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Gene Review

Cdk5  -  cyclin-dependent kinase 5

Mus musculus

Synonyms: AW048668, CR6 protein kinase, CRK6, Cdkn5, Cell division protein kinase 5, ...
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Disease relevance of Cdk5


Psychiatry related information on Cdk5

  • These results further support the view that Cdk5 and its regulation may be key players in the execution of cell death regardless of how the cell dies, whether through biological mechanisms, disease states such as Alzheimer's disease, or induction by CP [5].
  • Mice deficient in Cdk5, p35, or both p35 and p39 display the hallmarks of disturbed cortical development, including cortical layer inversion, neuronal disorientation, and abnormal fiber infiltration [6].

High impact information on Cdk5

  • Serine 732 phosphorylation of FAK by Cdk5 is important for microtubule organization, nuclear movement, and neuronal migration [7].
  • The serine/threonine kinase Cdk5 plays an essential role in neuronal positioning during corticogenesis, but the underlying mechanisms are unknown [7].
  • Taken together, these results suggest that Cdk5 phosphorylation of FAK is critical for neuronal migration through regulation of a microtubule fork important for nuclear translocation [7].
  • The inhibitory regulation by Cdk5 on the L-VDCC was attributed to the phosphorylation of loop II-III of the alpha(1C) subunit of L-VDCC at Ser783, which prevented the binding to SNARE proteins and subsequently resulted in a decrease of the activity of L-VDCC [8].
  • Cdk5-dependent regulation of glucose-stimulated insulin secretion [8].

Chemical compound and disease context of Cdk5

  • These findings, together with the known ability of CDK5 inhibitors to prevent degeneration of dopaminergic neurons, suggest that this class of compounds could potentially be used as a novel treatment for disorders associated with dopamine deficiency, such as Parkinson's disease [9].

Biological context of Cdk5

  • Cdk5 phosphorylation of doublecortin ser297 regulates its effect on neuronal migration [10].
  • Hence, our data both characterize the functional significance of the cell cycle Cdk4 and neuronal Cdk5 signals as well as define the pathways and circumstances by which they act to control ischemic/hypoxic damage [1].
  • Severe neuronal migration defects in p35-/-Cdk5 +/- mice further support the idea that the redundant expression of the Cdk5 activators may cause a milder phenotype in p35-/- mice compared with Cdk5-/- mice [11].
  • These results support the idea that Cdk5 activity is involved in altered gene expression after chronic exposure to cocaine and hence impacts the long-lasting changes in neuronal function underlying cocaine addiction [12].
  • Our results suggest a role for Cdk5 and its regulatory proteins during CP induced cell death [5].

Anatomical context of Cdk5

  • These results suggest that Dcx phosphorylation by Cdk5 regulates its actions on migration through an effect on microtubules [10].
  • Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles [13].
  • Moreover, we unexpectedly discovered that the agrin-induced formation of large AChR clusters is significantly increased in primary muscle cultures prepared from Cdk5-null mice and in C2C12 myotubes when Cdk5 activity was suppressed [14].
  • To further elucidate whether Cdk5 activity contributes to neuromuscular junction (NMJ) development in vivo, the NMJ of Cdk5-/- mice was examined [14].
  • The central band of acetylcholine receptor (AChR) clusters is also wider in Cdk5-/- diaphragms, together with the absence of S100 immunoreactivity along the phrenic nerve during late embryonic stages [14].

Associations of Cdk5 with chemical compounds

  • We report here that increased Cdk5 activity, as a result of p35 but not of Cdk5 overexpression, leads to attenuation of cocaine-mediated dopamine signaling [12].
  • We report here that cyclophosphamide (CP) induces massive apoptotic cell death in mouse embryos and that Cdk5 is expressed in apoptotic cells displaying fragmented DNA [5].
  • The potent Cdk5 inhibitor, roscovitine, completely blocks GTP-stimulated granule Cdk5 activity, which accompanies lactoferrin secretion from neutrophil-specific granules [15].
  • Inhibition of Cdk5 with olomoucine decreased evoked norepinephrine secretion from chromaffin cells, an effect not observed with the inactive analogue iso-olomoucine [16].
  • Finally, the association of apoptosis and Cdk5 expression and associated kinase activity was examined in the limb and in an induced cell death system, that of androgen withdrawal-induced regression of the prostate gland in male mice [17].

Physical interactions of Cdk5

  • We report here that the Cdk5/p35 complex associates with STAT3 and phosphorylates STAT3 on the Ser-727 residue in vitro and in vivo [18].

Enzymatic interactions of Cdk5

  • The ability of Cdk5 to phosphorylate tau was higher when in association with p39 than in association with p35 [19].
  • We have now demonstrated that Cdk5 is capable of phosphorylating Munc18a in vitro within a preformed Munc18a.syntaxin 1a heterodimer complex and that this results in the disassembly of the complex [16].
  • Recently, we found that Cdk5 phosphorylates focal adhesion kinase (FAK) at Serine 732 in vitro and is responsible for this phosphorylation in the developing brain [20].
  • The active Cdk7-containing enzyme also phosphorylates and activates wt Cdk5 but not mutated Cdk5(Ser159Ala) [21].
  • Cdk5 purified from nervous tissue phosphorylates neuronal cytoskeletal proteins including neurofilament proteins and microtubule-associated protein tau in vitro [22].

Regulatory relationships of Cdk5

  • Cdk5 inhibits anterograde axonal transport of neurofilaments but not that of tau by inhibition of mitogen-activated protein kinase activity [23].
  • Conversely, blocked Cdk7 immunoprecipitate does not phosphorylate nor activate Cdk5 [21].
  • We report here that glutamate, acting via NMDA or kainate receptors, can induce a transient Ca(2+)/calmodulin-dependent activation of Cdk5 that results in enhanced autophosphorylation and proteasome-dependent degradation of a Cdk5 activator p35, and thus ultimately down-regulation of Cdk5 activity [24].
  • Previous studies of Abeta-induced neuronal damage of hippocampal cells in culture have provided strong evidence that deregulation of the Cdk5/p35 kinase system is involved in the neurodegeneration pathway [25].
  • For example, immunocytochemistry of embryonic day 16 (E16) cortex reveals that the expression of microtubule-associated protein 2c (Map-2c), a marker of mature neurons, is nearly absent in Cdk5(-/-) cells that have migrated to the cortical plate while these same cells continue to express nestin [26].

Other interactions of Cdk5


Analytical, diagnostic and therapeutic context of Cdk5


  1. Multiple cyclin-dependent kinases signals are critical mediators of ischemia/hypoxic neuronal death in vitro and in vivo. Rashidian, J., Iyirhiaro, G., Aleyasin, H., Rios, M., Vincent, I., Callaghan, S., Bland, R.J., Slack, R.S., During, M.J., Park, D.S. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  2. Cdk5 is involved in NFT-like tauopathy induced by transient cerebral ischemia in female rats. Wen, Y., Yang, S.H., Liu, R., Perez, E.J., Brun-Zinkernagel, A.M., Koulen, P., Simpkins, J.W. Biochim. Biophys. Acta (2007) [Pubmed]
  3. Opposing roles of transient and prolonged expression of p25 in synaptic plasticity and hippocampus-dependent memory. Fischer, A., Sananbenesi, F., Pang, P.T., Lu, B., Tsai, L.H. Neuron (2005) [Pubmed]
  4. Deregulation of Cdk5 in a mouse model of ALS: toxicity alleviated by perikaryal neurofilament inclusions. Nguyen, M.D., Larivière, R.C., Julien, J.P. Neuron (2001) [Pubmed]
  5. Cyclin dependent kinase 5 and its interacting proteins in cell death induced in vivo by cyclophosphamide in developing mouse embryos. Zhu, Y., Lin, L., Kim, S., Quaglino, D., Lockshin, R.A., Zakeri, Z. Cell Death Differ. (2002) [Pubmed]
  6. Control of cortical neuron migration and layering: cell and non cell-autonomous effects of p35. Hammond, V., Tsai, L.H., Tan, S.S. J. Neurosci. (2004) [Pubmed]
  7. Serine 732 phosphorylation of FAK by Cdk5 is important for microtubule organization, nuclear movement, and neuronal migration. Xie, Z., Sanada, K., Samuels, B.A., Shih, H., Tsai, L.H. Cell (2003) [Pubmed]
  8. Cdk5-dependent regulation of glucose-stimulated insulin secretion. Wei, F.Y., Nagashima, K., Ohshima, T., Saheki, Y., Lu, Y.F., Matsushita, M., Yamada, Y., Mikoshiba, K., Seino, Y., Matsui, H., Tomizawa, K. Nat. Med. (2005) [Pubmed]
  9. Cyclin-dependent kinase 5 regulates dopaminergic and glutamatergic transmission in the striatum. Chergui, K., Svenningsson, P., Greengard, P. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  10. Cdk5 phosphorylation of doublecortin ser297 regulates its effect on neuronal migration. Tanaka, T., Serneo, F.F., Tseng, H.C., Kulkarni, A.B., Tsai, L.H., Gleeson, J.G. Neuron (2004) [Pubmed]
  11. Synergistic contributions of cyclin-dependant kinase 5/p35 and Reelin/Dab1 to the positioning of cortical neurons in the developing mouse brain. Ohshima, T., Ogawa, M., Veeranna, n.u.l.l., Hirasawa, M., Longenecker, G., Ishiguro, K., Pant, H.C., Brady, R.O., Kulkarni, A.B., Mikoshiba, K. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  12. Increased activity of cyclin-dependent kinase 5 leads to attenuation of cocaine-mediated dopamine signaling. Takahashi, S., Ohshima, T., Cho, A., Sreenath, T., Iadarola, M.J., Pant, H.C., Kim, Y., Nairn, A.C., Brady, R.O., Greengard, P., Kulkarni, A.B. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  13. Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles. Cruz, J.C., Tseng, H.C., Goldman, J.A., Shih, H., Tsai, L.H. Neuron (2003) [Pubmed]
  14. Aberrant motor axon projection, acetylcholine receptor clustering, and neurotransmission in cyclin-dependent kinase 5 null mice. Fu, A.K., Ip, F.C., Fu, W.Y., Cheung, J., Wang, J.H., Yung, W.H., Ip, N.Y. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  15. GTP-dependent secretion from neutrophils is regulated by Cdk5. Rosales, J.L., Ernst, J.D., Hallows, J., Lee, K.Y. J. Biol. Chem. (2004) [Pubmed]
  16. Regulation of exocytosis by cyclin-dependent kinase 5 via phosphorylation of Munc18. Fletcher, A.I., Shuang, R., Giovannucci, D.R., Zhang, L., Bittner, M.A., Stuenkel, E.L. J. Biol. Chem. (1999) [Pubmed]
  17. Cyclin-dependent kinase 5 is associated with apoptotic cell death during development and tissue remodeling. Zhang, Q., Ahuja, H.S., Zakeri, Z.F., Wolgemuth, D.J. Dev. Biol. (1997) [Pubmed]
  18. Cyclin-dependent kinase 5 phosphorylates signal transducer and activator of transcription 3 and regulates its transcriptional activity. Fu, A.K., Fu, W.Y., Ng, A.K., Chien, W.W., Ng, Y.P., Wang, J.H., Ip, N.Y. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  19. Tau phosphorylation by cyclin-dependent kinase 5/p39 during brain development reduces its affinity for microtubules. Takahashi, S., Saito, T., Hisanaga, S., Pant, H.C., Kulkarni, A.B. J. Biol. Chem. (2003) [Pubmed]
  20. Cdk5 phosphorylation of FAK regulates centrosome-associated miocrotubules and neuronal migration. Xie, Z., Tsai, L.H. Cell Cycle (2004) [Pubmed]
  21. Cdk7 functions as a cdk5 activating kinase in brain. Rosales, J., Han, B., Lee, K.Y. Cell. Physiol. Biochem. (2003) [Pubmed]
  22. Targeted disruption of the cyclin-dependent kinase 5 gene results in abnormal corticogenesis, neuronal pathology and perinatal death. Ohshima, T., Ward, J.M., Huh, C.G., Longenecker, G., Veeranna, n.u.l.l., Pant, H.C., Brady, R.O., Martin, L.J., Kulkarni, A.B. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  23. Cdk5 inhibits anterograde axonal transport of neurofilaments but not that of tau by inhibition of mitogen-activated protein kinase activity. Moran, C.M., Donnelly, M., Ortiz, D., Pant, H.C., Mandelkow, E.M., Shea, T.B. Brain Res. Mol. Brain Res. (2005) [Pubmed]
  24. Control of cyclin-dependent kinase 5 (Cdk5) activity by glutamatergic regulation of p35 stability. Wei, F.Y., Tomizawa, K., Ohshima, T., Asada, A., Saito, T., Nguyen, C., Bibb, J.A., Ishiguro, K., Kulkarni, A.B., Pant, H.C., Mikoshiba, K., Matsui, H., Hisanaga, S. J. Neurochem. (2005) [Pubmed]
  25. AbetaPP induces cdk5-dependent tau hyperphosphorylation in transgenic mice Tg2576. Otth, C., Concha, I.I., Arendt, T., Stieler, J., Schliebs, R., González-Billault, C., Maccioni, R.B. J. Alzheimers Dis. (2002) [Pubmed]
  26. Cyclin-dependent kinase 5 is essential for neuronal cell cycle arrest and differentiation. Cicero, S., Herrup, K. J. Neurosci. (2005) [Pubmed]
  27. Involvement of cyclin dependent kinase 5 and its activator p35 in staurosporine-induced apoptosis of cortical neurons. Zhang, B.F., Peng, F.F., Zhang, W., Shen, H., Wu, S.B., Wu, D.C. Acta Pharmacol. Sin. (2004) [Pubmed]
  28. The brain-specific activator p35 allows Cdk5 to escape inhibition by p27Kip1 in neurons. Lee, M.H., Nikolic, M., Baptista, C.A., Lai, E., Tsai, L.H., Massagué, J. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  29. Regulation of contextual fear conditioning by baseline and inducible septo-hippocampal cyclin-dependent kinase 5. Fischer, A., Sananbenesi, F., Schrick, C., Spiess, J., Radulovic, J. Neuropharmacology (2003) [Pubmed]
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