Cell division protein kinase 5 is an enzyme that in humans is encoded by the CDK5gene.[1][2] The protein encoded by this gene is part of the cyclin-dependent kinase family.
Recently Cdk5 has emerged as an essential kinase in sensory pathways. Recent reports of Pareek et al. suggest its necessity in pain signaling. CDK5 is required for proper development of the brain and to be activated, CDK5 must associate with CDK5R1 or CDK5R2.[3][4] Unlike other cyclin dependent kinases, CDK5 does not also require phosphorylation on the T loop so that binding with the activator is sufficient to activate the kinase.[5]
Experiments performed on mice lacking p35 (CDK5R1), a necessary activator of cdk5 in early brain development, showed that the normal layering of neurons was reversed in the cortex. This disrupted lamination again implicated cdk5 in neuronal migration and plasticity.[8]
Blocking Cdk5 in mice helps them get over fear learned in a particular context. Conversely, the learned fear persisted when the enzyme's activity was increased in the hippocampus, the brain's centre for storing memories.[10]
Role in disease
Dysregulation of this enzyme has been implicated in several neurodegenerative diseases[11] including Alzheimer's.[12][13]
It is involved in invasive cancers, apparently by reducing the activity of the actin regulatory protein caldesmon.[14]
History
CDK5 was originally named NCLK (Neuronal CDC2-Like Kinase) due to its similar phosphorylation motif. CDK5 in combination with an activator was also referred to as Tau Protein Kinase II.[15] Furthermore, Cdk5 has been reported to be involved in T cell activation and play an important role in development of autoimmune disorders, such as multiple sclerosis.[16]
Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.[§ 1]
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↑Patrick GN, Zukerberg L, Nikolic M, de la Monte S, Dikkes P, Tsai LH (December 1999). "Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration". Nature. 402 (6762): 615–22. doi:10.1038/45159. PMID10604467.
↑Paglini G, Cáceres A (March 2001). "The role of the Cdk5--p35 kinase in neuronal development". European Journal of Biochemistry. 268 (6): 1528–33. doi:10.1046/j.1432-1327.2001.02023.x. PMID11248669.
↑ 5.05.1Tarricone C, Dhavan R, Peng J, Areces LB, Tsai LH, Musacchio A (September 2001). "Structure and regulation of the CDK5-p25(nck5a) complex". Molecular Cell. 8 (3): 657–69. doi:10.1016/S1097-2765(01)00343-4. PMID11583627.
↑Fletcher AI, Shuang R, Giovannucci DR, Zhang L, Bittner MA, Stuenkel EL (February 1999). "Regulation of exocytosis by cyclin-dependent kinase 5 via phosphorylation of Munc18". The Journal of Biological Chemistry. 274 (7): 4027–35. doi:10.1074/jbc.274.7.4027. PMID9933594.
↑Kobayashi S, Ishiguro K, Omori A, Takamatsu M, Arioka M, Imahori K, Uchida T (December 1993). "A cdc2-related kinase PSSALRE/cdk5 is homologous with the 30 kDa subunit of tau protein kinase II, a proline-directed protein kinase associated with microtubule". FEBS Letters. 335 (2): 171–5. doi:10.1016/0014-5793(93)80723-8. PMID8253190.
↑Kesavapany S, Lau KF, Ackerley S, Banner SJ, Shemilt SJ, Cooper JD, Leigh PN, Shaw CE, McLoughlin DM, Miller CC (June 2003). "Identification of a novel, membrane-associated neuronal kinase, cyclin-dependent kinase 5/p35-regulated kinase". The Journal of Neuroscience. 23 (12): 4975–83. PMID12832520.
↑Niethammer M, Smith DS, Ayala R, Peng J, Ko J, Lee MS, Morabito M, Tsai LH (December 2000). "NUDEL is a novel Cdk5 substrate that associates with LIS1 and cytoplasmic dynein". Neuron. 28 (3): 697–711. doi:10.1016/S0896-6273(00)00147-1. PMID11163260.
↑Chen F, Studzinski GP (June 2001). "Expression of the neuronal cyclin-dependent kinase 5 activator p35Nck5a in human monocytic cells is associated with differentiation". Blood. 97 (12): 3763–7. doi:10.1182/blood.V97.12.3763. PMID11389014.
↑Rashid T, Banerjee M, Nikolic M (December 2001). "Phosphorylation of Pak1 by the p35/Cdk5 kinase affects neuronal morphology". The Journal of Biological Chemistry. 276 (52): 49043–52. doi:10.1074/jbc.M105599200. PMID11604394.
Further reading
Morishima-Kawashima M, Hasegawa M, Takio K, Suzuki M, Yoshida H, Watanabe A, Titani K, Ihara Y (1995). "Hyperphosphorylation of tau in PHF". Neurobiology of Aging. 16 (3): 365–71, discussion 371-80. doi:10.1016/0197-4580(95)00027-C. PMID7566346.
Peruzzi F, Gordon J, Darbinian N, Amini S (December 2002). "Tat-induced deregulation of neuronal differentiation and survival by nerve growth factor pathway". Journal of Neurovirology. 8 Suppl 2 (2): 91–6. doi:10.1080/13550280290167885. PMID12491158.
