UniProt Accession

 CDK5_HUMAN; Q00535; A1XKG3 

Genbank Protein ID

 X66364; DQ411039; AY049778; BT006680; AC010973; BC005115 

Genbank Nucleotide ID

 CAA47007.1; ABD66016.1; AAL15435.1; AAP35326.1; AAH05115.1 

Protein Name

 Cyclin-dependent kinase 5 

Protein Synonyms/Alias

 Cell division protein kinase 5; Serine/threonine-protein kinase PSSALRE; Tau protein kinase II catalytic subunit; TPKII catalytic subunit 

Gene Name

 CDK5 

Gene Synonyms/Alias

 CDKN5 

Created Date

 July 27, 2013 

Organism

 Homo sapiens (Human) 

NCBI Taxa ID

 9606 

Lysine Modification

Position	Peptide	Type	References
3	*****MQKYEKLEKI	ubiquitination	[1]
9	QKYEKLEKIGEGTYG	acetylation	[2]
9	QKYEKLEKIGEGTYG	ubiquitination	[1]
20	GTYGTVFKAKNRETH	ubiquitination	[1, 3]
33	THEIVALKRVRLDDD	ubiquitination	[1]
56	LREICLLKELKHKNI	acetylation	[2, 4, 5]
56	LREICLLKELKHKNI	ubiquitination	[1, 2, 3]
75	DVLHSDKKLTLVFEF	ubiquitination	[6]
88	EFCDQDLKKYFDSCN	ubiquitination	[6]
89	FCDQDLKKYFDSCNG	ubiquitination	[1]
128	NVLHRDLKPQNLLIN	ubiquitination	[1, 2, 3, 7]
141	INRNGELKLADFGLA	ubiquitination	[1, 2, 3]
232	EQWPSMTKLPDYKPY	ubiquitination	[1]
237	MTKLPDYKPYPMYPA	ubiquitination	[1, 6, 8]
254	SLVNVVPKLNATGRD	ubiquitination	[1]
268	DLLQNLLKCNPVQRI	ubiquitination	[1, 2, 3, 8, 9]

Reference

 [1] Refined preparation and use of anti-diglycine remnant (K-ε-GG) antibody enables routine quantification of 10,000s of ubiquitination sites in single proteomics experiments.
 Udeshi ND, Svinkina T, Mertins P, Kuhn E, Mani DR, Qiao JW, Carr SA.
 Mol Cell Proteomics. 2013 Mar;12(3):825-31. [PMID: 23266961]
 [2] Integrated proteomic analysis of post-translational modifications by serial enrichment.
 Mertins P, Qiao JW, Patel J, Udeshi ND, Clauser KR, Mani DR, Burgess MW, Gillette MA, Jaffe JD, Carr SA.
 Nat Methods. 2013 Jul;10(7):634-7. [PMID: 23749302]
 [3] Methods for quantification of in vivo changes in protein ubiquitination following proteasome and deubiquitinase inhibition.
 Udeshi ND, Mani DR, Eisenhaure T, Mertins P, Jaffe JD, Clauser KR, Hacohen N, Carr SA.
 Mol Cell Proteomics. 2012 May;11(5):148-59. [PMID: 22505724]
 [4] Lysine acetylation targets protein complexes and co-regulates major cellular functions.
 Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, Olsen JV, Mann M.
 Science. 2009 Aug 14;325(5942):834-40. [PMID: 19608861]
 [5] Proteomic investigations of lysine acetylation identify diverse substrates of mitochondrial deacetylase sirt3.
 Sol EM, Wagner SA, Weinert BT, Kumar A, Kim HS, Deng CX, Choudhary C.
 PLoS One. 2012;7(12):e50545. [PMID: 23236377]
 [6] Systematic and quantitative assessment of the ubiquitin-modified proteome.
 Kim W, Bennett EJ, Huttlin EL, Guo A, Li J, Possemato A, Sowa ME, Rad R, Rush J, Comb MJ, Harper JW, Gygi SP.
 Mol Cell. 2011 Oct 21;44(2):325-40. [PMID: 21906983]
 [7] A proteome-wide, quantitative survey of in vivo ubiquitylation sites reveals widespread regulatory roles.
 Wagner SA, Beli P, Weinert BT, Nielsen ML, Cox J, Mann M, Choudhary C.
 Mol Cell Proteomics. 2011 Oct;10(10):M111.013284. [PMID: 21890473]
 [8] Global identification of modular cullin-RING ligase substrates.
 Emanuele MJ, Elia AE, Xu Q, Thoma CR, Izhar L, Leng Y, Guo A, Chen YN, Rush J, Hsu PW, Yen HC, Elledge SJ.
 Cell. 2011 Oct 14;147(2):459-74. [PMID: 21963094]
 [9] Ubiquitin ligase substrate identification through quantitative proteomics at both the protein and peptide levels.
 Lee KA, Hammerle LP, Andrews PS, Stokes MP, Mustelin T, Silva JC, Black RA, Doedens JR.
 J Biol Chem. 2011 Dec 2;286(48):41530-8. [PMID: 21987572] 

Functional Description

 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 CDK5R2 (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. 

Sequence Annotation

 DOMAIN 4 286 Protein kinase.
 NP_BIND 10 18 ATP (By similarity).
 ACT_SITE 126 126 Proton acceptor (By similarity).
 BINDING 33 33 ATP (By similarity).
 MOD_RES 15 15 Phosphotyrosine; by ABL1, EPHA4 and FYN.
 MOD_RES 56 56 N6-acetyllysine.
 MOD_RES 72 72 Phosphoserine.
 MOD_RES 159 159 Phosphoserine.  

Keyword

 3D-structure; Acetylation; Alternative splicing; Apoptosis; ATP-binding; Cell cycle; Cell division; Cell junction; Cell membrane; Cell projection; Complete proteome; Cytoplasm; Kinase; Membrane; Neurodegeneration; Neurogenesis; Nucleotide-binding; Nucleus; Phosphoprotein; Polymorphism; Postsynaptic cell membrane; Reference proteome; Serine/threonine-protein kinase; Synapse; Transferase. 

Sequence Source

 UniProt (SWISSPROT/TrEMBL); GenBank; EMBL 

Protein Length

 292 AA 

Protein Sequence

Gene Ontology

 GO:0030424; C:axon; ISS:UniProtKB.
 GO:0030054; C:cell junction; IEA:UniProtKB-KW.
 GO:0016533; C:cyclin-dependent protein kinase 5 holoenzyme complex; IEA:Compara.
 GO:0005829; C:cytosol; TAS:Reactome.
 GO:0030175; C:filopodium; IEA:Compara.
 GO:0030426; C:growth cone; ISS:UniProtKB.
 GO:0030027; C:lamellipodium; IEA:UniProtKB-SubCell.
 GO:0016020; C:membrane; ISS:UniProtKB.
 GO:0031594; C:neuromuscular junction; ISS:UniProtKB.
 GO:0043025; C:neuronal cell body; ISS:UniProtKB.
 GO:0005634; C:nucleus; ISS:UniProtKB.
 GO:0043204; C:perikaryon; IEA:UniProtKB-SubCell.
 GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
 GO:0014069; C:postsynaptic density; ISS:UniProtKB.
 GO:0045211; C:postsynaptic membrane; IEA:UniProtKB-KW.
 GO:0030549; F:acetylcholine receptor activator activity; ISS:UniProtKB.
 GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
 GO:0004693; F:cyclin-dependent protein serine/threonine kinase activity; ISS:UniProtKB.
 GO:0005176; F:ErbB-2 class receptor binding; ISS:UniProtKB.
 GO:0043125; F:ErbB-3 class receptor binding; ISS:UniProtKB.
 GO:0050321; F:tau-protein kinase activity; ISS:UniProtKB.
 GO:0048675; P:axon extension; TAS:UniProtKB.
 GO:0007411; P:axon guidance; TAS:Reactome.
 GO:0048148; P:behavioral response to cocaine; IEA:Compara.
 GO:0007596; P:blood coagulation; TAS:Reactome.
 GO:0070509; P:calcium ion import; IEA:Compara.
 GO:0051301; P:cell division; IEA:UniProtKB-KW.
 GO:0008283; P:cell proliferation; TAS:ProtInc.
 GO:0007160; P:cell-matrix adhesion; IEA:Compara.
 GO:0021954; P:central nervous system neuron development; IEA:Compara.
 GO:0021697; P:cerebellar cortex formation; IEA:Compara.
 GO:0022038; P:corpus callosum development; IEA:Compara.
 GO:0030866; P:cortical actin cytoskeleton organization; IEA:Compara.
 GO:0048813; P:dendrite morphogenesis; IEA:Compara.
 GO:0009790; P:embryo development; ISS:UniProtKB.
 GO:0021766; P:hippocampus development; IEA:Compara.
 GO:0006886; P:intracellular protein transport; IEA:Compara.
 GO:0021819; P:layer formation in cerebral cortex; IEA:Compara.
 GO:0008045; P:motor neuron axon guidance; IEA:Compara.
 GO:0045786; P:negative regulation of cell cycle; IEA:Compara.
 GO:0046826; P:negative regulation of protein export from nucleus; IEA:Compara.
 GO:0031397; P:negative regulation of protein ubiquitination; IEA:Compara.
 GO:0031914; P:negative regulation of synaptic plasticity; IEA:Compara.
 GO:0045892; P:negative regulation of transcription, DNA-dependent; IMP:DFLAT.
 GO:0051402; P:neuron apoptotic process; TAS:UniProtKB.
 GO:0001764; P:neuron migration; TAS:UniProtKB.
 GO:0006913; P:nucleocytoplasmic transport; IEA:Compara.
 GO:0048709; P:oligodendrocyte differentiation; IDA:UniProtKB.
 GO:0018105; P:peptidyl-serine phosphorylation; IDA:UniProtKB.
 GO:0018107; P:peptidyl-threonine phosphorylation; IEA:Compara.
 GO:2000251; P:positive regulation of actin cytoskeleton reorganization; TAS:UniProtKB.
 GO:0045956; P:positive regulation of calcium ion-dependent exocytosis; IEA:Compara.
 GO:0043525; P:positive regulation of neuron apoptotic process; ISS:UniProtKB.
 GO:0032092; P:positive regulation of protein binding; IEA:Compara.
 GO:0045860; P:positive regulation of protein kinase activity; IEA:Compara.
 GO:0090314; P:positive regulation of protein targeting to membrane; IEA:Compara.
 GO:0046777; P:protein autophosphorylation; IEA:Compara.
 GO:0035418; P:protein localization to synapse; IEA:Compara.
 GO:0032801; P:receptor catabolic process; IEA:Compara.
 GO:0043113; P:receptor clustering; IEA:Compara.
 GO:0045055; P:regulated secretory pathway; IEA:Compara.
 GO:0071156; P:regulation of cell cycle arrest; TAS:UniProtKB.
 GO:0030334; P:regulation of cell migration; IEA:Compara.
 GO:0061001; P:regulation of dendritic spine morphogenesis; ISS:UniProtKB.
 GO:0060079; P:regulation of excitatory postsynaptic membrane potential; IEA:Compara.
 GO:0048167; P:regulation of synaptic plasticity; ISS:UniProtKB.
 GO:0014044; P:Schwann cell development; IEA:Compara.
 GO:0019233; P:sensory perception of pain; IEA:Compara.
 GO:0033136; P:serine phosphorylation of STAT3 protein; IEA:Compara.
 GO:0007519; P:skeletal muscle tissue development; IEA:Compara.
 GO:0007416; P:synapse assembly; TAS:UniProtKB.
 GO:0001963; P:synaptic transmission, dopaminergic; IEA:Compara.
 GO:0035249; P:synaptic transmission, glutamatergic; IEA:Compara.
 GO:0048488; P:synaptic vesicle endocytosis; TAS:UniProtKB.
 GO:0016079; P:synaptic vesicle exocytosis; TAS:UniProtKB.
 GO:0008542; P:visual learning; IEA:Compara. 

Interpro

 IPR011009; Kinase-like_dom.
 IPR000719; Prot_kinase_cat_dom.
 IPR017441; Protein_kinase_ATP_BS.
 IPR002290; Ser/Thr_dual-sp_kinase_dom.
 IPR008271; Ser/Thr_kinase_AS. 

Pfam

 PF00069; Pkinase 

SMART

 SM00220; S_TKc 

PROSITE

 PS00107; PROTEIN_KINASE_ATP
 PS50011; PROTEIN_KINASE_DOM
 PS00108; PROTEIN_KINASE_ST 

PRINTS