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Cyclin-dependent kinase 5

Definition:

Proline-directed serine/threonine-protein kinase essential for neuronal cell cycle arrest and differentiation and may be involved in apoptotic cell death in neuronal diseases by triggering abortive cell cycle re-entry. Interacts with D1 and D3-type G1 cyclins. Phosphorylates SRC, NOS3, VIM/vimentin, p35/CDK5R1, MEF2A, SIPA1L1, SH3GLB1, PXN, PAK1, MCAM/MUC18, SEPT5, SYN1, DNM1, AMPH, SYNJ1, CDK16, RAC1, RHOA, CDC42, TONEBP/NFAT5, MAPT/TAU, MAP1B, histone H1, p53/TP53, HDAC1, APEX1, PTK2/FAK1, huntingtin/HTT, ATM, MAP2, NEFH and NEFM. Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission, by phosphorylating key proteins. Negatively regulates the CACNA1B/CAV2.2 -mediated Ca(2+) release probability at hippocampal neuronal soma and synaptic terminals (By similarity). Activated by interaction with CDK5R1 (p35) and CDK5R2 (p39), especially in postmitotic neurons, and promotes CDK5R1 (p35) expression in an autostimulation loop. Phosphorylates many downstream substrates such as Rho and Ras family small GTPases (e.g. PAK1, RAC1, RHOA, CDC42) or microtubule-binding proteins (e.g. MAPT/TAU, MAP2, MAP1B), and modulates actin dynamics to regulate neurite growth and/or spine morphogenesis. Phosphorylates also exocytosis associated proteins such as MCAM/MUC18, SEPT5, SYN1, and CDK16/PCTAIRE1 as well as endocytosis associated proteins such as DNM1, AMPH and SYNJ1 at synaptic terminals. In the mature central nervous system (CNS), regulates neurotransmitter movements by phosphorylating substrates associated with neurotransmitter release and synapse plasticity; synaptic vesicle exocytosis, vesicles fusion with the presynaptic membrane, and endocytosis. Promotes cell survival by activating anti-apoptotic proteins BCL2 and STAT3, and negatively regulating of JNK3/MAPK10 activity. Phosphorylation of p53/TP53 in response to genotoxic and oxidative stresses enhances its stabilization by preventing ubiquitin ligase-mediated proteasomal degradation, and induces transactivation of p53/TP53 target genes, thus regulating apoptosis. Phosphorylation of p35/CDK5R1 enhances its stabilization by preventing calpain-mediated proteolysis producing p25/CDK5R1 and avoiding ubiquitin ligase-mediated proteasomal degradation. During aberrant cell-cycle activity and DNA damage, p25/CDK5 activity elicits cell-cycle activity and double-strand DNA breaks that precedes neuronal death by deregulating HDAC1. DNA damage triggered phosphorylation of huntingtin/HTT in nuclei of neurons protects neurons against polyglutamine expansion as well as DNA damage mediated toxicity. Phosphorylation of PXN reduces its interaction with PTK2/FAK1 in matrix-cell focal adhesions (MCFA) during oligodendrocytes (OLs) differentiation. Negative regulator of Wnt/beta-catenin signaling pathway. Activator of the GAIT (IFN-gamma-activated inhibitor of translation) pathway, which suppresses expression of a post-transcriptional regulon of proinflammatory genes in myeloid cells; phosphorylates the linker domain of glutamyl-prolyl tRNA synthetase (EPRS) in a IFN-gamma-dependent manner, the initial event in assembly of the GAIT complex. Phosphorylation of SH3GLB1 is required for autophagy induction in starved neurons. Phosphorylation of TONEBP/NFAT5 in response to osmotic stress mediates its rapid nuclear localization. MEF2 is inactivated by phosphorylation in nucleus in response to neurotoxin, thus leading to neuronal apoptosis. APEX1 AP-endodeoxyribonuclease is repressed by phosphorylation, resulting in accumulation of DNA damage and contributing to neuronal death. NOS3 phosphorylation down regulates NOS3-derived nitrite (NO) levels. SRC phosphorylation mediates its ubiquitin-dependent degradation and thus leads to cytoskeletal reorganization. May regulate endothelial cell migration and angiogenesis via the modulation of lamellipodia formation. Involved in dendritic spine morphogenesis by mediating the EFNA1-EPHA4 signaling. The complex p35/CDK5 participates in the regulation of the circadian clock by modulating the function of CLOCK protein: phosphorylates CLOCK at 'Thr-451' and 'Thr-461' and regulates the transcriptional activity of the CLOCK-BMAL1 heterodimer in association with altered stability and subcellular distribution.

References:

[1]. Vassiliki Lalioti, et al. Cdk5, the multifunctional surveyor. Cell Cycle. 2010 Jan 15;9(2):284-311. [Content Brief]

[2]. Dohoon Kim, et al. Deregulation of HDAC1 by p25/Cdk5 in neurotoxicity. Neuron. 2008 Dec 10;60(5):803-17. [Content Brief]

[3]. Chien-Hsing Lee, et al. CDK5 phosphorylates eNOS at Ser-113 and regulates NO production. J Cell Biochem. 2010 May;110(1):112-7. [Content Brief]

[4]. Juan P Muñoz, et al. cdk5 modulates beta- and delta-catenin/Pin1 interactions in neuronal cells. J Cell Biochem. 2007 Feb 15;100(3):738-49. [Content Brief]

[5]. Johanna Liebl, et al. Cyclin-dependent kinase 5 regulates endothelial cell migration and angiogenesis. J Biol Chem. 2010 Nov 12;285(46):35932-43. [Content Brief]

[6]. Q Pan, et al. Cdk5 targets active Src for ubiquitin-dependent degradation by phosphorylating Src(S75). Cell Mol Life Sci. 2011 Oct;68(20):3425-36. [Content Brief]

[7]. Ki-Young Lee, et al. Cdk5 mediates vimentin Ser56 phosphorylation during GTP-induced secretion by neutrophils. J Cell Physiol. 2012 Feb;227(2):739-50. [Content Brief]

[8]. Jong-Hee Lee, et al. Stabilization and activation of p53 induced by Cdk5 contributes to neuronal cell death. J Cell Sci. 2007 Jul 1;120(Pt 13):2259-71. [Content Brief]

[9]. Ko Sato, et al. Regulation of membrane association and kinase activity of Cdk5-p35 by phosphorylation of p35. J Neurosci Res. 2007 Nov 1;85(14):3071-8. [Content Brief]

[10]. Qiang Li, et al. Characterization of a novel human CDK5 splicing variant that inhibits Wnt/beta-catenin signaling. Mol Biol Rep. 2010 Jun;37(5):2415-21. [Content Brief]

[11]. Ying-Shan Zhu, et al. Activation of latent cyclin-dependent kinase 5 (Cdk5)-p35 complexes by membrane dissociation. J Neurochem. 2005 Sep;94(6):1535-45. [Content Brief]

[12]. Yongdo Kwak, et al. Cyclin-dependent kinase 5 (Cdk5) regulates the function of CLOCK protein by direct phosphorylation. J Biol Chem. 2013 Dec 27;288(52):36878-89. [Content Brief]

[13]. G Paglini, et al. Evidence for the participation of the neuron-specific CDK5 activator P35 during laminin-enhanced axonal growth. J Neurosci. 1998 Dec 1;18(23):9858-69. [Content Brief]

[14]. Xiaoming Gong, et al. Cdk5-mediated inhibition of the protective effects of transcription factor MEF2 in neurotoxicity-induced apoptosis. Neuron. 2003 Apr 10;38(1):33-46. [Content Brief]

[15]. Hirotsugu Kamei, et al. Suppression of calpain-dependent cleavage of the CDK5 activator p35 to p25 by site-specific phosphorylation. J Biol Chem. 2007 Jan 19;282(3):1687-94. [Content Brief]

[16]. Alan S L Wong, et al. Cdk5-mediated phosphorylation of endophilin B1 is required for induced autophagy in models of Parkinson's disease. Nat Cell Biol. 2011 May;13(5):568-79. [Content Brief]

[17]. Yuki Miyamoto, et al. Cdk5 regulates differentiation of oligodendrocyte precursor cells through the direct phosphorylation of paxillin. J Cell Sci. 2007 Dec 15;120(Pt 24):4355-66. [Content Brief]

[18]. Petri Kerokoski, et al. Influence of phosphorylation of p35, an activator of cyclin-dependent kinase 5 (cdk5), on the proteolysis of p35. Brain Res Mol Brain Res. 2002 Oct 15;106(1-2):50-6. [Content Brief]

[19]. Abul Arif, et al. Phosphorylation of glutamyl-prolyl tRNA synthetase by cyclin-dependent kinase 5 dictates transcript-selective translational control. Proc Natl Acad Sci U S A. 2011 Jan 25;108(4):1415-20. [Content Brief]

[20]. Sandrine L Anne, et al. Phosphorylation of huntingtin by cyclin-dependent kinase 5 is induced by DNA damage and regulates wild-type and mutant huntingtin toxicity in neurons. J Neurosci. 2007 Jul 4;27(27):7318-28. [Content Brief]

[21]. Morgan Gallazzini, et al. High NaCl-induced activation of CDK5 increases phosphorylation of the osmoprotective transcription factor TonEBP/OREBP at threonine 135, which contributes to its rapid nuclear localization. Mol Biol Cell. 2011 Mar 1;22(5):703-14. [Content Brief]

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