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Gene Review

CDK5  -  cyclin-dependent kinase 5

Homo sapiens

Synonyms: CDKN5, Cell division protein kinase 5, Cyclin-dependent-like kinase 5, PSSALRE, Serine/threonine-protein kinase PSSALRE, ...
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Disease relevance of CDK5


Psychiatry related information on CDK5


High impact information on CDK5

  • 14-3-3epsilon binds to CDK5/p35-phosphorylated NUDEL and this binding maintains NUDEL phosphorylation [11].
  • These results establish a crucial role for 14-3-3epsilon in neuronal development by sustaining the effects of CDK5 phosphorylation and provide a molecular explanation for the differences in severity of human neuronal migration defects with 17p13.3 deletions [11].
  • Cyclin-dependent kinase 5 (Cdk5) is required for proper development of the mammalian central nervous system [12].
  • Because the Rho family of GTPases and the Pak kinases are implicated in actin polymerization, the modification of Pak1, imposed by the p35/Cdk5 kinase, is likely to have an impact on the dynamics of the reorganization of the actin cytoskeleton in neurons, thus promoting neuronal migration and neurite outgrowth [13].
  • In addition, p35/Cdk5 kinase concentrates at the leading edges of axonal growth cones and regulates neurite outgrowth in cortical neurons in culture [13].

Chemical compound and disease context of CDK5


Biological context of CDK5

  • Finally, we provide evidence that the CDK5-p25 complex employs a distinct mechanism from the phospho-CDK2-cyclin A complex to establish substrate specificity [19].
  • In this study, we have examined the kinetic characteristics of in vitro phosphorylation of the longest isoform of human tau by CDK5 and its activators using recombinant proteins [7].
  • We have used site-directed mutagenesis ("charged to alanine") and molecular modeling techniques to probe the recognition interactions for substrate peptide (PKTPKKAKKL) derived from histone H1 docked in the active site of CDK5 [20].
  • Specifically, aberrant activation of cell cycle CDKs or CDK5 is associated with apoptosis and neuronal dysfunction in response to various neuronal stressors [21].
  • Inhibition of CDK5 is protective in necrotic and apoptotic paradigms of neuronal cell death and prevents mitochondrial dysfunction [22].

Anatomical context of CDK5

  • CDK5 plays an indispensable role in the central nervous system, and its deregulation is involved in neurodegeneration [19].
  • This has led to the hypothesis that increased p25 levels could promote neurofibrillary tangles (NFT) through CDK5-mediated hyperphosphorylation of tau, the principal component of NFTs [23].
  • In this study we report that both the p35 and CDK5 genes are expressed in insulin-producing beta-cells of the pancreas [24].
  • OBJECTIVES: We sought to investigate the expression and functions of CDK5 in human keratinocytes [2].
  • This expression, restricted to podocytes in mature glomeruli, appears associated with CDK5 [25].

Associations of CDK5 with chemical compounds

  • A detailed analysis is presented of the dynamics of human CDK5 in complexes with the protein activator p25 and the purine-like inhibitor roscovitine [26].
  • Our findings indicate that the expression of p35 and CDK5 in insulin-producing beta-cells ensembles a new signaling pathway, the activity of which is controlled by glucose, and its functional role may comprise the regulation of various biological processes in beta-cells, such as is the case for expression of the insulin gene [24].
  • Phosphorylation of STAT3 at Serine 727 by CDK5 decreased during serum deprivation, and partly recovered by mu-opioid agonist [27].
  • Overexpression of CDK5 in serum-free medium reversed activation of caspase cascade and augmented DAMGO neuroprotection [27].
  • BACKGROUND: CDK5 is a member of proline-directed serine/threonine kinases [2].

Physical interactions of CDK5

  • In turn, the p25/Cdk5 complex aberrantly phosphorylates its substrates tau and neurofilaments, which has been implicated in the pathogenesis of these disorders [28].
  • OBJECTIVE: To analyze cdk5/p35 complex, a kinase that regulates neurite outgrowth, as a potential cellular mechanism underlying tau phosphorylation in brain tissues from PSP and control cases and comparatively in cerebral cortex from subjects with AD [29].

Enzymatic interactions of CDK5

  • Although the kinase activity of CDK5 in phosphorylating tau was significantly higher in the presence of p25, the affinity of CDK5 for tau was not different [7].
  • DARPP-32 is also phosphorylated at Thr75 by Cdk5 and this converts DARPP-32 into an inhibitor of PKA [30].
  • Amphiphysin is phosphorylated by cdk5 in a region including serines 272, 276, and 285 [31].
  • These results demonstrate that CDK-5 is a major proline-directed kinase phosphorylating the human NF-H tail domain [32].

Co-localisations of CDK5


Regulatory relationships of CDK5


Other interactions of CDK5

  • They also play a role in apoptosis (CDK2), in neuronal cells (CDK5) and in the control of transcription (CDK 7, 8, 9) [37].
  • Although GW8510 inhibits CDK2 and other CDKs when tested in in vitro biochemical assays, when used on cultured neurons it only inhibits CDK5, a cytoplasmic CDK that is not associated with cell-cycle progression [38].
  • Western blotting of the intermediate filament-enriched cytoskeletal fraction and coimmunoprecipitation of nestin with anti-CDK5 antibodies confirmed these results [25].
  • Anti-cdk5 antibody diffusely stained the perikarya of some tau2-positive or neurofibrillary tangle (NFT)-bearing neurons in ATD brains, while cdk5-positive staining was scarcely found in control brains [39].
  • Secondly, unlike the other members of the Cdk family, Cdk5 is not activated by association with a cyclin, although it can bind them [28].

Analytical, diagnostic and therapeutic context of CDK5


  1. Mechanism of CDK5/p25 binding by CDK inhibitors. Mapelli, M., Massimiliano, L., Crovace, C., Seeliger, M.A., Tsai, L.H., Meijer, L., Musacchio, A. J. Med. Chem. (2005) [Pubmed]
  2. CDK5 regulates cell-cell and cell-matrix adhesion in human keratinocytes. Nakano, N., Nakao, A., Ishidoh, K., Tsuboi, R., Kominami, E., Okumura, K., Ogawa, H. Br. J. Dermatol. (2005) [Pubmed]
  3. Involvement of Cdk5/p25 in digoxin-triggered prostate cancer cell apoptosis. Lin, H., Juang, J.L., Wang, P.S. J. Biol. Chem. (2004) [Pubmed]
  4. Aberrant expression of cyclin-dependent kinase 5 in inclusion body myositis. Nakano, S., Akiguchi, I., Nakamura, S., Satoi, H., Kawashima, S., Kimura, J. Neurology (1999) [Pubmed]
  5. Cyclin-dependent kinase 5 and mitogen-activated protein kinase in glial cytoplasmic inclusions in multiple system atrophy. Nakamura, S., Kawamoto, Y., Nakano, S., Akiguchi, I., Kimura, J. J. Neuropathol. Exp. Neurol. (1998) [Pubmed]
  6. Cyclin-dependent kinase 5 is amplified and overexpressed in pancreatic cancer and activated by mutant k-ras. Eggers, J.P., Grandgenett, P.M., Collisson, E.C., Lewallen, M.E., Tremayne, J., Singh, P.K., Swanson, B.J., Andersen, J.M., Caffrey, T.C., High, R.R., Ouellette, M., Hollingsworth, M.A. Clin. Cancer Res. (2011) [Pubmed]
  7. Truncation of CDK5 activator p35 induces intensive phosphorylation of Ser202/Thr205 of human tau. Hashiguchi, M., Saito, T., Hisanaga, S., Hashiguchi, T. J. Biol. Chem. (2002) [Pubmed]
  8. Downregulation of neuronal cdk5/p35 in opioid addicts and opiate-treated rats: relation to neurofilament phosphorylation. Ferrer-Alcón, M., La Harpe, R., Guimón, J., García-Sevilla, J.A. Neuropsychopharmacology (2003) [Pubmed]
  9. A decade of CDK5. Dhavan, R., Tsai, L.H. Nat. Rev. Mol. Cell Biol. (2001) [Pubmed]
  10. Neuroadaptations of Cdk5 in cholinergic interneurons of the nucleus accumbens and prefrontal cortex of inbred alcohol-preferring rats following voluntary alcohol drinking. Camp, M.C., Mayfield, R.D., McCracken, M., McCracken, L., Alcantara, A.A. Alcohol. Clin. Exp. Res. (2006) [Pubmed]
  11. 14-3-3epsilon is important for neuronal migration by binding to NUDEL: a molecular explanation for Miller-Dieker syndrome. Toyo-oka, K., Shionoya, A., Gambello, M.J., Cardoso, C., Leventer, R., Ward, H.L., Ayala, R., Tsai, L.H., Dobyns, W., Ledbetter, D., Hirotsune, S., Wynshaw-Boris, A. Nat. Genet. (2003) [Pubmed]
  12. Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Patrick, G.N., Zukerberg, L., Nikolic, M., de la Monte, S., Dikkes, P., Tsai, L.H. Nature (1999) [Pubmed]
  13. The p35/Cdk5 kinase is a neuron-specific Rac effector that inhibits Pak1 activity. Nikolic, M., Chou, M.M., Lu, W., Mayer, B.J., Tsai, L.H. Nature (1998) [Pubmed]
  14. Inhibition of cyclin-dependent kinases, GSK-3beta and CK1 by hymenialdisine, a marine sponge constituent. Meijer, L., Thunnissen, A.M., White, A.W., Garnier, M., Nikolic, M., Tsai, L.H., Walter, J., Cleverley, K.E., Salinas, P.C., Wu, Y.Z., Biernat, J., Mandelkow, E.M., Kim, S.H., Pettit, G.R. Chem. Biol. (2000) [Pubmed]
  15. Induction of cyclin-dependent kinase 5 and its activator p35 through the extracellular-signal-regulated kinase and protein kinase A pathways during retinoic-acid mediated neuronal differentiation in human neuroblastoma SK-N-BE(2)C cells. Lee, J.H., Kim, K.T. J. Neurochem. (2004) [Pubmed]
  16. CDK5 is a novel regulatory protein in PPARgamma ligand-induced antiproliferation. Kim, E., Chen, F., Wang, C.C., Harrison, L.E. Int. J. Oncol. (2006) [Pubmed]
  17. Discovery and SAR of 2-aminothiazole inhibitors of cyclin-dependent kinase 5/p25 as a potential treatment for Alzheimer's disease. Helal, C.J., Sanner, M.A., Cooper, C.B., Gant, T., Adam, M., Lucas, J.C., Kang, Z., Kupchinsky, S., Ahlijanian, M.K., Tate, B., Menniti, F.S., Kelly, K., Peterson, M. Bioorg. Med. Chem. Lett. (2004) [Pubmed]
  18. Networking with proline-directed protein kinases implicated in tau phosphorylation. Pelech, S.L. Neurobiol. Aging (1995) [Pubmed]
  19. Structure and regulation of the CDK5-p25(nck5a) complex. Tarricone, C., Dhavan, R., Peng, J., Areces, L.B., Tsai, L.H., Musacchio, A. Mol. Cell (2001) [Pubmed]
  20. Identification of substrate binding site of cyclin-dependent kinase 5. Sharma, P., Steinbach, P.J., Sharma, M., Amin, N.D., Barchi, J.J., Pant, H.C. J. Biol. Chem. (1999) [Pubmed]
  21. Cyclin-dependent kinase inhibitors: cancer killers to neuronal guardians. Monaco, E.A., Vallano, M.L. Current medicinal chemistry. (2003) [Pubmed]
  22. Inhibition of CDK5 is protective in necrotic and apoptotic paradigms of neuronal cell death and prevents mitochondrial dysfunction. Weishaupt, J.H., Kussmaul, L., Grötsch, P., Heckel, A., Rohde, G., Romig, H., Bähr, M., Gillardon, F. Mol. Cell. Neurosci. (2003) [Pubmed]
  23. Brain levels of CDK5 activator p25 are not increased in Alzheimer's or other neurodegenerative diseases with neurofibrillary tangles. Tandon, A., Yu, H., Wang, L., Rogaeva, E., Sato, C., Chishti, M.A., Kawarai, T., Hasegawa, H., Chen, F., Davies, P., Fraser, P.E., Westaway, D., St George-Hyslop, P.H. J. Neurochem. (2003) [Pubmed]
  24. 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. Ubeda, M., Kemp, D.M., Habener, J.F. Endocrinology (2004) [Pubmed]
  25. Nestin expression in adult and developing human kidney. Bertelli, E., Regoli, M., Fonzi, L., Occhini, R., Mannucci, S., Ermini, L., Toti, P. J. Histochem. Cytochem. (2007) [Pubmed]
  26. Different mechanisms of CDK5 and CDK2 activation as revealed by CDK5/p25 and CDK2/cyclin A dynamics. Otyepka, M., Bártová, I., Kríz, Z., Koca, J. J. Biol. Chem. (2006) [Pubmed]
  27. Role of CDK5 in neuroprotection from serum deprivation by mu-opioid receptor agonist. Wang, Y., Xie, W.Y., He, Y., Wang, M., Yang, Y.R., Zhang, Y., Yin, D.M., Jordan-Sciutto, K.L., Han, J.S., Wang, Y. Exp. Neurol. (2006) [Pubmed]
  28. Neuronal cyclin-dependent kinase 5: role in nervous system function and its specific inhibition by the Cdk5 inhibitory peptide. Kesavapany, S., Li, B.S., Amin, N., Zheng, Y.L., Grant, P., Pant, H.C. Biochim. Biophys. Acta (2004) [Pubmed]
  29. Increase of cdk5 is related to neurofibrillary pathology in progressive supranuclear palsy. Borghi, R., Giliberto, L., Assini, A., Delacourte, A., Perry, G., Smith, M.A., Strocchi, P., Zaccheo, D., Tabaton, M. Neurology (2002) [Pubmed]
  30. DARPP-32: an integrator of neurotransmission. Svenningsson, P., Nishi, A., Fisone, G., Girault, J.A., Nairn, A.C., Greengard, P. Annu. Rev. Pharmacol. Toxicol. (2004) [Pubmed]
  31. Amphiphysin 1 binds the cyclin-dependent kinase (cdk) 5 regulatory subunit p35 and is phosphorylated by cdk5 and cdc2. Floyd, S.R., Porro, E.B., Slepnev, V.I., Ochoa, G.C., Tsai, L.H., De Camilli, P. J. Biol. Chem. (2001) [Pubmed]
  32. CDK-5-mediated neurofilament phosphorylation in SHSY5Y human neuroblastoma cells. Sharma, M., Sharma, P., Pant, H.C. J. Neurochem. (1999) [Pubmed]
  33. p35nck5a and cyclin-dependent kinase 5 colocalize in Lewy bodies of brains with Parkinson's disease. Nakamura, S., Kawamoto, Y., Nakano, S., Akiguchi, I., Kimura, J. Acta Neuropathol. (1997) [Pubmed]
  34. Cdk5/p35 and Rho-kinase mediate ephrin-A5-induced signaling in retinal ganglion cells. Cheng, Q., Sasaki, Y., Shoji, M., Sugiyama, Y., Tanaka, H., Nakayama, T., Mizuki, N., Nakamura, F., Takei, K., Goshima, Y. Mol. Cell. Neurosci. (2003) [Pubmed]
  35. Cyclin-dependent kinase-5 prevents neuronal apoptosis through ERK-mediated upregulation of Bcl-2. Wang, C.X., Song, J.H., Song, D.K., Yong, V.W., Shuaib, A., Hao, C. Cell Death Differ. (2006) [Pubmed]
  36. Cdk5 Regulates STAT3 Activation and Cell Proliferation in Medullary Thyroid Carcinoma Cells. Lin, H., Chen, M.C., Chiu, C.Y., Song, Y.M., Lin, S.Y. J. Biol. Chem. (2007) [Pubmed]
  37. ATP-site directed inhibitors of cyclin-dependent kinases. Gray, N., Détivaud, L., Doerig, C., Meijer, L. Current medicinal chemistry. (1999) [Pubmed]
  38. Inhibition of neuronal apoptosis by the cyclin-dependent kinase inhibitor GW8510: identification of 3' substituted indolones as a scaffold for the development of neuroprotective drugs. Johnson, K., Liu, L., Majdzadeh, N., Chavez, C., Chin, P.C., Morrison, B., Wang, L., Park, J., Chugh, P., Chen, H.M., D'Mello, S.R. J. Neurochem. (2005) [Pubmed]
  39. Cdk5 and munc-18/p67 co-localization in early stage neurofibrillary tangles-bearing neurons in Alzheimer type dementia brains. Takahashi, M., Iseki, E., Kosaka, K. J. Neurol. Sci. (2000) [Pubmed]
  40. Involvement of cyclin-dependent kinases in axotomy-induced retinal ganglion cell death. Lefèvre, K., Clarke, P.G., Danthe, E.E., Castagné, V. J. Comp. Neurol. (2002) [Pubmed]
  41. Cdk5 regulates the organization of Nestin and its association with p35. Sahlgren, C.M., Mikhailov, A., Vaittinen, S., Pallari, H.M., Kalimo, H., Pant, H.C., Eriksson, J.E. Mol. Cell. Biol. (2003) [Pubmed]
  42. Involvement of cyclin D1-cdk5 overexpression and MCM3 cleavage in bax-associated spontaneous apoptosis and differentiation in an A253 human head and neck carcinoma xenograft model. Yin, M.B., Tóth, K., Cao, S., Guo, B., Frank, C., Slocum, H.K., Rustum, Y.M. Int. J. Cancer (1999) [Pubmed]
  43. Structure, function, and regulation of neuronal Cdc2-like protein kinase. Lew, J., Qi, Z., Huang, Q.Q., Paudel, H., Matsuura, I., Matsushita, M., Zhu, X., Wang, J.H. Neurobiol. Aging (1995) [Pubmed]
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