-5 to oncogenesis. BMC Cancer 15:885. https://doi.org/10.1186/s12885-015-1691-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Couderc C, Bollard J, Coute Y, Massoma P, Poncet G, Lepinasse F, Hervieu V, Gadot N et al (2015) Mechanisms of local invasion in enteroendocrine tumors: Identification of novel candidate cytoskeleton-associated proteins in an experimental mouse model by a proteomic approach and validation in human tumors. Mol Cell Endocrinol 399:154–163. https://doi.org/10.1016/j.mce.2014.09.006

    Article  CAS  PubMed  Google Scholar 

  102. Tahimic CG, Tomimatsu N, Nishigaki R, Fukuhara A, Toda T, Kaibuchi K, Shiota G, Oshimura M et al (2006) Evidence for a role of Collapsin response mediator protein-2 in signaling pathways that regulate the proliferation of non-neuronal cells. Biochem Biophys Res Commun 340(4):1244–1250. https://doi.org/10.1016/j.bbrc.2005.12.132

    Article  CAS  PubMed  Google Scholar 

  103. Marques JM, Rodrigues RJ, Valbuena S, Rozas JL, Selak S, Marin P, Aller MI, Lerma J (2013) CRMP2 tethers kainate receptor activity to cytoskeleton dynamics during neuronal maturation. J Neurosci 33(46):18298–18310. https://doi.org/10.1523/JNEUROSCI.3136-13.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Arimura N, Inagaki N, Chihara K, Menager C, Nakamura N, Amano M, Iwamatsu A, Goshima Y et al (2000) Phosphorylation of collapsin response mediator protein-2 by Rho-kinase. Evidence for two separate signaling pathways for growth cone collapse. J Biol Chem 275(31):23973–23980. https://doi.org/10.1074/jbc.M001032200

    Article  CAS  PubMed  Google Scholar 

  105. Quarta S, Camprubi-Robles M, Schweigreiter R, Matusica D, Haberberger RV, Proia RL, Bandtlow CE, Ferrer-Montiel A et al (2017) Sphingosine-1-phosphate and the S1P3 receptor initiate neuronal retraction via RhoA/ROCK associated with CRMP2 phosphorylation. Front Mol Neurosci 10:317. https://doi.org/10.3389/fnmol.2017.00317

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Arimura N, Menager C, Kawano Y, Yoshimura T, Kawabata S, Hattori A, Fukata Y, Amano M et al (2005) Phosphorylation by Rho kinase regulates CRMP-2 activity in growth cones. Mol Cell Biol 25(22):9973–9984. https://doi.org/10.1128/MCB.25.22.9973-9984.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Ju W, Li Q, Wilson SM, Brittain JM, Meroueh L, Khanna R (2013) SUMOylation alters CRMP2 regulation of calcium influx in sensory neurons. Channels 7(3):153–159. https://doi.org/10.4161/chan.24224

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Francois-Moutal L, Scott DD, Perez-Miller S, Gokhale V, Khanna M, Khanna R (2018) Chemical shift perturbation mapping of the Ubc9-CRMP2 interface identifies a pocket in CRMP2 amenable for allosteric modulation of Nav1.7 channels. Channels (Austin) 12(1):219–227. https://doi.org/10.1080/19336950.2018.1491244

    Article  Google Scholar 

  109. Pace PE, Peskin AV, Konigstorfer A, Jasoni CJ, Winterbourn CC, Hampton MB (2018) Peroxiredoxin interaction with the cytoskeletal-regulatory protein CRMP2: Investigation of a putative redox relay. Free Radic Biol Med 129:383–393. https://doi.org/10.1016/j.freeradbiomed.2018.10.407

    Article  CAS  PubMed  Google Scholar 

  110. Morinaka A, Yamada M, Itofusa R, Funato Y, Yoshimura Y, Nakamura F, Yoshimura T, Kaibuchi K et al (2011) Thioredoxin mediates oxidation-dependent phosphorylation of CRMP2 and growth cone collapse. Sci Signal 4(170):ra26. https://doi.org/10.1126/scisignal.2001127

    Article  CAS  PubMed  Google Scholar 

  111. Gellert M, Venz S, Mitlohner J, Cott C, Hanschmann EM, Lillig CH (2013) Identification of a dithiol-disulfide switch in collapsin response mediator protein 2 (CRMP2) that is toggled in a model of neuronal differentiation. J Biol Chem 288(49):35117–35125. https://doi.org/10.1074/jbc.M113.521443

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Hu S, Zhu L (2018) Semaphorins and their receptors: From axonal guidance to atherosclerosis. Front Physiol 9:1236. https://doi.org/10.3389/fphys.2018.01236

    Article  PubMed  PubMed Central  Google Scholar 

  113. Ito Y, Oinuma I, Katoh H, Kaibuchi K, Negishi M (2006) Sema4D/plexin-B1 activates GSK-3beta through R-Ras GAP activity, inducing growth cone collapse. EMBO Rep 7(7):704–709. https://doi.org/10.1038/sj.embor.7400737

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Arbeille E, Reynaud F, Sanyas I, Bozon M, Kindbeiter K, Causeret F, Pierani A, Falk J et al (2015) Cerebrospinal fluid-derived Semaphorin3B orients neuroepithelial cell divisions in the apicobasal axis. Nat Commun 6:6366. https://doi.org/10.1038/ncomms7366

    Article  CAS  PubMed  Google Scholar 

  115. Uchida Y, Ohshima T, Sasaki Y, Suzuki H, Yanai S, Yamashita N, Nakamura F, Takei K et al (2005) Semaphorin3A signalling is mediated via sequential Cdk5 and GSK3beta phosphorylation of CRMP2: Implication of common phosphorylating mechanism underlying axon guidance and Alzheimer's disease. Genes Cells : devoted to molecular & cellular mechanisms 10(2):165–179. https://doi.org/10.1111/j.1365-2443.2005.00827.x

    Article  CAS  Google Scholar 

  116. Cole AR, Causeret F, Yadirgi G, Hastie CJ, McLauchlan H, McManus EJ, Hernandez F, Eickholt BJ et al (2006) Distinct priming kinases contribute to differential regulation of collapsin response mediator proteins by glycogen synthase kinase-3 in vivo. J Biol Chem 281(24):16591–16598. https://doi.org/10.1074/jbc.M513344200

    Article  CAS  PubMed  Google Scholar 

  117. Brown M, Jacobs T, Eickholt B, Ferrari G, Teo M, Monfries C, Qi RZ, Leung T et al (2004) 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 24(41):8994–9004. https://doi.org/10.1523/JNEUROSCI.3184-04.2004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Shapovalova Z, Tabunshchyk K, Greer PA (2007) The Fer tyrosine kinase regulates an axon retraction response to Semaphorin 3A in dorsal root ganglion neurons. BMC Dev Biol 7:133. https://doi.org/10.1186/1471-213X-7-133

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Cole AR, Knebel A, Morrice NA, Robertson LA, Irving AJ, Connolly CN, Sutherland C (2004) GSK-3 phosphorylation of the Alzheimer epitope within collapsin response mediator proteins regulates axon elongation in primary neurons. J Biol Chem 279(48):50176–50180. https://doi.org/10.1074/jbc.C400412200

    Article  CAS  PubMed  Google Scholar 

  120. Morimura R, Nozawa K, Tanaka H, Ohshima T (2013) Phosphorylation of Dpsyl2 (CRMP2) and Dpsyl3 (CRMP4) is required for positioning of caudal primary motor neurons in the zebrafish spinal cord. Dev Neurobiol 73(12):911–920. https://doi.org/10.1002/dneu.22117

    Article  CAS  PubMed  Google Scholar 

  121. Niisato E, Nagai J, Yamashita N, Nakamura F, Goshima Y, Ohshima T (2013) Phosphorylation of CRMP2 is involved in proper bifurcation of the apical dendrite of hippocampal CA1 pyramidal neurons. Dev Neurobiol 73(2):142–151. https://doi.org/10.1002/dneu.22048

    Article  CAS  PubMed  Google Scholar 

  122. Gu Y, Ihara Y (2000) Evidence that collapsin response mediator protein-2 is involved in the dynamics of microtubules. J Biol Chem 275(24):17917–17920. https://doi.org/10.1074/jbc.C000179200

    Article  CAS  PubMed  Google Scholar 

  123. Lin PC, Chan PM, Hall C, Manser E (2011) Collapsin response mediator proteins (CRMPs) are a new class of microtubule-associated protein (MAP) that selectively interacts with assembled microtubules via a taxol-sensitive binding interaction. J Biol Chem 286(48):41466–41478. https://doi.org/10.1074/jbc.M111.283580

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Jauffred B, Llense F, Sommer B, Wang Z, Martin C, Bellaiche Y (2013) Regulation of centrosome movements by numb and the collapsin response mediator protein during Drosophila sensory progenitor asymmetric division. Development 140(13):2657–2668. https://doi.org/10.1242/dev.087338

    Article  CAS  PubMed  Google Scholar 

  125. Nishimura T, Fukata Y, Kato K, Yamaguchi T, Matsuura Y, Kamiguchi H, Kaibuchi K (2003) CRMP-2 regulates polarized Numb-mediated endocytosis for axon growth. Nat Cell Biol 5(9):819–826. https://doi.org/10.1038/ncb1039

    Article  CAS  PubMed  Google Scholar 

  126. Santolini E, Puri C, Salcini AE, Gagliani MC, Pelicci PG, Tacchetti C, Di Fiore PP (2000) Numb is an endocytic protein. J Cell Biol 151(6):1345–1352

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Quach TT, Duchemin AM, Rogemond V, Aguera M, Honnorat J, Belin MF, Kolattukudy PE (2004) Involvement of collapsin response mediator proteins in the neurite extension induced by neurotrophins in dorsal root ganglion neurons. Mol Cell Neurosci 25(3):433–443. https://doi.org/10.1016/j.mcn.2003.11.006

    Article  CAS  PubMed  Google Scholar 

  128. Fang WQ, Ip JP, Li R, Ng YP, Lin SC, Chen Y, Fu AK, Ip NY (2011) Cdk5-mediated phosphorylation of Axin directs axon formation during cerebral cortex development. J Neurosci 31(38):13613–13624. https://doi.org/10.1523/JNEUROSCI.3120-11.2011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Chadborn NH, Ahmed AI, Holt MR, Prinjha R, Dunn GA, Jones GE, Eickholt BJ (2006) PTEN couples Sema3A signalling to growth cone collapse. J Cell Sci 119(Pt 5):951–957. https://doi.org/10.1242/jcs.02801

    Article  CAS  PubMed  Google Scholar 

  130. Jiang H, Guo W, Liang X, Rao Y (2005) Both the establishment and the maintenance of neuronal polarity require active mechanisms: Critical roles of GSK-3beta and its upstream regulators. Cell 120(1):123–135. https://doi.org/10.1016/j.cell.2004.12.033

    Article  CAS  PubMed  Google Scholar 

  131. Arimura N, Hattori A, Kimura T, Nakamuta S, Funahashi Y, Hirotsune S, Furuta K, Urano T et al (2009) CRMP-2 directly binds to cytoplasmic dynein and interferes with its activity. J Neurochem 111(2):380–390. https://doi.org/10.1111/j.1471-4159.2009.06317.x

    Article  CAS  PubMed  Google Scholar 

  132. Kawano Y, Yoshimura T, Tsuboi D, Kawabata S, Kaneko-Kawano T, Shirataki H, Takenawa T, Kaibuchi K (2005) CRMP-2 is involved in kinesin-1-dependent transport of the Sra-1/WAVE1 complex and axon formation. Mol Cell Biol 25(22):9920–9935. https://doi.org/10.1128/MCB.25.22.9920-9935.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Rahajeng J, Giridharan SS, Naslavsky N, Caplan S (2010) Collapsin response mediator protein-2 (Crmp2) regulates trafficking by linking endocytic regulatory proteins to dynein motors. J Biol Chem 285(42):31918–31922. https://doi.org/10.1074/jbc.C110.166066

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Booze ML, Hansen JM, Vitiello PF (2016) A novel mouse model for the identification of thioredoxin-1 protein interactions. Free Radic Biol Med 99:533–543. https://doi.org/10.1016/j.freeradbiomed.2016.09.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Wilson C, Gonzalez-Billault C (2015) Regulation of cytoskeletal dynamics by redox signaling and oxidative stress: Implications for neuronal development and trafficking. Front Cell Neurosci 9:381. https://doi.org/10.3389/fncel.2015.00381

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Xu X, Wicki-Stordeur LE, Sanchez-Arias JC, Liu M, Weaver MS, Choi CSW, Swayne LA (2018) Probenecid disrupts a novel pannexin 1-collapsin response mediator protein 2 interaction and increases microtubule stability. Front Cell Neurosci 12:124. https://doi.org/10.3389/fncel.2018.00124

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Saitoh F, Hagiwara H, Wakatsuki S, Araki T (2018) Carboxymethylation of CRMP2 is associated with decreased Schwann cell myelination efficiency. Neurosci Res 139:58–62. https://doi.org/10.1016/j.neures.2018.08.015

    Article  CAS  PubMed  Google Scholar 

  138. Dai X, Sun Z, Liang R, Li Y, Luo H, Huang Y, Chen M, Su Z et al (2015) Recombinant Nogo-66 via soluble expression with SUMO fusion in Escherichia coli inhibits neurite outgrowth in vitro. Appl Microbiol Biotechnol 99(14):5997–6007. https://doi.org/10.1007/s00253-015-6477-5

    Article  CAS  PubMed  Google Scholar 

  139. Khidekel N, Ficarro SB, Clark PM, Bryan MC, Swaney DL, Rexach JE, Sun YE, Coon JJ et al (2007) Probing the dynamics of O-GlcNAc glycosylation in the brain using quantitative proteomics. Nat Chem Biol 3(6):339–348. https://doi.org/10.1038/nchembio881

    Article  CAS  PubMed  Google Scholar 

  140. Zhang JN, Koch JC (2017) Collapsin response mediator protein-2 plays a major protective role in acute axonal degeneration. Neural Regen Res 12(5):692–695. https://doi.org/10.4103/1673-5374.206631

    Article  PubMed  PubMed Central  Google Scholar 

  141. Hensley K, Kursula P (2016) Collapsin response mediator protein-2 (CRMP2) is a plausible etiological factor and potential therapeutic target in Alzheimer’s disease: Comparison and contrast with microtubule-associated protein tau. J Alzheimers Dis 53(1):1–14. https://doi.org/10.3233/JAD-160076

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Shah K, Lahiri DK (2017) A tale of the good and bad: Remodeling of the microtubule network in the brain by Cdk5. Mol Neurobiol 54(3):2255–2268. https://doi.org/10.1007/s12035-016-9792-7

    Article  CAS  PubMed  Google Scholar 

  143. Hensley K, Venkova K, Christov A, Gunning W, Park J (2011) Collapsin response mediator protein-2: An emerging pathologic feature and therapeutic target for neurodisease indications. Mol Neurobiol 43(3):180–191. https://doi.org/10.1007/s12035-011-8166-4

    Article  CAS  PubMed  Google Scholar 

  144. Quach TT, Honnorat J, Kolattukudy PE, Khanna R, Duchemin AM (2015) CRMPs: Critical molecules for neurite morphogenesis and neuropsychiatric diseases. Mol Psychiatry 20(9):1037–1045. https://doi.org/10.1038/mp.2015.77

    Article  CAS  PubMed  Google Scholar 

  145. Watamura N, Toba J, Yoshii A, Nikkuni M, Ohshima T (2016) Colocalization of phosphorylated forms of WAVE1, CRMP2, and tau in Alzheimer’s disease model mice: Involvement of Cdk5 phosphorylation and the effect of ATRA treatment. J Neurosci Res 94(1):15–26. https://doi.org/10.1002/jnr.23674

    Article  CAS  PubMed  Google Scholar 

  146. Wang Y, Yin H, Li J, Zhang Y, Han B, Zeng Z, Qiao N, Cui X et al (2013) Amelioration of beta-amyloid-induced cognitive dysfunction and hippocampal axon degeneration by curcumin is associated with suppression of CRMP-2 hyperphosphorylation. Neurosci Lett 557(Pt B):112–117. https://doi.org/10.1016/j.neulet.2013.10.024

    Article  CAS  PubMed  Google Scholar 

  147. Castillo C, Martinez JC, Longart M, Garcia L, Hernandez M, Carballo J, Rojas H, Matteo L et al (2018) Extracellular application of CRMP2 increases cytoplasmic calcium through NMDA receptors. Neuroscience 376:204–223. https://doi.org/10.1016/j.neuroscience.2018.02.002

    Article  CAS  PubMed  Google Scholar 

  148. Moutal A, Khanna R (2018) Unconventional signaling by extracellular CRMP2: Possible role as an atypical neurotransmitter? Neuroscience 376:224–226. https://doi.org/10.1016/j.neuroscience.2018.02.025

    Article  CAS  PubMed  Google Scholar 

  149. Mudher A, Colin M, Dujardin S, Medina M, Dewachter I, Alavi Naini SM, Mandelkow EM, Mandelkow E et al (2017) What is the evidence that tau pathology spreads through prion-like propagation? Acta Neuropathol Commun 5(1):99. https://doi.org/10.1186/s40478-017-0488-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Numata-Uematsu Y, Wakatsuki S, Nagano S, Shibata M, Sakai K, Ichinohe N, Mikoshiba K, Ohshima T et al (2018) Inhibition of collapsin response mediator protein-2 phosphorylation ameliorates motor phenotype of ALS model mice expressing SOD1G93A. Neurosci Res 139:63–68. https://doi.org/10.1016/j.neures.2018.08.016

    Article  CAS  PubMed  Google Scholar 

  151. Chung MA, Lee JE, Lee JY, Ko MJ, Lee ST, Kim HJ (2005) Alteration of collapsin response mediator protein-2 expression in focal ischemic rat brain. Neuroreport 16(15):1647–1653

    Article  CAS  PubMed  Google Scholar 

  152. Liu W, Zhou XW, Liu S, Hu K, Wang C, He Q, Li M (2009) Calpain-truncated CRMP-3 and -4 contribute to potassium deprivation-induced apoptosis of cerebellar granule neurons. Proteomics 9(14):3712–3728. https://doi.org/10.1002/pmic.200800979

    Article  CAS  PubMed  Google Scholar 

  153. Bretin S, Rogemond V, Marin P, Maus M, Torrens Y, Honnorat J, Glowinski J, Premont J et al (2006) Calpain product of WT-CRMP2 reduces the amount of surface NR2B NMDA receptor subunit. J Neurochem 98(4):1252–1265. https://doi.org/10.1111/j.1471-4159.2006.03969.x

    Article  CAS  PubMed  Google Scholar 

  154. Al-Hallaq RA, Conrads TP, Veenstra TD, Wenthold RJ (2007) NMDA di-heteromeric receptor populations and associated proteins in rat hippocampus. J Neurosci 27(31):8334–8343. https://doi.org/10.1523/JNEUROSCI.2155-07.2007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Brittain JM, Pan R, You H, Brustovetsky T, Brustovetsky N, Zamponi GW, Lee WH, Khanna R (2012) Disruption of NMDAR-CRMP-2 signaling protects against focal cerebral ischemic damage in the rat middle cerebral artery occlusion model. Channels (Austin) 6(1):52–59

    Article  CAS  Google Scholar 

  156. Brustovetsky T, Pellman JJ, Yang XF, Khanna R, Brustovetsky N (2014) Collapsin response mediator protein 2 (CRMP2) interacts with N-methyl-D-aspartate (NMDA) receptor and Na+/Ca2+ exchanger and regulates their functional activity. J Biol Chem 289(11):7470–7482. https://doi.org/10.1074/jbc.M113.518472

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Brittain JM, Chen L, Wilson SM, Brustovetsky T, Gao X, Ashpole NM, Molosh AI, You H et al (2011) Neuroprotection against traumatic brain injury by a peptide derived from the collapsin response mediator protein 2 (CRMP2). J Biol Chem 286(43):37778–37792. https://doi.org/10.1074/jbc.M111.255455

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Zhang H, Kang E, Wang Y, Yang C, Yu H, Wang Q, Chen Z, Zhang C et al (2016) Brain-specific Crmp2 deletion leads to neuronal development deficits and behavioural impairments in mice. Nat Commun 7:11773. https://doi.org/10.1038/ncomms11773

    Article  CAS  PubMed Central  Google Scholar 

  159. Boudreau AC, Ferrario CR, Glucksman MJ, Wolf ME (2009) Signaling pathway adaptations and novel protein kinase A substrates related to behavioral sensitization to cocaine. J Neurochem 110(1):363–377. https://doi.org/10.1111/j.1471-4159.2009.06140.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Catterall WA, Few AP (2008) Calcium channel regulation and presynaptic plasticity. Neuron 59(6):882–901. https://doi.org/10.1016/j.neuron.2008.09.005

    Article  CAS  PubMed  Google Scholar 

  161. Khanna R, Zougman A, Stanley EF (2007) A proteomic screen for presynaptic terminal N-type calcium channel (CaV2.2) binding partners. J Biochem Mol Biol 40(3):302–314

    CAS  PubMed  Google Scholar 

  162. Brittain JM, Piekarz AD, Wang Y, Kondo T, Cummins TR, Khanna R (2009) An atypical role for collapsin response mediator protein 2 (CRMP-2) in neurotransmitter release via interaction with presynaptic voltage-gated calcium channels. J Biol Chem 284(45):31375–31390. https://doi.org/10.1074/jbc.M109.009951

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Schwarze SR, Ho A, Vocero-Akbani A, Dowdy SF (1999) In vivo protein transduction: Delivery of a biologically active protein into the mouse. Science 285(5433):1569–1572

    Article  CAS  PubMed  Google Scholar 

  164. Wilson SM, Brittain JM, Piekarz AD, Ballard CJ, Ripsch MS, Cummins TR, Hurley JH, Khanna M et al (2011) Further insights into the antinociceptive potential of a peptide disrupting the N-type calcium channel-CRMP-2 signaling complex. Channels (Austin) 5(5):449–456. https://doi.org/10.4161/chan.5.5.17363

    Article  CAS  Google Scholar 

  165. Chi XX, Schmutzler BS, Brittain JM, Hingtgen CM, Nicol GD, Khanna R (2009) Regulation of N-type voltage-gated calcium (CaV2.2) channels and transmitter release by collapsin response mediator protein-2 (CRMP-2) in sensory neurons. J Cell Sci 23:4351–4362

    Article  Google Scholar 

  166. Brittain JM, Wang Y, Eruvwetere O, Khanna R (2012) Cdk5-mediated phosphorylation of CRMP-2 enhances its interaction with CaV2.2. FEBS Lett 586(21):3813–3818. https://doi.org/10.1016/j.febslet.2012.09.022

    Article  CAS  PubMed  Google Scholar 

  167. Sheets PL, Heers C, Stoehr T, Cummins TR (2008) Differential block of sensory neuronal voltage-gated sodium channels by lacosamide [(2R)-2-(acetylamino)-N-benzyl-3-methoxypropanamide], lidocaine, and carbamazepine. J Pharmacol Exp Ther 326(1):89–99. https://doi.org/10.1124/jpet.107.133413

    Article  CAS  PubMed  Google Scholar 

  168. Kanellopoulos AH, Koenig J, Huang H, Pyrski M, Millet Q, Lolignier S, Morohashi T, Gossage SJ et al (2018) Mapping protein interactions of sodium channel NaV1.7 using epitope-tagged gene-targeted mice. EMBO J 37(3):427–445. https://doi.org/10.15252/embj.201796692

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Laedermann CJ, Decosterd I, Abriel H (2014) Ubiquitylation of voltage-gated sodium channels. Handb Exp Pharmacol 221:231–250. https://doi.org/10.1007/978-3-642-41588-3_11

    Article  CAS  PubMed  Google Scholar 

  170. Creange A, Zeller J, Rostaing-Rigattieri S, Brugieres P, Degos JD, Revuz J, Wolkenstein P (1999) Neurological complications of neurofibromatosis type 1 in adulthood. Brain J Neurol 122(Pt 3):473–481

    Article  Google Scholar 

  171. Ferner RE, Thomas M, Mercer G, Williams V, Leschziner GD, Afridi SK, Golding JF (2017) Evaluation of quality of life in adults with neurofibromatosis 1 (NF1) using the Impact of NF1 on Quality Of Life (INF1-QOL) questionnaire. Health Qual Life Outcomes 15(1):34. https://doi.org/10.1186/s12955-017-0607-y

    Article  PubMed  PubMed Central  Google Scholar 

  172. White KA, Swier VJ, Cain JT, Kohlmeyer JL, Meyerholz DK, Tanas MR, Uthoff J, Hammond E et al (2018) A porcine model of neurofibromatosis type 1 that mimics the human disease. JCI Insight 3(12). https://doi.org/10.1172/jci.insight.120402

  173. Moutal A, Wang Y, Yang X, Ji Y, Luo S, Dorame A, Bellampalli SS, Chew LA et al (2017) Dissecting the role of the CRMP2-neurofibromin complex on pain behaviors. Pain 158(11):2203–2221. https://doi.org/10.1097/j.pain.0000000000001026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Nagai J, Owada K, Kitamura Y, Goshima Y, Ohshima T (2016) Inhibition of CRMP2 phosphorylation repairs CNS by regulating neurotrophic and inhibitory responses. Exp Neurol 277:283–295. https://doi.org/10.1016/j.expneurol.2016.01.015

    Article  CAS  PubMed  Google Scholar 

  175. Siddall PJ, McClelland JM, Rutkowski SB, Cousins MJ (2003) A longitudinal study of the prevalence and characteristics of pain in the first 5 years following spinal cord injury. Pain 103(3):249–257

    Article  PubMed  Google Scholar 

  176. Hergenroeder GW, Redell JB, Choi HA, Schmitt L, Donovan W, Francisco GE, Schmitt K, Moore AN et al (2018) Increased levels of circulating glial fibrillary acidic protein and collapsin response mediator protein-2 autoantibodies in the acute stage of spinal cord injury predict the subsequent development of neuropathic pain. J Neurotrauma 35(21):2530–2539. https://doi.org/10.1089/neu.2018.5675

    Article  PubMed  PubMed Central  Google Scholar 

  177. Adamus G, Bonnah R, Brown L, David L (2013) Detection of autoantibodies against heat shock proteins and collapsin response mediator proteins in autoimmune retinopathy. BMC Ophthalmol 13:48. https://doi.org/10.1186/1471-2415-13-48

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Braunschweig D, Krakowiak P, Duncanson P, Boyce R, Hansen RL, Ashwood P, Hertz-Picciotto I, Pessah IN et al (2013) Autism-specific maternal autoantibodies recognize critical proteins in developing brain. Transl Psychiatry 3:e277. https://doi.org/10.1038/tp.2013.50

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Lubec G, Nonaka M, Krapfenbauer K, Gratzer M, Cairns N, Fountoulakis M (1999) Expression of the dihydropyrimidinase related protein 2 (DRP-2) in Down syndrome and Alzheimer's disease brain is downregulated at the mRNA and dysregulated at the protein level. J Neural Transm Suppl 57:161–177

    CAS  PubMed  Google Scholar 

  180. Khawaja X, Xu J, Liang JJ, Barrett JE (2004) Proteomic analysis of protein changes developing in rat hippocampus after chronic antidepressant treatment: Implications for depressive disorders and future therapies. J Neurosci Res 75(4):451–460. https://doi.org/10.1002/jnr.10869

    Article  CAS  PubMed  Google Scholar 

  181. Ozgen HM, Staal WG, Barber JC, de Jonge MV, Eleveld MJ, Beemer FA, Hochstenbach R, Poot M (2009) A novel 6.14 Mb duplication of chromosome 8p21 in a patient with autism and self mutilation. J Autism Dev Disord 39(2):322–329. https://doi.org/10.1007/s10803-008-0627-x

    Article  PubMed  Google Scholar 

  182. Liu Y, Pham X, Zhang L, Chen PL, Burzynski G, McGaughey DM, He S, McGrath JA et al (2014) Functional variants in DPYSL2 sequence increase risk of schizophrenia and suggest a link to mTOR signaling. G3 (Bethesda) 5(1):61–72. https://doi.org/10.1534/g3.114.015636

    Article  CAS  Google Scholar 

  183. Garza JC, Qi X, Gjeluci K, Leussis MP, Basu H, Reis SA, Zhao WN, Piguel NH et al (2018) Disruption of the psychiatric risk gene Ankyrin 3 enhances microtubule dynamics through GSK3/CRMP2 signaling. Transl Psychiatry 8(1):135. https://doi.org/10.1038/s41398-018-0182-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Pilotte J, Kiosses W, Chan SW, Makarenkova HP, Dupont-Versteegden E, Vanderklish PW (2018) Morphoregulatory functions of the RNA-binding motif protein 3 in cell spreading, polarity and migration. Sci Rep 8(1):7367. https://doi.org/10.1038/s41598-018-25668-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Geraets RD, Koh S, Hastings ML, Kielian T, Pearce DA, Weimer JM (2016) Moving towards effective therapeutic strategies for neuronal ceroid lipofuscinosis. Orphanet J Rare Dis 11:40. https://doi.org/10.1186/s13023-016-0414-2

    Article  PubMed  PubMed Central  Google Scholar 

  186. Cooper JD, Tarczyluk MA, Nelvagal HR (2015) Towards a new understanding of NCL pathogenesis. Biochim Biophys Acta 1852(10 Pt B):2256–2261. https://doi.org/10.1016/j.bbadis.2015.05.014

    Article  CAS  PubMed  Google Scholar 

  187. Mole SE, Cotman SL (2015) Genetics of the neuronal ceroid lipofuscinoses (Batten disease). Biochim Biophys Acta 1852(10 Pt B):2237–2241. https://doi.org/10.1016/j.bbadis.2015.05.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Moutal A, Eyde N, Telemi E, Park KD, Xie JY, Dodick DW, Porreca F, Khanna R (2016) Efficacy of (S)-Lacosamide in preclinical models of cephalic pain. Pain Rep 1(1):e565. https://doi.org/10.1097/PR9.0000000000000565

    Article  PubMed  PubMed Central  Google Scholar 

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Funding

This work was supported by National Institutes of Health Awards (1R01NS098772, 1R01DA042852, and 1R01AT009716 to RK, R01NS082283 to JMW, and R01HL135112 to PFV), a Neurofibromatosis New Investigator Award from the Department of Defense Congressionally Directed Military Medical Research and Development Program (NF1000099 to RK), funding from the Synodos for NF1 program at the Children’s Tumor Foundation to JMW, and a research award from the Children’s Tumor Foundation (2015-04-009A) to RK and JMW. A.M. was supported by a Young Investigator’s Award from the Children’s Tumor Foundation.

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  1. Aubin Moutal and Katherine A. White contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology, College of Medicine, University of Arizona, 1501 North Campbell Drive, P.O. Box 245050, Tucson, AZ, 85724, USA

    Aubin Moutal, Aude Chefdeville, Peter F. Vitiello, Jill M. Weimer & Rajesh Khanna

  2. Pediatrics and Rare Diseases Group, Sanford Research, 2301 E 60th St N, Sioux Falls, SD, 57104, USA

    Katherine A. White, Rachel N. Laufmann & Rajesh Khanna

  3. Department of Pediatrics, Sanford School of Medicine, University of South Dakota, Sioux Falls, SD, USA

    Peter F. Vitiello & Jill M. Weimer

  4. Department of Veterans Affairs, Jesse Brown VA Medical Center, University of Illinois at Chicago, Chicago, IL, USA

    Douglas Feinstein

  5. Department of Anesthesiology, University of Arizona, Tucson, AZ, USA

    Rajesh Khanna

  6. The Center for Innovation in Brain Sciences, The University of Arizona Health Sciences, Tucson, AZ, USA

    Rajesh Khanna

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  1. Aubin Moutal
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Moutal, A., White, K.A., Chefdeville, A. et al. Dysregulation of CRMP2 Post-Translational Modifications Drive Its Pathological Functions. Mol Neurobiol 56, 6736–6755 (2019). https://doi.org/10.1007/s12035-019-1568-4

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