Cyclin-dependent kinase 5
Cell division protein kinase 5 is an enzyme that in humans is encoded by the CDK5 gene.[3][4] The protein encoded by this gene is part of the cyclin-dependent kinase family.
Physiological role
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.[5][6] 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.[7]
Cdk5 is involved in the processes of neuronal maturation[8] and migration, phosphorylating the key intracellular adaptor of the reelin signaling chain.[9]
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.[10]
Cdk5 is also involved in the regulation of synaptic vesicle exocytosis via phosphorylation of munc-18.[11]
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.[12]
Role in disease
Dysregulation of this enzyme has been implicated in several neurodegenerative diseases[13] including Alzheimer's.[14][15]
It is involved in invasive cancers, apparently by reducing the activity of the actin regulatory protein caldesmon.[16]
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.[17] 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.[18]
Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
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Nicotine Activity on Dopaminergic Neurons edit
- ↑ The interactive pathway map can be edited at WikiPathways: "NicotineDopaminergic_WP1602".
Interactions
Cyclin-dependent kinase 5 has been shown to interact with LMTK2,[19] NDEL1,[20] CDK5R1,[7][21] Nestin[22] and PAK1.[23]
References
- ↑ "Human PubMed Reference:".
- ↑ "Mouse PubMed Reference:".
- ↑ Demetrick DJ, Zhang H, Beach DH (February 1994). "Chromosomal mapping of human CDK2, CDK4, and CDK5 cell cycle kinase genes". Cytogenetics and Cell Genetics. 66 (1): 72–4. PMID 8275715. doi:10.1159/000133669.
- ↑ Meyerson M, Enders GH, Wu CL, Su LK, Gorka C, Nelson C, Harlow E, Tsai LH (August 1992). "A family of human cdc2-related protein kinases". The EMBO Journal. 11 (8): 2909–17. PMC 556772
. PMID 1639063. - ↑ 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. PMID 10604467. doi:10.1038/45159.
- ↑ Paglini G, Cáceres A (March 2001). "The role of the Cdk5--p35 kinase in neuronal development". European Journal of Biochemistry. 268 (6): 1528–33. PMID 11248669. doi:10.1046/j.1432-1327.2001.02023.x.
- 1 2 Tarricone 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. PMID 11583627. doi:10.1016/S1097-2765(01)00343-4.
- ↑ Jessberger S, Aigner S, Clemenson GD, Toni N, Lie DC, Karalay O, Overall R, Kempermann G, Gage FH (November 2008). Danzer S, ed. "Cdk5 regulates accurate maturation of newborn granule cells in the adult hippocampus". PLoS Biology. 6 (11): e272. PMC 2581629 . PMID 18998770. doi:10.1371/journal.pbio.0060272.
- ↑ Ohshima T, Suzuki H, Morimura T, Ogawa M, Mikoshiba K (April 2007). "Modulation of Reelin signaling by Cyclin-dependent kinase 5". Brain Research. 1140: 84–95. PMID 16529723. doi:10.1016/j.brainres.2006.01.121.
- ↑ Rakić S, Yanagawa Y, Obata K, Faux C, Parnavelas JG, Nikolić M (August 2009). "Cortical interneurons require p35/Cdk5 for their migration and laminar organization". Cerebral Cortex. 19 (8): 1857–69. PMC 2705696 . PMID 19037081. doi:10.1093/cercor/bhn213.
- ↑ 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. PMID 9933594. doi:10.1074/jbc.274.7.4027.
- ↑ Sananbenesi F, Fischer A, Wang X, Schrick C, Neve R, Radulovic J, Tsai LH (August 2007). "A hippocampal Cdk5 pathway regulates extinction of contextual fear". Nature Neuroscience. 10 (8): 1012–9. PMC 2441763 . PMID 17632506. doi:10.1038/nn1943. Lay summary – CBC.
- ↑ Dhavan R, Tsai LH (October 2001). "A decade of CDK5". Nature Reviews. Molecular Cell Biology. 2 (10): 749–59. PMID 11584302. doi:10.1038/35096019.
- ↑ Monaco EA (February 2004). "Recent evidence regarding a role for Cdk5 dysregulation in Alzheimer's disease". Current Alzheimer Research. 1 (1): 33–8. PMID 15975083. doi:10.2174/1567205043480519.
- ↑ Qu J, Nakamura T, Cao G, Holland EA, McKercher SR, Lipton SA (August 2011). "S-Nitrosylation activates Cdk5 and contributes to synaptic spine loss induced by beta-amyloid peptide". Proceedings of the National Academy of Sciences of the United States of America. 108 (34): 14330–5. PMC 3161554 . PMID 21844361. doi:10.1073/pnas.1105172108.
- ↑ Quintavalle M, Elia L, Price JH, Heynen-Genel S, Courtneidge SA (July 2011). "A cell-based high-content screening assay reveals activators and inhibitors of cancer cell invasion". Science Signaling. 4 (183): ra49. PMC 3291516 . PMID 21791703. doi:10.1126/scisignal.2002032.
- ↑ 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. PMID 8253190. doi:10.1016/0014-5793(93)80723-8.
- ↑ Pareek TK, Lam E, Zheng X, Askew D, Kulkarni AB, Chance MR, Huang AY, Cooke KR, Letterio JJ (October 2010). "Cyclin-dependent kinase 5 activity is required for T cell activation and induction of experimental autoimmune encephalomyelitis". The Journal of Experimental Medicine. 207 (11): 2507–19. PMC 2964575 . PMID 20937706. doi:10.1084/jem.20100876.
- ↑ 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. PMID 12832520.
- ↑ 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. PMID 11163260. doi:10.1016/S0896-6273(00)00147-1.
- ↑ 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. PMID 11389014. doi:10.1182/blood.V97.12.3763.
- ↑ Sahlgren CM, Mikhailov A, Vaittinen S, Pallari HM, Kalimo H, Pant HC, Eriksson JE (July 2003). "Cdk5 regulates the organization of Nestin and its association with p35". Molecular and Cellular Biology. 23 (14): 5090–106. PMC 162223 . PMID 12832492. doi:10.1128/MCB.23.14.5090-5106.2003.
- ↑ 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. PMID 11604394. doi:10.1074/jbc.M105599200.
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. PMID 7566346. doi:10.1016/0197-4580(95)00027-C.
- 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. PMID 12491158. doi:10.1080/13550280290167885.
External links
- Cyclin-Dependent Kinase 5 at the US National Library of Medicine Medical Subject Headings (MeSH)
- CDK5 human gene location in the UCSC Genome Browser.
- CDK5 human gene details in the UCSC Genome Browser.
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