| Structural highlights
Function
[CDK5_HUMAN] 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. Activated by interaction with CDK5R1 (p35) and ATP6V0D1 (p39), especially in post-mitotic 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.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [CD5R1_HUMAN] p35 is a neuron specific activator of CDK5. The complex p35/CDK5 is required for neurite outgrowth and cortical lamination. Involved in dendritic spine morphogenesis by mediating the EFNA1-EPHA4 signaling. Activator of TPKII.
Publication Abstract from PubMed
Cyclin-dependent kinase 5 (Cdk5) is widely viewed as a possible target for a wide variety of neurological disorders. One pathological role attributed to Cdk5 is the abnormal phosphorylation of tau that may lead to the neuronal inclusions known as neurofibrillary tangles. A high through-put screen for inhibitors of Cdk5-mediated phosphorylation of tau resulted in three compounds with distinct mechanisms of action. One compound is competitive with ATP and has a high affinity for the Cdk5 ATP binding pocket. The second compound also competes with ATP, is noncompetitive with tau, and (uniquely among this class of inhibitors) displaces adjacent amino acid residues to make room for the nitrophenyl group. A third compound did not compete with ATP, but did compete with tau at low concentrations of tau. The SAR and charge optimization derived from cocrystals of the two ATP competitors along with cocrystals of three other ATP competitors map out the importance of filling and properly charging different regions of the ATP binding pocket. Taken together, this analysis shows how the structure of Cdk5 constrains the space of potential inhibitors and reveals a pocket unfilled in all of the structures. These leads could be a starting point for structure-based drug design of more potent and selective inhibitors.
Defining Cdk5 ligand chemical space with small molecule inhibitors of tau phosphorylation.,Ahn JS, Radhakrishnan ML, Mapelli M, Choi S, Tidor B, Cuny GD, Musacchio A, Yeh LA, Kosik KS Chem Biol. 2005 Jul;12(7):811-23. PMID:16039528[20]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Li Q, Liu X, Zhang M, Ye G, Qiao Q, Ling Y, Wu Y, Zhang Y, Yu L. Characterization of a novel human CDK5 splicing variant that inhibits Wnt/beta-catenin signaling. Mol Biol Rep. 2010 Jun;37(5):2415-21. doi: 10.1007/s11033-009-9752-7. Epub 2009, Aug 20. PMID:19693690 doi:10.1007/s11033-009-9752-7
- ↑ Paglini G, Pigino G, Kunda P, Morfini G, Maccioni R, Quiroga S, Ferreira A, Caceres A. 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. PMID:9822744
- ↑ Kerokoski P, Suuronen T, Salminen A, Soininen H, Pirttila T. 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. PMID:12393264
- ↑ Gong X, Tang X, Wiedmann M, Wang X, Peng J, Zheng D, Blair LA, Marshall J, Mao Z. Cdk5-mediated inhibition of the protective effects of transcription factor MEF2 in neurotoxicity-induced apoptosis. Neuron. 2003 Apr 10;38(1):33-46. PMID:12691662
- ↑ Zhu YS, Saito T, Asada A, Maekawa S, Hisanaga S. Activation of latent cyclin-dependent kinase 5 (Cdk5)-p35 complexes by membrane dissociation. J Neurochem. 2005 Sep;94(6):1535-45. Epub 2005 Jun 30. PMID:15992363 doi:10.1111/j.1471-4159.2005.03301.x
- ↑ Kamei H, Saito T, Ozawa M, Fujita Y, Asada A, Bibb JA, Saido TC, Sorimachi H, Hisanaga S. 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. Epub 2006 Nov 22. PMID:17121855 doi:10.1074/jbc.M610541200
- ↑ Munoz JP, Huichalaf CH, Orellana D, Maccioni RB. cdk5 modulates beta- and delta-catenin/Pin1 interactions in neuronal cells. J Cell Biochem. 2007 Feb 15;100(3):738-49. PMID:17009320 doi:10.1002/jcb.21041
- ↑ Lee JH, Kim HS, Lee SJ, Kim KT. Stabilization and activation of p53 induced by Cdk5 contributes to neuronal cell death. J Cell Sci. 2007 Jul 1;120(Pt 13):2259-71. PMID:17591690 doi:10.1242/jcs.03468
- ↑ Miyamoto Y, Yamauchi J, Chan JR, Okada A, Tomooka Y, Hisanaga S, Tanoue A. Cdk5 regulates differentiation of oligodendrocyte precursor cells through the direct phosphorylation of paxillin. J Cell Sci. 2007 Dec 15;120(Pt 24):4355-66. Epub 2007 Nov 27. PMID:18042622 doi:10.1242/jcs.018218
- ↑ Anne SL, Saudou F, Humbert S. 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. PMID:17611284 doi:10.1523/JNEUROSCI.1831-07.2007
- ↑ Sato K, Zhu YS, Saito T, Yotsumoto K, Asada A, Hasegawa M, Hisanaga S. Regulation of membrane association and kinase activity of Cdk5-p35 by phosphorylation of p35. J Neurosci Res. 2007 Nov 1;85(14):3071-8. PMID:17671990 doi:10.1002/jnr.21438
- ↑ Kim D, Frank CL, Dobbin MM, Tsunemoto RK, Tu W, Peng PL, Guan JS, Lee BH, Moy LY, Giusti P, Broodie N, Mazitschek R, Delalle I, Haggarty SJ, Neve RL, Lu Y, Tsai LH. Deregulation of HDAC1 by p25/Cdk5 in neurotoxicity. Neuron. 2008 Dec 10;60(5):803-17. doi: 10.1016/j.neuron.2008.10.015. PMID:19081376 doi:10.1016/j.neuron.2008.10.015
- ↑ Liebl J, Weitensteiner SB, Vereb G, Takacs L, Furst R, Vollmar AM, Zahler S. Cyclin-dependent kinase 5 regulates endothelial cell migration and angiogenesis. J Biol Chem. 2010 Nov 12;285(46):35932-43. doi: 10.1074/jbc.M110.126177. Epub, 2010 Sep 7. PMID:20826806 doi:10.1074/jbc.M110.126177
- ↑ Lee CH, Wei YW, Huang YT, Lin YT, Lee YC, Lee KH, Lu PJ. CDK5 phosphorylates eNOS at Ser-113 and regulates NO production. J Cell Biochem. 2010 May;110(1):112-7. doi: 10.1002/jcb.22515. PMID:20213743 doi:10.1002/jcb.22515
- ↑ Pan Q, Qiao F, Gao C, Norman B, Optican L, Zelenka PS. Cdk5 targets active Src for ubiquitin-dependent degradation by phosphorylating Src(S75). Cell Mol Life Sci. 2011 Oct;68(20):3425-36. doi: 10.1007/s00018-011-0638-1. Epub , 2011 Mar 27. PMID:21442427 doi:10.1007/s00018-011-0638-1
- ↑ Lee KY, Liu L, Jin Y, Fu SB, Rosales JL. Cdk5 mediates vimentin Ser56 phosphorylation during GTP-induced secretion by neutrophils. J Cell Physiol. 2012 Feb;227(2):739-50. doi: 10.1002/jcp.22782. PMID:21465480 doi:10.1002/jcp.22782
- ↑ Gallazzini M, Heussler GE, Kunin M, Izumi Y, Burg MB, Ferraris JD. 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. doi: 10.1091/mbc.E10-08-0681. Epub 2011, Jan 5. PMID:21209322 doi:10.1091/mbc.E10-08-0681
- ↑ Wong AS, Lee RH, Cheung AY, Yeung PK, Chung SK, Cheung ZH, Ip NY. 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. doi: 10.1038/ncb2217. Epub 2011 Apr 17. PMID:21499257 doi:10.1038/ncb2217
- ↑ Arif A, Jia J, Moodt RA, DiCorleto PE, Fox PL. 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. doi:, 10.1073/pnas.1011275108. Epub 2011 Jan 10. PMID:21220307 doi:10.1073/pnas.1011275108
- ↑ Ahn JS, Radhakrishnan ML, Mapelli M, Choi S, Tidor B, Cuny GD, Musacchio A, Yeh LA, Kosik KS. Defining Cdk5 ligand chemical space with small molecule inhibitors of tau phosphorylation. Chem Biol. 2005 Jul;12(7):811-23. PMID:16039528 doi:10.1016/j.chembiol.2005.05.011
|
