Encyclopedia of Signaling Molecules

Living Edition
| Editors: Sangdun Choi

CDK5

  • Yumeng Guo
  • Yu Wang
  • Bo Bai
Living reference work entry
DOI: https://doi.org/10.1007/978-1-4614-6438-9_101554-1

Synonyms

Historical Background

Cyclin-dependent kinase 5 (CDK5), a proline-directed serine/threonine-protein kinase, was originally purified from bovine brain and defined as a neuronal CDC2 (CDK1)-like kinase (NCLK) (Roder and Ingram 1991; Hellmich et al. 1992). Later on, CDK5 demonstrated capability to induce the Alzheimer-like characteristics by phosphorylation of tau protein (Baumann et al. 1993). p35 (CDK5R1) was then characterized as a regulatory subunit of CDK5 to activate its kinase activity, with subsequent identification of its isoform p39 (CDK5R2) (Tsai et al. 1994; Tang et al. 1995). CDK5/p35 is the first example of a CDC2-like kinase with neuronal function. A truncated form of p35, p25, was purified with CDK5 as a hetero-dimer exhibiting activity in vitro and regarded as a novel regulatory subunit of CDK5 (Lew et al. 1994). Accumulation of p25 is found in...

Keywords

Neuronal Migration Postmitotic Neuron CDK5 Expression Paired Helical Filament Cell Cycle Reentry 
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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References

  1. Alvarez A, Toro R, Cáceres A, Maccioni RB. Inhibition of tau phosphorylating protein kinase cdk5 prevents β-amyloid-induced neuronal death. FEBS Lett. 1999;459:421–6.PubMedCrossRefGoogle Scholar
  2. Amato AA, Rajagopalan S, Lin JZ, Carvalho BM, Figueira ACM, Lu J, et al. GQ-16, a novel peroxisome proliferator-activated receptor gamma (PPAR gamma) ligand, promotes insulin sensitization without weight gain. J Biol Chem. 2012;287:28169–79. doi: 10.1074/jbc.M111.332106.PubMedPubMedCentralCrossRefGoogle Scholar
  3. Asada A, Yamamoto N, Gohda M, Saito T, Hayashi N, Hisanaga S. Myristoylation of p39 and p35 is a determinant of cytoplasmic or nuclear localization of active cycline-dependent kinase 5 complexes. J Neurochem. 2008;106:1325–36. doi: 10.1111/j.1471-4159.2008.05500.x.PubMedCrossRefGoogle Scholar
  4. Asada A, Saito T, Hisanaga S. Phosphorylation of p35 and p39 by Cdk5 determines the subcellular location of the holokinase in a phosphorylation-site-specific manner. J Cell Sci. 2012;125:3421–9. doi: 10.1242/jcs.100503.PubMedCrossRefGoogle Scholar
  5. Avraham E, Rott R, Liani E, Szargel R, Engelender S. Phosphorylation of Parkin by the cyclin-dependent kinase 5 at the linker region modulates its ubiquitin-ligase activity and aggregation. J Biol Chem. 2007;282:12842–50.PubMedCrossRefGoogle Scholar
  6. Bai B, Wang Y. Methods to investigate the role of SIRT1 in endothelial senescence. Methods Mol Biol. 2013;965:327–39. doi: 10.1007/978-1-62703-239-1_22.PubMedCrossRefGoogle Scholar
  7. Bai B, Liang Y, Xu C, Lee MY, Xu A, Wu D, et al. Cyclin-dependent kinase 5-mediated hyperphosphorylation of sirtuin-1 contributes to the development of endothelial senescence and atherosclerosis. Circulation. 2012;126:729–40. doi: 10.1161/CIRCULATIONAHA.112.118778.PubMedCrossRefGoogle Scholar
  8. Bai B, Vanhoutte PM, Wang Y. Loss-of-SIRT1 function during vascular ageing: hyperphosphorylation mediated by cyclin-dependent kinase 5. Trends Cardiovasc Med. 2014;24:81–4. doi: 10.1016/j.tcm.2013.07.001.PubMedCrossRefGoogle Scholar
  9. Baumann K, Mandelkow E-M, Biernat J, Piwnica-Worms H, Mandelkow E. Abnormal Alzheimer-like phosphorylation of tau-protein by cyclin-dependent kinases cdk2 and cdk5. FEBS Lett. 1993;336:417–24.PubMedCrossRefGoogle Scholar
  10. Benson C, White J, De Bono J, O’Donnell A, Raynaud F, Cruickshank C, et al. A phase I trial of the selective oral cyclin-dependent kinase inhibitor seliciclib (CYC202; R-Roscovitine), administered twice daily for 7 days every 21 days. Br J Cancer. 2007;96:29–37. doi: 10.1038/sj.bjc.6603509.PubMedCrossRefGoogle Scholar
  11. Bianchetta MJ, Lam TT, Jones SN, Morabito MA. Cyclin-dependent kinase 5 regulates PSD-95 ubiquitination in neurons. J Neurosci. 2011;31:12029–35. doi: 10.1523/Jneurosci.2388-11.2011.PubMedPubMedCentralCrossRefGoogle Scholar
  12. Bibb JA, Snyder GL, Nishi A, Yan Z, Meijer L, Fienberg AA, et al. Phosphorylation of DARPP-32 by Cdk5 modulates dopamine signalling in neurons. Nature. 1999;402:669–71.PubMedCrossRefGoogle Scholar
  13. Bibb JA, Chen J, Taylor JR, Svenningsson P, Nishi A, Snyder GL, et al. Effects of chronic exposure to cocaine are regulated by the neuronal protein Cdk5. Nature. 2001;410:376–80.PubMedCrossRefGoogle Scholar
  14. Binukumar BK, Shukla V, Amin ND, Bhaskar M, Skuntz S, Steiner J, et al. Analysis of the inhibitory elements in the p5 peptide fragment of the CDK5 activator, p35, CDKR1 protein. J Alzheimers Dis. 2015;48:1009–17. doi: 10.3233/Jad-150412.PubMedPubMedCentralCrossRefGoogle Scholar
  15. Bisht S, Nolting J, Schutte U, Haarmann J, Jain P, Shah D, et al. Cyclin-dependent kinase 5 (CDK5) controls melanoma cell motility, invasiveness, and metastatic spread-identification of a promising novel therapeutic target. Transl Oncol. 2015;8:295–307. doi: 10.1016/j.tranon.2015.06.002.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Bos JL, de Rooij J, Reedquist KA. Rap1 signalling: adhering to new models. Nat Rev Mol Cell Biol. 2001;2:369–77. doi: 10.1038/35073073.PubMedCrossRefGoogle Scholar
  17. Brandes RP, Fleming I, Busse R. Endothelial aging. Cardiovasc Res. 2005;66:286–94. doi: 10.1016/j.cardiores.2004.12.027.PubMedCrossRefGoogle Scholar
  18. Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes. 2003;52:102–10.PubMedCrossRefGoogle Scholar
  19. Chang KH, De Pablo Y, HP L, HG L, Smith MA, Shah K. Cdk5 is a major regulator of p38 cascade: relevance to neurotoxicity in Alzheimer’s disease. J Neurochem. 2010;113:1221–9.PubMedGoogle Scholar
  20. Chang KH, Multani PS, Sun KH, Vincent F, de Pablo Y, Ghosh S, et al. Nuclear envelope dispersion triggered by deregulated Cdk5 precedes neuronal death. Mol Biol Cell. 2011;22:1452–62. doi: 10.1091/mbc.E10-07-0654.PubMedPubMedCentralCrossRefGoogle Scholar
  21. Chang KH, Vincent F, Shah K. Deregulated Cdk5 triggers aberrant activation of cell cycle kinases and phosphatases inducing neuronal death. J Cell Sci. 2012;125:5124–37. doi: 10.1242/jcs.108183.PubMedCrossRefGoogle Scholar
  22. Cheung ZH, Gong K, Ip NY. Cyclin-dependent kinase 5 supports neuronal survival through phosphorylation of Bcl-2. J Neurosci. 2008;28:4872–7. doi: 10.1523/Jneurosci.0689-08.2008.PubMedCrossRefGoogle Scholar
  23. Ching Y-P, Pang AS, Lam W-H, Qi RZ, Wang JH. Identification of a neuronal Cdk5 activator-binding protein as Cdk5 inhibitor. J Biol Chem. 2002;277:15237–40.PubMedCrossRefGoogle Scholar
  24. Cho DH, Seo J, Park JH, Jo C, Choi YJ, Soh JW, et al. Cyclin-dependent kinase 5 phosphorylates endothelial nitric oxide synthase at serine 116. Hypertension. 2010;55:345–52. doi: 10.1161/HYPERTENSIONAHA.109.140210.PubMedCrossRefGoogle Scholar
  25. Choi HS, Lee Y, Park KH, Sung JS, Lee JE, Shin ES, et al. Single-nucleotide polymorphisms in the promoter of the CDK5 gene and lung cancer risk in a Korean population. J Hum Genet. 2009;54:298–303. doi: 10.1038/jhg.2009.29.PubMedCrossRefGoogle Scholar
  26. Choi JH, Banks AS, Estall JL, Kajimura S, Bostrom P, Laznik D, et al. Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARgamma by Cdk5. Nature. 2010;466:451–6. doi: 10.1038/nature09291.PubMedPubMedCentralCrossRefGoogle Scholar
  27. Choi JH, Banks AS, Kamenecka TM, Busby SA, Chalmers MJ, Kumar N, et al. Antidiabetic actions of a non-agonist PPAR gamma ligand blocking Cdk5-mediated phosphorylation. Nature. 2011;477:477–U131. doi: 10.1038/nature10383.PubMedPubMedCentralCrossRefGoogle Scholar
  28. Chow HM, Guo D, Zhou JC, Zhang GY, Li HF, Herrup K, et al. CDK5 activator protein p25 preferentially binds and activates GSK3beta. Proc Natl Acad Sci U S A. 2014;111:E4887–95. doi: 10.1073/pnas.1402627111.PubMedPubMedCentralCrossRefGoogle Scholar
  29. Cicero S, Herrup K. Cyclin-dependent kinase 5 is essential for neuronal cell cycle arrest and differentiation. J Neurosci. 2005;25:9658–68. doi: 10.1523/Jneurosci.1773-05.2005.PubMedCrossRefGoogle Scholar
  30. Coats S, Flanagan WM, Nourse J, Roberts JM. Requirement of p27Kip1 for restriction point control of the fibroblast cell cycle. Science. 1996;272:877–80.PubMedCrossRefGoogle Scholar
  31. Contreras-Vallejos E, Utreras E, Borquez DA, Prochazkova M, Terse A, Jaffe H, et al. Searching for novel Cdk5 substrates in brain by comparative phosphoproteomics of wild type and Cdk5−/− mice. PLoS One. 2014;9:e90363. doi: 10.1371/journal.pone.0090363.PubMedPubMedCentralCrossRefGoogle Scholar
  32. Cruz JC, Tsai LH. Cdk5 deregulation in the pathogenesis of Alzheimer’s disease. Trends Mol Med. 2004;10:452–8. doi: 10.1016/j.molmed.2004.07.001.PubMedCrossRefGoogle Scholar
  33. Cruz JC, Tseng H-C, Goldman JA, Shih H, Tsai L-H. Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles. Neuron. 2003;40:471–83.PubMedCrossRefGoogle Scholar
  34. Czapski GA, Gąssowska M, Wilkaniec A, Cieślik M, Adamczyk A. Extracellular alpha-synuclein induces calpain-dependent overactivation of cyclin-dependent kinase 5 in vitro. FEBS Lett. 2013;587:3135–41.PubMedCrossRefGoogle Scholar
  35. Daval M, Gurlo T, Costes S, Huang CJ, Butler PC. Cyclin-dependent kinase 5 promotes pancreatic beta-cell survival via Fak-Akt signaling pathways. Diabetes. 2011;60:1186–97. doi: 10.2337/db10-1048.PubMedPubMedCentralCrossRefGoogle Scholar
  36. Dickey CA, Koren J, Zhang YJ, Xu YF, Jinwal UK, Birnbaum MJ, et al. Akt and CHIP coregulate tau degradation through coordinated interactions. Proc Natl Acad Sci USA. 2008;105:3622–7. doi: 10.1073/pnas.0709180105.PubMedPubMedCentralCrossRefGoogle Scholar
  37. Draney C, Hobson AE, Grover SG, Jack BO, Tessem JS. Cdk5r1 overexpression induces primary beta-cell proliferation. J Diabetes Res. 2016;2016:6375804. doi: 10.1155/2016/6375804.PubMedCrossRefGoogle Scholar
  38. Ehrlich SM, Liebl J, Ardelt MA, Lehr T, De Toni EN, Mayr D, et al. Targeting cyclin dependent kinase 5 in hepatocellular carcinoma – a novel therapeutic approach. J Hepatol. 2015;63:102–13. doi: 10.1016/j.jhep.2015.01.031.PubMedCrossRefGoogle Scholar
  39. Erusalimsky JD. Vascular endothelial senescence: from mechanisms to pathophysiology. J Appl Physiol. 2009;106:326–32. doi: 10.1152/japplphysiol.91353.2008.PubMedCrossRefGoogle Scholar
  40. Folch J, Junyent F, Verdaguer E, Auladell C, Pizarro JG, Beas-Zarate C, et al. Role of cell cycle re-entry in neurons: a common apoptotic mechanism of neuronal cell death. Neurotox Res. 2012;22:195–207.PubMedCrossRefGoogle Scholar
  41. Goodwin PR, Sasaki JM, Juo P. Cyclin-dependent kinase 5 regulates the polarized trafficking of neuropeptide-containing dense-core vesicles in Caenorhabditis elegans motor neurons. J Neurosci. 2012;32:8158–72. doi: 10.1523/Jneurosci.0251-12.2012.PubMedPubMedCentralCrossRefGoogle Scholar
  42. Goodyear S, Sharma MC. Roscovitine regulates invasive breast cancer cell (MDA-MB231) proliferation and survival through cell cycle regulatory protein cdk5. Exp Mol Pathol. 2007;82:25–32.PubMedCrossRefGoogle Scholar
  43. Grynspan F, Griffin WR, Cataldo A, Katayama S, Nixon RA. Active site-directed antibodies identify calpain II as an early-appearing and pervasive component of neurofibrillary pathology in Alzheimer’s disease. Brain Res. 1997;763:145–58. doi: 10.1016/S0006-8993(97)00384-3.PubMedCrossRefGoogle Scholar
  44. Harmon JS, Tanaka Y, Olson LK, Robertson RP. Reconstitution of glucotoxic HIT-T15 cells with somatostatin transcription factor-1 partially restores insulin promoter activity. Diabetes. 1998;47:900–4.PubMedCrossRefGoogle Scholar
  45. Hellmich MR, Pant HC, Wada E, Battey JF. Neuronal cdc2-like kinase: a cdc2-related protein kinase with predominantly neuronal expression. Proc Natl Acad Sci U S A. 1992;89:10867–71.PubMedPubMedCentralCrossRefGoogle Scholar
  46. Herrup K, Yang Y. Cell cycle regulation in the postmitotic neuron: oxymoron or new biology? Nat Rev Neurosci. 2007;8:368–78. doi: 10.1038/nrn2124.PubMedCrossRefGoogle Scholar
  47. Hilton GD, Stoica BA, Byrnes KR, Faden AI. Roscovitine reduces neuronal loss, glial activation, and neurologic deficits after brain trauma. J Cereb Blood Flow Metab. 2008;28:1845–59.PubMedPubMedCentralCrossRefGoogle Scholar
  48. Hisanaga S, Endo R. Regulation and role of cyclin-dependent kinase activity in neuronal survival and death. J Neurochem. 2010;115:1309–21. doi: 10.1111/j.1471-4159.2010.07050.x.PubMedCrossRefGoogle Scholar
  49. Hsieh WS, Soo R, Peh BK, Loh T, Dong D, Soh D, et al. Pharmacodynamic effects of seliciclib, an orally administered cell cycle modulator, in undifferentiated nasopharyngeal cancer. Clin Cancer Res. 2009;15:1435–42. doi: 10.1158/1078-0432.CCR-08-1748.PubMedCrossRefGoogle Scholar
  50. Hsu FN, Chen MC, Lin KC, Peng YT, Li PC, Lin E, et al. Cyclin-dependent kinase 5 modulates STAT3 and androgen receptor activation through phosphorylation of Ser(7)(2)(7) on STAT3 in prostate cancer cells. Am J Physiol Endocrinol Metab. 2013;305:E975–86. doi: 10.1152/ajpendo.00615.2012.PubMedCrossRefGoogle Scholar
  51. Huang C, Rajfur Z, Yousefi N, Chen Z, Jacobson K, Ginsberg MH. Talin phosphorylation by Cdk5 regulates Smurf1-mediated talin head ubiquitylation and cell migration. Nat Cell Biol. 2009;11:624–30. doi: 10.1038/ncb1868.PubMedPubMedCentralCrossRefGoogle Scholar
  52. Huang E, Qu D, Zhang Y, Venderova K, Haque ME, Rousseaux MW, et al. The role of Cdk5-mediated apurinic/apyrimidinic endonuclease 1 phosphorylation in neuronal death. Nat Cell Biol. 2010;12:563–71.PubMedCrossRefGoogle Scholar
  53. Jimenez-Blasco D, Santofimia-Castano P, Gonzalez A, Almeida A, Bolanos JP. Astrocyte NMDA receptors’ activity sustains neuronal survival through a Cdk5-Nrf2 pathway. Cell Death Differ. 2015;22:1877–89. doi: 10.1038/cdd.2015.49.PubMedPubMedCentralCrossRefGoogle Scholar
  54. Kamei H, Saito T, Ozawa M, Fujita Y, Asada A, Bibb JA, et al. Suppression of calpain-dependent cleavage of the CDK5 activator p35 to p25 by site-specific phosphorylation. J Biol Chem. 2007;282:1687–94. doi: 10.1074/jbc.M610541200.PubMedCrossRefGoogle Scholar
  55. Kawahara M. Neurotoxicity of β-amyloid protein: oligomerization, channel formation and calcium dyshomeostasis. Curr Pharm Des. 2010;16:2779–89.PubMedCrossRefGoogle Scholar
  56. Kawauchi T, Chihama K, Nishimura YV, Nabeshima Y, Hoshino M. MAP1B phosphorylation is differentially regulated by Cdk5/p35, Cdk5/p25, and JNK. Biochem Biophys Res Commun. 2005;331:50–5. doi: 10.1016/j.bbrc.2005.03.132.PubMedCrossRefGoogle Scholar
  57. Kawauchi T, Chihama K, Nabeshima Y-i, Hoshino M. Cdk5 phosphorylates and stabilizes p27kip1 contributing to actin organization and cortical neuronal migration. Nat Cell Biol. 2006;8:17–26.PubMedCrossRefGoogle Scholar
  58. Ke K, Shen J, Song Y, Cao M, Lu H, Liu C, et al. CDK5 contributes to neuronal apoptosis via promoting MEF2D phosphorylation in rat model of intracerebral hemorrhage. J Mol Neurosci. 2015;56:48–59. doi: 10.1007/s12031-014-0466-5.PubMedCrossRefGoogle Scholar
  59. Kesavapany S, Li BS, Amin N, Zheng YL, Grant P, Pant HC. Neuronal cyclin-dependent kinase 5: role in nervous system function and its specific inhibition by the Cdk5 inhibitory peptide. Biochim Biophys Acta. 2004;1697:143–53. doi: 10.1016/j.bbapap.2003.11.020.PubMedCrossRefGoogle Scholar
  60. Kesavapany S, Zheng YL, Amin N, Pant HC. Peptides derived from Cdk5 activator p35, specifically inhibit deregulated activity of Cdk5. Biotechnol J. 2007;2:978–87. doi: 10.1002/biot.200700057.PubMedCrossRefGoogle Scholar
  61. Kim SH, Ryan TA. CDK5 serves as a major control point in neurotransmitter release. Neuron. 2010;67:797–809. doi: 10.1016/j.neuron.2010.08.003.PubMedPubMedCentralCrossRefGoogle Scholar
  62. Kim Y, Sung JY, Ceglia I, Lee KW, Ahn JH, Halford JM, et al. Phosphorylation of WAVE1 regulates actin polymerization and dendritic spine morphology. Nature. 2006;442:814–7. doi: 10.1038/nature04976.PubMedCrossRefGoogle Scholar
  63. Kim BS, Serebreni L, Fallica J, Hamdan O, Wang L, Johnston L, et al. Cyclin-dependent kinase five mediates activation of lung xanthine oxidoreductase in response to hypoxia. PLoS One. 2015;10:e0124189. doi: 10.1371/journal.pone.0124189.PubMedPubMedCentralCrossRefGoogle Scholar
  64. Lai KO, Ip NY. Recent advances in understanding the roles of Cdk5 in synaptic plasticity. Biochim Biophys Acta. 2009;1792:741–5. doi: 10.1016/j.bbadis.2009.05.001.PubMedCrossRefGoogle Scholar
  65. Lai KO, Wong ASL, Cheung MC, Xu P, Liang ZY, Lok KC, et al. TrkB phosphorylation by Cdk5 is required for activity-dependent structural plasticity and spatial memory. Nat Neurosci. 2012;15:1506–15. doi: 10.1038/nn.3237.PubMedCrossRefGoogle Scholar
  66. Lalioti V, Muruais G, Dinarina A, van Damme J, Vandekerckhove J, Sandoval IV. The atypical kinase Cdk5 is activated by insulin, regulates the association between GLUT4 and E-Syt1, and modulates glucose transport in 3T3-L1 adipocytes. Proc Natl Acad Sci USA. 2009;106:4249–53. doi: 10.1073/pnas.0900218106.PubMedPubMedCentralCrossRefGoogle Scholar
  67. Lau K-F, Howlett DR, Kesavapany S, Standen CL, Dingwall C, McLoughlin DM, et al. Cyclin-dependent kinase-5/p35 phosphorylates Presenilin 1 to regulate carboxy-terminal fragment stability. Mol Cell Neurosci. 2002;20:13–20.PubMedCrossRefGoogle Scholar
  68. Le Tourneau C, Faivre S, Laurence V, Delbaldo C, Vera K, Girre V, et al. Phase I evaluation of seliciclib (R-roscovitine), a novel oral cyclin-dependent kinase inhibitor, in patients with advanced malignancies. Eur J Cancer. 2010;46:3243–50. doi: 10.1016/j.ejca.2010.08.001.PubMedCrossRefGoogle Scholar
  69. Lee KY, Clark AW, Rosales JL, Chapman K, Fung T, Johnston RN. Elevated neuronal Cdc2-like kinase activity in the Alzheimer disease brain. Neurosci Res. 1999;34:21–9.PubMedCrossRefGoogle Scholar
  70. Lee J-H, Kim H-S, Lee S-J, Kim K-T. Stabilization and activation of p53 induced by Cdk5 contributes to neuronal cell death. J Cell Sci. 2007;120:2259–71.PubMedCrossRefGoogle Scholar
  71. Lee HY, Jung H, Jang IH, Suh P-G, Ryu SH. Cdk5 phosphorylates PLD2 to mediate EGF-dependent insulin secretion. Cell Signal. 2008;20:1787–94. doi: 10.1016/j.cellsig.2008.06.009.PubMedCrossRefGoogle Scholar
  72. Lew J, Huang Q-Q, Qi Z, Winkfein RJ, Aebersold R, Hunt T, et al. A brain-specific activator of cyclin-dependent kinase 5. Nature. 1994;371(6496):423–6.PubMedCrossRefGoogle Scholar
  73. Li BS, Zhang L, Takahashi S, Ma W, Jaffe H, Kulkarni AB, et al. Cyclin-dependent kinase 5 prevents neuronal apoptosis by negative regulation of c-Jun N-terminal kinase 3. EMBO J. 2002;21:324–33. doi: 10.1093/emboj/21.3.324.PubMedPubMedCentralCrossRefGoogle Scholar
  74. Li BS, Ma W, Jaffe H, Zheng YL, Takahashi S, Zhang L, et al. Cyclin-dependent kinase-5 is involved in neuregulin-dependent activation of phosphatidylinositol 3-kinase and Akt activity mediating neuronal survival. J Biol Chem. 2003;278:35702–9. doi: 10.1074/jbc.M302004200.PubMedCrossRefGoogle Scholar
  75. Liang Q, Li L, Zhang J, Lei Y, Wang L, Liu DX, et al. CDK5 is essential for TGF-beta1-induced epithelial-mesenchymal transition and breast cancer progression. Sci Report. 2013;3:2932. doi: 10.1038/srep02932.Google Scholar
  76. Liebl J, Weitensteiner SB, Vereb G, Takacs L, Furst R, Vollmar AM, et al. Cyclin-dependent kinase 5 regulates endothelial cell migration and angiogenesis. J Biol Chem. 2010;285:35932–43. doi: 10.1074/jbc.M110.126177.PubMedPubMedCentralCrossRefGoogle Scholar
  77. Liebl J, Zhang S, Moser M, Agalarov Y, Demir CS, Hager B, et al. Cdk5 controls lymphatic vessel development and function by phosphorylation of Foxc2. Nat Commun. 2015;6:7274. doi: 10.1038/ncomms8274.PubMedCrossRefGoogle Scholar
  78. Lilja L, Johansson JU, Gromada J, Mandic SA, Fried G, Berggren PO, et al. Cyclin-dependent kinase 5 associated with p39 promotes Munc18-1 phosphorylation and Ca(2+)-dependent exocytosis. J Biol Chem. 2004;279:29534–41. doi: 10.1074/jbc.M312711200.PubMedCrossRefGoogle Scholar
  79. Liu R, Tian B, Gearing M, Hunter S, Ye K, Mao Z. Cdk5-mediated regulation of the PIKE-A-Akt pathway and glioblastoma cell invasion. Proc Natl Acad Sci U S A. 2008;105:7570–5. doi: 10.1073/pnas.0712306105.PubMedPubMedCentralCrossRefGoogle Scholar
  80. Liu JL, Wang XY, Huang BX, Zhu F, Zhang RG, Wu G. Expression of CDK5/p35 in resected patients with non-small cell lung cancer: relation to prognosis. Med Oncol. 2011;28:673–8. doi: 10.1007/s12032-010-9510-7.PubMedCrossRefGoogle Scholar
  81. Liu SL, Wang C, Jiang T, Tan L, Xing A, Yu JT. The role of Cdk5 in Alzheimer’s disease. Mol Neurobiol. 2016;53:4328–42. doi: 10.1007/s12035-015-9369-x.PubMedCrossRefGoogle Scholar
  82. Lopes JP, Oliveira CR, Agostinho P. Cdk5 acts as a mediator of neuronal cell cycle re-entry triggered by amyloid-β and prion peptides. Cell Cycle. 2009;8:97–104.PubMedCrossRefGoogle Scholar
  83. Malumbres M, Harlow E, Hunt T, Hunter T, Lahti JM, Manning G, et al. Cyclin-dependent kinases: a family portrait. Nat Cell Biol. 2009;11:1275–6.PubMedPubMedCentralCrossRefGoogle Scholar
  84. Marra V, Burden JJ, Thorpe JR, Smith IT, Smith SL, Hausser M, et al. A preferentially segregated recycling vesicle pool of limited size supports neurotransmission in native central synapses. Neuron. 2012;76:579–89. doi: 10.1016/j.neuron.2012.08.042.PubMedPubMedCentralCrossRefGoogle Scholar
  85. Meijer L, Borgne A, Mulner O, Chong JP, Blow JJ, Inagaki N, et al. Biochemical and cellular effects of roscovitine, a potent and selective inhibitor of the cyclin-dependent kinases cdc2, cdk2 and cdk5. Eur J Biochem. 1997;243:527–36.PubMedCrossRefGoogle Scholar
  86. Minegishi S, Asada A, Miyauchi S, Fuchigami T, Saito T, Hisanaga S. Membrane association facilitates degradation and cleavage of the cyclin-dependent kinase 5 activators p35 and p39. Biochemistry. 2010;49:5482–93. doi: 10.1021/bi100631f.PubMedCrossRefGoogle Scholar
  87. Mishiba T, Tanaka M, Mita N, He XJ, Sasamoto K, Itohara S, et al. Cdk5/p35 functions as a crucial regulator of spatial learning and memory. Mol Brain. 2014;7:82. doi: 10.1186/s13041-014-0082-x.PubMedPubMedCentralCrossRefGoogle Scholar
  88. Mitsios N, Pennucci R, Krupinski J, Sanfeliu C, Gaffney J, Kumar P, et al. Expression of cyclin-dependent kinase 5 mRNA and protein in the human brain following acute ischemic stroke. Brain Pathol. 2007;17:11–23. doi: 10.1111/j.1750-3639.2006.00031.x.PubMedCrossRefGoogle Scholar
  89. Miyajima M, Nornes HO, Neuman T. Cyclin-E is expressed in neurons and forms complexes with Cdk5. Neuroreport. 1995;6:1130–2. doi: 10.1097/00001756-199505300-00014.PubMedCrossRefGoogle Scholar
  90. Moorthamer M, Chaudhuri B. Identification of ribosomal protein L34 as a novel Cdk5 inhibitor. Biochem Biophys Res Commun. 1999;255:631–8.PubMedCrossRefGoogle Scholar
  91. Moorthamer M, Zumstein-Mecker S, Chaudhuri B. DNA binding protein dbpA binds Cdk5 and inhibits its activity. FEBS Lett. 1999;446:343–50.PubMedCrossRefGoogle Scholar
  92. Morabito MA, Sheng M, Tsai LH. Cyclin-dependent kinase 5 phosphorylates the N-terminal domain of the postsynaptic density protein PSD-95 in neurons. J Neurosci. 2004;24:865–76. doi: 10.1523/Jneurosci.4582-03.2004.PubMedCrossRefGoogle Scholar
  93. Mouatt-Prigent A, Karlsson J, Agid Y, Hirsch E. Increased M-calpain expression in the mesencephalon of patients with Parkinson’s disease but not in other neurodegenerative disorders involving the mesencephalon: a role in nerve cell death? Neuroscience. 1996;73:979–87.PubMedCrossRefGoogle Scholar
  94. Nagano T, Hashimoto T, Nakashima A, Hisanaga S-i, Kikkawa U, Kamada S. Cyclin I is involved in the regulation of cell cycle progression. Cell Cycle. 2013;12:2617–24.PubMedPubMedCentralCrossRefGoogle Scholar
  95. Nakamura S, Kawamoto Y, Nakano S, Akiguchi I, Kimura J. p35nck5a and cyclin-dependent kinase 5 colocalize in Lewy bodies of brains with Parkinson’s disease. Acta Neuropathol. 1997;94:153–7.PubMedCrossRefGoogle Scholar
  96. Nikolic M, Dudek H, Kwon YT, Ramos Y, Tsai L-H. The cdk5/p35 kinase is essential for neurite outgrowth during neuronal differentiation. Genes Dev. 1996;10:816–25.PubMedCrossRefGoogle Scholar
  97. Nikolic M, Chou MM, Lu W, Mayer BJ, Tsai L-H. The p35/Cdk5 kinase is a neuron-specific Rac effector that inhibits Pak1 activity. Nature. 1998;395:194–8.PubMedCrossRefGoogle Scholar
  98. Nishimura YV, Sekine K, Chihama K, Nakajima K, Hoshino M, Nabeshima Y, et al. Dissecting the factors involved in the locomotion mode of neuronal migration in the developing cerebral cortex. J Biol Chem. 2010;285:5878–87. doi: 10.1074/jbc.M109.033761.PubMedCrossRefGoogle Scholar
  99. Ohshima T, Ward JM, Huh CG, Longenecker G, Veeranna, Pant HC, et al. Targeted disruption of the cyclin-dependent kinase 5 gene results in abnormal corticogenesis, neuronal pathology and perinatal death. Proc Natl Acad Sci USA. 1996;93:11173–8.PubMedPubMedCentralCrossRefGoogle Scholar
  100. Ohshima T, Ogawa M, Veeranna, Hirasawa M, Longenecker G, Ishiguro K, et al. Synergistic contributions of cyclin-dependant kinase 5/p35 and Reelin/Dab1 to the positioning of cortical neurons in the developing mouse brain. Proc Natl Acad Sci U S A. 2001;98:2764–9. doi: 10.1073/pnas.051628498.PubMedPubMedCentralCrossRefGoogle Scholar
  101. Ohshima T, Ogawa M, Takeuchi K, Takahashi S, Kulkarni AB, Mikoshiba K. Cyclin-dependent kinase 5/p35 contributes synergistically with Reelin/Dab1 to the positioning of facial branchiomotor and inferior olive neurons in the developing mouse hindbrain. J Neurosci. 2002;22:4036–44.PubMedGoogle Scholar
  102. Ohshima T, Ogura H, Tomizawa K, Hayashi K, Suzuki H, Saito T, et al. Impairment of hippocampal long-term depression and defective spatial learning and memory in p35 mice. J Neurochem. 2005;94:917–25. doi: 10.1111/j.1471-4159.2005.03233.x.PubMedCrossRefGoogle Scholar
  103. Okada S, Yamada E, Saito T, Ohshima K, Hashimoto K, Yamada M, et al. CDK5-dependent phosphorylation of the Rho family GTPase TC10(alpha) regulates insulin-stimulated GLUT4 translocation. J Biol Chem. 2008;283:35455–63. doi: 10.1074/jbc.M806531200.PubMedCrossRefGoogle Scholar
  104. Patrick GN, Zhou P, Kwon YT, Howley PM, Tsai L-H. p35, the neuronal-specific activator of cyclin-dependent kinase 5 (Cdk5) is degraded by the ubiquitin-proteasome pathway. J Biol Chem. 1998;273:24057–64.PubMedCrossRefGoogle Scholar
  105. Patrick GN, Zukerberg L, Nikolic M, de La Monte S, Dikkes P, Tsai L-H. Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature. 1999;402:615–22.PubMedCrossRefGoogle Scholar
  106. Patzke H, Tsai LH. Calpain-mediated cleavage of the cyclin-dependent kinase-5 activator p39 to p29. J Biol Chem. 2002;277:8054–60. doi: 10.1074/jbc.M109645200.PubMedCrossRefGoogle Scholar
  107. Plattner F, Hernandez A, Kistler TM, Pozo K, Zhong P, Yuen EY, et al. Memory enhancement by targeting Cdk5 regulation of NR2B. Neuron. 2014;81:1070–83. doi: 10.1016/j.neuron.2014.01.022.PubMedPubMedCentralCrossRefGoogle Scholar
  108. Pozo K, Castro-Rivera E, Tan C, Plattner F, Schwach G, Siegl V, et al. The role of Cdk5 in neuroendocrine thyroid cancer. Cancer Cell. 2013;24:499–511. doi: 10.1016/j.ccr.2013.08.027.PubMedCrossRefGoogle Scholar
  109. Qu D, Li Q, Lim H-Y, Cheung NS, Li R, Wang JH, et al. The protein SET binds the neuronal Cdk5 activator p35 nck5a and modulates Cdk5/p35 nck5a activity. J Biol Chem. 2002;277:7324–32.PubMedCrossRefGoogle Scholar
  110. Qu D, Rashidian J, Mount MP, Aleyasin H, Parsanejad M, Lira A, et al. Role of Cdk5-mediated phosphorylation of Prx2 in MPTP toxicity and Parkinson’s disease. Neuron. 2007;55:37–52.PubMedCrossRefGoogle Scholar
  111. Qu J, Nakamura T, Cao G, Holland EA, McKercher SR, Lipton SA. S-Nitrosylation activates Cdk5 and contributes to synaptic spine loss induced by β-amyloid peptide. Proc Natl Acad Sci USA. 2011;108:14330–5.PubMedPubMedCentralCrossRefGoogle Scholar
  112. Qu J, Nakamura T, Holland EA, McKercher SR, Lipton SA. S-nitrosylation of Cdk5: potential implications in amyloid-β-related neurotoxicity in Alzheimer disease. Prion. 2012;6:364–70.PubMedPubMedCentralCrossRefGoogle Scholar
  113. Rashid T, Banerjee M, Nikolic M. Phosphorylation of Pak1 by the p35/Cdk5 kinase affects neuronal morphology. J Biol Chem. 2001;276:49043–52. doi: 10.1074/jbc.M105599200.PubMedCrossRefGoogle Scholar
  114. Roder H, Ingram V. Two novel kinases phosphorylate tau and the KSP site of heavy neurofilament subunits in high stoichiometric ratios. J Neurosci. 1991;11:3325–43.PubMedGoogle Scholar
  115. Schubert S, Knoch KP, Ouwendijk J, Mohammed S, Bodrov Y, Jager M, et al. beta 2-Syntrophin is a Cdk5 substrate that restrains the motility of insulin secretory granules. Plos One. 2010;5:e12929. doi: 10.1371/journal.pone.0012929.PubMedPubMedCentralCrossRefGoogle Scholar
  116. Sharma MR, Tuszynski GP, Sharma MC. Angiostatin-induced inhibition of endothelial cell proliferation/apoptosis is associated with the down-regulation of cell cycle regulatory protein cdk5. J Cell Biochem. 2004;91:398–409. doi: 10.1002/jcb.10762.PubMedCrossRefGoogle Scholar
  117. Shi C, Viccaro K, Lee H-g, Shah K. Cdk5–Foxo3 axis: initially neuroprotective, eventually neurodegenerative in Alzheimer’s disease models. J Cell Sci. 2016;129:1815–30.CrossRefGoogle Scholar
  118. Smith PD, Mount MP, Shree R, Callaghan S, Slack RS, Anisman H, et al. Calpain-regulated p35/cdk5 plays a central role in dopaminergic neuron death through modulation of the transcription factor myocyte enhancer factor 2. J Neurosci. 2006;26:440–7.PubMedCrossRefGoogle Scholar
  119. Su SC, Seo J, Pan JQ, Samuels BA, Rudenko A, Ericsson M, et al. Regulation of N-type voltage-gated calcium channels and presynaptic function by cyclin-dependent kinase 5. Neuron. 2012;75:675–87. doi: 10.1016/j.neuron.2012.06.023.PubMedPubMedCentralCrossRefGoogle Scholar
  120. Sundaram JR, Poore CP, Bin Sulaimee NH, Pareek T, Asad ABMA, Rajkumar R, et al. Specific inhibition of p25/Cdk5 activity by the Cdk5 inhibitory peptide reduces neurodegeneration in vivo. J Neurosci. 2013;33:334–43. doi: 10.1523/Jneurosci.3593-12.2013.PubMedCrossRefGoogle Scholar
  121. Takahashi S, Ohshima T, Hirasawa M, Pareek TK, Bugge TH, Morozov A, et al. Conditional deletion of neuronal cyclin-dependent kinase 5 in developing forebrain results in microglial activation and neurodegeneration. Am J Pathol. 2010;176:320–9. doi: 10.2353/ajpath.2010.081158.PubMedPubMedCentralCrossRefGoogle Scholar
  122. Tan TC, Valova VA, Malladi CS, Graham ME, Berven LA, Jupp OJ, et al. Cdk5 is essential for synaptic vesicle endocytosis. Nat Cell Biol. 2003;5:701–10. doi: 10.1038/ncb1020.PubMedCrossRefGoogle Scholar
  123. Tanabe K, Yamazaki H, Inaguma Y, Asada A, Kimura T, Takahashi J, et al. Phosphorylation of drebrin by cyclin-dependent kinase 5 and its role in neuronal migration. PLoS One. 2014;9:e92291. doi: 10.1371/journal.pone.0092291.PubMedPubMedCentralCrossRefGoogle Scholar
  124. Tanaka T, Serneo FF, Tseng HC, Kulkarni AB, Tsai LH, Gleeson JG. Cdk5 phosphorylation of doublecortin ser297 regulates its effect on neuronal migration. Neuron. 2004;41:215–27. doi: 10.1016/S0896-6273(03)00852-3.PubMedCrossRefGoogle Scholar
  125. Tang D, Yeung J, Lee K-Y, Matsushita M, Matsui H, Tomizawa K, et al. An isoform of the neuronal cyclin-dependent kinase 5 (Cdk5) activator. J Biol Chem. 1995;270:26897–903.PubMedCrossRefGoogle Scholar
  126. Tarricone C, Dhavan R, Peng J, Areces LB, Tsai L-H, Musacchio A. Structure and regulation of the CDK5-p25 nck5a complex. Mol Cell. 2001;8:657–69.PubMedCrossRefGoogle Scholar
  127. Tomizawa K, Ohta J, Matsushita M, Moriwaki A, Li ST, Takei K, et al. Cdk5/p35 regulates neurotransmitter release through phosphorylation and downregulation of P/Q-type voltage-dependent calcium channel activity. J Neurosci. 2002;22:2590–7.PubMedGoogle Scholar
  128. Trimarchi JM, Lees JA. Sibling rivalry in the E2F family. Nat Rev Mol Cell Biol. 2002;3:11–20. doi: 10.1038/nrm714.PubMedCrossRefGoogle Scholar
  129. Tsai L-H, Delalle I, Caviness VS, Chae T, Harlow E. p35 is a neural-specific regulatory subunit of cyclin-dependent kinase 5. Nature. 1994;371:5.CrossRefGoogle Scholar
  130. Tseng HC, Zhou Y, Shen Y, Tsai LH. A survey of Cdk5 activator p35 and p25 levels in Alzheimer’s disease brains. FEBS Lett. 2002;523:58–62.PubMedCrossRefGoogle Scholar
  131. Ubeda M, Kemp DM, Habener JF. Glucose-induced expression of the cyclin-dependent protein kinase 5 activator p35 involved in Alzheimer’s disease regulates insulin gene transcription in pancreatic beta-cells. Endocrinology. 2004;145:3023–31. doi: 10.1210/en.2003-1522.PubMedCrossRefGoogle Scholar
  132. Ubeda M, Rukstalis JM, Habener JF. Inhibition of cyclin-dependent kinase 5 activity protects pancreatic beta cells from glucotoxicity. J Biol Chem. 2006;281:28858–64. doi: 10.1074/jbc.M604690200.PubMedCrossRefGoogle Scholar
  133. Utreras E, Henriquez D, Contreras-Vallejos E, Olmos C, Di Genova A, Maass A, et al. Cdk5 regulates Rap1 activity. Neurochem Int. 2013;62:848–53. doi: 10.1016/j.neuint.2013.02.011.PubMedPubMedCentralCrossRefGoogle Scholar
  134. van den Heuvel S, Harlow E. Distinct roles for cyclin-dependent kinases in cell cycle control. Science. 1993;262:2050–4.PubMedCrossRefGoogle Scholar
  135. Wang Y, Liang Y, Vanhoutte PM. SIRT1 and AMPK in regulating mammalian senescence: a critical review and a working model. FEBS Lett. 2011;585:986–94. doi: 10.1016/j.febslet.2010.11.047.PubMedCrossRefGoogle Scholar
  136. Wei FY, Nagashima K, Ohshima T, Saheki Y, Lu YF, Matsushita M, et al. Cdk5-dependent regulation of glucose-stimulated insulin secretion. Nat Med. 2005;11:1104–8. doi: 10.1038/nm1299.PubMedCrossRefGoogle Scholar
  137. Wen Y, Yu WH, Maloney B, Bailey J, Ma J, Marié I, et al. Transcriptional regulation of β-secretase by p25/cdk5 leads to enhanced amyloidogenic processing. Neuron. 2008;57:680–90.PubMedPubMedCentralCrossRefGoogle Scholar
  138. Wilkaniec A, Czapski GA, Adamczyk A. Cdk5 at crossroads of protein oligomerization in neurodegenerative diseases: facts and hypotheses. J Neurochem. 2016;136:222–33.PubMedCrossRefGoogle Scholar
  139. Wong AS, Lee RH, Cheung AY, Yeung PK, Chung SK, Cheung ZH, et al. Cdk5-mediated phosphorylation of endophilin B1 is required for induced autophagy in models of Parkinson’s disease. Nat Cell Biol. 2011;13:568–79.PubMedCrossRefGoogle Scholar
  140. Xie ZG, Sanada K, Samuels BA, Shih H, Tsai LH. Serine 732 phosphorylation of FAK by Cdk5 is important for microtubule organization, nuclear movement, and neuronal migration. Cell. 2003;114:469–82. doi: 10.1016/S0092-8674(03)00605-6.PubMedCrossRefGoogle Scholar
  141. Xie W, Liu C, Wu D, Li Z, Li C, Zhang Y. Phosphorylation of kinase insert domain receptor by cyclin-dependent kinase 5 at serine 229 is associated with invasive behavior and poor prognosis in prolactin pituitary adenomas. Oncotarget. 2016; doi: 10.18632/oncotarget.10550.Google Scholar
  142. Xu J, Kurup P, Zhang YF, Goebel-Goody SM, Wu PH, Hawasli AH, et al. Extrasynaptic NMDA receptors couple preferentially to excitotoxicity via calpain-mediated cleavage of STEP. J Neurosci. 2009;29:9330–43. doi: 10.1523/Jneurosci.2212-09.2009.PubMedPubMedCentralCrossRefGoogle Scholar
  143. Yang S. Gene amplifications at chromosome 7 of the human gastric cancer genome. Int J Mol Med. 2007;20:225–31.PubMedGoogle Scholar
  144. Ye T, Ip JP, Fu AK, Ip NY. Cdk5-mediated phosphorylation of RapGEF2 controls neuronal migration in the developing cerebral cortex. Nat Commun. 2014;5:4826. doi: 10.1038/ncomms5826.PubMedPubMedCentralCrossRefGoogle Scholar
  145. Yildiz-Unal A, Korulu S, Karabay A. Neuroprotective strategies against calpain-mediated neurodegeneration. Neuropsychiatr Dis Treat. 2015;11:297–310.PubMedPubMedCentralCrossRefGoogle Scholar
  146. Zhang J, Herrup K. Nucleocytoplasmic Cdk5 is involved in neuronal cell cycle and death in post-mitotic neurons. Cell Cycle. 2011;10:1208–14.PubMedCrossRefGoogle Scholar
  147. Zhang J, Cicero SA, Wang L, Romito-DiGiacomo RR, Yang Y, Herrup K. Nuclear localization of Cdk5 is a key determinant in the postmitotic state of neurons. Proc Natl Acad Sci USA. 2008;105:8772–7. doi: 10.1073/pnas.0711355105.PubMedPubMedCentralCrossRefGoogle Scholar
  148. Zhang J, Li H, Herrup K. Cdk5 nuclear localization is p27-dependent in nerve cells implications for cell cycle suppression and caspase-3 activation. J Biol Chem. 2010a;285:14052–61.PubMedPubMedCentralCrossRefGoogle Scholar
  149. Zhang J, Li H, Yabut O, Fitzpatrick H, D’Arcangelo G, Herrup K. Cdk5 suppresses the neuronal cell cycle by disrupting the E2F1-DP1 complex. J Neurosci. 2010b;30:5219–28. doi: 10.1523/JNEUROSCI.5628-09.2010.PubMedPubMedCentralCrossRefGoogle Scholar
  150. Zhang X, Zhong T, Dang Y, Li Z, Li P, Chen G. Aberrant expression of CDK5 infers poor outcomes for nasopharyngeal carcinoma patients. Int J Clin Exp Pathol. 2015;8:8066–74.PubMedPubMedCentralGoogle Scholar
  151. Zheng YL, Kesavapany S, Gravell M, Hamilton RS, Schubert M, Amin N, et al. A Cdk5 inhibitory peptide reduces tau hyperphosphorylation and apoptosis in neurons. EMBO J. 2005;24:209–20. doi: 10.1038/sj.emboj.7600441.PubMedCrossRefGoogle Scholar
  152. Zheng YL, Li BS, Kanungo J, Kesavapany S, Amin N, Grant P, et al. Cdk5 modulation of mitogen-activated protein kinase signaling regulates neuronal survival. Mol Biol Cell. 2007;18:404–13. doi: 10.1091/mbc.E06-09-0851.PubMedPubMedCentralCrossRefGoogle Scholar
  153. Zheng YL, Li CY, Hu YF, Cao L, Wang H, Li B, et al. Cdk5 Inhibitory Peptide (CIP) Inhibits Cdk5/p25 Activity Induced by High Glucose in Pancreatic Beta Cells and Recovers Insulin Secretion from p25 Damage. Plos One. 2013;8:e63332. doi: 10.1371/journal.pone.0063332.PubMedPubMedCentralCrossRefGoogle Scholar
  154. Zu Y, Liu L, Lee MY, Xu C, Liang Y, Man RY, et al. SIRT1 promotes proliferation and prevents senescence through targeting LKB1 in primary porcine aortic endothelial cells. Circ Res. 2010;106:1384–93. doi: 10.1161/CIRCRESAHA.109.215483.PubMedCrossRefGoogle Scholar
  155. Zukerberg LR, Patrick GN, Nikolic M, Humbert S, Wu C-L, Lanier LM, et al. Cables links Cdk5 and c-Abl and facilitates Cdk5 tyrosine phosphorylation, kinase upregulation, and neurite outgrowth. Neuron. 2000;26:633–46.PubMedCrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.State Key Laboratory of Pharmaceutical Biotechnology and Department of Pharmacology and PharmacyThe University of Hong KongHong KongChina