Q00535 (CDK5_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Cyclin-dependent kinase 5
EC=2.7.11.22

Alternative name(s):
Cell division protein kinase 5
Serine/threonine-protein kinase PSSALRE
Tau protein kinase II catalytic subunit
Short name=TPKII catalytic subunit

Gene names

Name:	CDK5
Synonyms:	CDKN5

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	292 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	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, oligodendrocytes 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 PCTAIRE 1/CDK16 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 elicites 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. Ref.3 Ref.9 Ref.10 Ref.12 Ref.13 Ref.15 Ref.16 Ref.17 Ref.18 Ref.19 Ref.20 Ref.24 Ref.30 Ref.31 Ref.34 Ref.35 Ref.37 Ref.38 Ref.39
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Enzyme regulation	Inhibited by 2-(1-ethyl-2-hydroxyethylamino)-6-benzylamino-9-isopropylpurine (roscovitine), 1-isopropyl-4-aminobenzyl-6-ether-linked benzimidazoles, resveratrol, AT-7519 and olomoucine. Activated by CDK5R1 (p35) and ATP6V0D1 (p39) during the development of the nervous system; degradation of CDK5R1 (p35) and ATP6V0D1 (p39) by proteasome result in down regulation of kinase activity, during this process, CDK5 phosphorylates p35 and induces its ubiquitination and subsequent degradation. Kinase activity is mainly determined by the amount of p35 available and subcellular location; reversible association to plasma membrane inhibits activity. Long-term inactivation as well as CDK5R1 (p25)-mediated hyperactivation of CDK5 triggers cell death. The pro-death activity of hyperactivated CDK5 is suppressed by membrane association of CDK5, via myristoylation of p35. Brain-derived neurotrophic factor, glial-derived neurotrophic factor, nerve growth factor (NGF), retinoic acid, laminin and neuregulin promote activity. Neurotoxicity enhances nuclear activity, thus leading to MEF2 phosphorylation and inhibition prior to apoptosis of cortical neurons. Repression by GSTP1 via p25/p35 translocation prevents neurodegeneration. Ref.8 Ref.12 Ref.13 Ref.19 Ref.36
Subunit structure	Heterodimer composed of a catalytic subunit CDK5 and a regulatory subunit CDK5R1 (p25) and macromolecular complex composed of at least CDK5, CDK5R1 (p35) and CDK5RAP1 or CDK5RAP2 or CDK5RAP3. Only the heterodimer shows kinase activity. Under neurotoxic stress and neuronal injury conditions, p35 is cleaved by calpain to generate p25 that hyperactivates CDK5, that becomes functionally disabled and often toxic. Found in a trimolecular complex with CABLES1 and ABL1. Interacts with CABLES1 and CABLES2 By similarity. Interacts with AATK and GSTP1. Binds to HDAC1 when in complex with p25. Interaction with myristoylation p35 promotes CDK5 association with membranes. Both isoforms 1 and 2 interacts with beta-catenin/CTNNB1. Interacts with delta-catenin/CTNND2 and APEX1. Interacts with P53/TP53 in neurons. Interacts with EPHA4; may mediate the activation of NGEF by EPHA4. Interacts with PTK2/FAK1 By similarity. Ref.3 Ref.11 Ref.16 Ref.17 Ref.20 Ref.36
Subcellular location	Isoform 1: Cytoplasm. Cell membrane; Peripheral membrane protein. Perikaryon. Cell projection › lamellipodium By similarity. Cell projection › growth cone By similarity. Cell junction › synapse › postsynaptic cell membrane › postsynaptic density By similarity. Note: In axonal growth cone with extension to the peripheral lamellipodia By similarity. Under neurotoxic stress and neuronal injury conditions, CDK5R (p35) is cleaved by calpain to generate CDK5R1 (p25) in response to increased intracellular calcium. The elevated level of p25, when in complex with CDK5, leads to its subcellular misallocation as well as its hyperactivation. Co-localizes with CTNND2 in the cell body of neuronal cells, and with CTNNB1 in the cell-cell contacts and plasma membrane of undifferentiated and differentiated neuroblastoma cells. Reversibly attached to the plasma membrane in an inactive form when complexed to dephosphorylated p35 or CDK5R2 (p39), p35 phosphorylation releases this attachment and activates CDK5. Ref.3 Ref.12 Ref.13 Ref.16 Ref.17 Ref.20 Ref.22 Ref.35 Isoform 2: Nucleus Ref.3 Ref.12 Ref.13 Ref.16 Ref.17 Ref.20 Ref.22 Ref.35.
Tissue specificity	Isoform 1 is ubiquitously expressed. Accumulates in cortical neurons (at protein level). Isoform 2 has only been detected in testis, skeletal muscle, colon, bone marrow and ovary. Ref.3 Ref.16
Post-translational modification	Phosphorylation on Tyr-15 by ABL1 and FYN, and on Ser-159 by casein kinase 1 promotes kinase activity. By contrast, phosphorylation at Thr-14 inhibits activity.
Miscellaneous	Dysregulation of CDK5 is associated with neurodegenerative disorders such as Alzheimer, Parkinson, and Niemann-Pick type C diseases, ischemia, and amyotrophic lateral sclerosis.
Sequence similarities	Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. CDC2/CDKX subfamily. Contains 1 protein kinase domain.

Ontologies

Keywords
Biological process	Apoptosis Cell cycle Cell division Neurogenesis
Cellular component	Cell junction Cell membrane Cell projection Cytoplasm Membrane Nucleus Postsynaptic cell membrane Synapse
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Neurodegeneration
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Acetylation Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	activation of pro-apoptotic gene products Inferred from direct assay. Source: UniProtKB axon extension Traceable author statement Ref.47. Source: UniProtKB blood coagulation Traceable author statement. Source: Reactome cell division Inferred from electronic annotation. Source: UniProtKB-KW cell proliferation Traceable author statement. Source: ProtInc embryo development Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of transcription, DNA-dependent Inferred from mutant phenotype. Source: DFLAT neuron apoptosis Traceable author statement Ref.47. Source: UniProtKB neuron migration Traceable author statement Ref.47. Source: UniProtKB oligodendrocyte differentiation Inferred from direct assay Ref.18. Source: UniProtKB positive regulation of actin cytoskeleton reorganization Traceable author statement Ref.47. Source: UniProtKB positive regulation of neuron apoptosis Inferred from sequence or structural similarity. Source: UniProtKB regulation of cell cycle arrest Traceable author statement Ref.47. Source: UniProtKB regulation of dendritic spine morphogenesis Inferred from sequence or structural similarity. Source: UniProtKB synapse assembly Traceable author statement Ref.47. Source: UniProtKB synaptic vesicle endocytosis Traceable author statement Ref.47. Source: UniProtKB synaptic vesicle exocytosis Traceable author statement Ref.47. Source: UniProtKB
Cellular component	axon Inferred from sequence or structural similarity. Source: UniProtKB cell junction Inferred from electronic annotation. Source: UniProtKB-KW cytosol Traceable author statement. Source: Reactome growth cone Inferred from sequence or structural similarity. Source: UniProtKB lamellipodium Inferred from electronic annotation. Source: UniProtKB-SubCell neuromuscular junction Inferred from sequence or structural similarity. Source: UniProtKB perikaryon Inferred from electronic annotation. Source: UniProtKB-SubCell plasma membrane Inferred from electronic annotation. Source: UniProtKB-SubCell postsynaptic density Inferred from sequence or structural similarity. Source: UniProtKB postsynaptic membrane Inferred from electronic annotation. Source: UniProtKB-KW
Molecular function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW ErbB-2 class receptor binding Inferred from sequence or structural similarity. Source: UniProtKB ErbB-3 class receptor binding Inferred from sequence or structural similarity. Source: UniProtKB acetylcholine receptor activator activity Inferred from sequence or structural similarity. Source: UniProtKB cyclin-dependent protein kinase activity Inferred from sequence or structural similarity. Source: UniProtKB tau-protein kinase activity Inferred from sequence or structural similarity. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
CDK5R1	Q15078	5	EBI-1041567,EBI-746189
CDKN1A	P38936	2	EBI-1041567,EBI-375077
CDKN1B	P46527	4	EBI-1041567,EBI-519280

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q00535-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: Q00535-2)

Also known as: CDK5-SV;

The sequence of this isoform differs from the canonical sequence as follows:
     105-136: Missing.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 292

292

Cyclin-dependent kinase 5

PRO_0000085784

Regions

Domain

4 – 286

283

Protein kinase

Nucleotide binding

10 – 18

9

ATP By similarity

Sites

Active site

126

1

Proton acceptor By similarity

Binding site

33

1

ATP By similarity

Amino acid modifications

Modified residue

14

1

Phosphothreonine Ref.27

Modified residue

15

1

Phosphotyrosine; by ABL1, EPHA4 and FYN Ref.14 Ref.23 Ref.25 Ref.26 Ref.27 Ref.28

Modified residue

17

1

Phosphothreonine Ref.23 Ref.27

Modified residue

46

1

Phosphoserine Ref.27

Modified residue

56

1

N6-acetyllysine Ref.29

Modified residue

72

1

Phosphoserine Ref.23 Ref.27

Modified residue

159

1

Phosphoserine By similarity

Modified residue

239

1

Phosphotyrosine Ref.27

Natural variations

Alternative sequence

105 – 136

32

Missing in isoform 2.

VSP_041948

Natural variant

225

1

E → D. Ref.50
Corresponds to variant rs35186917 [ dbSNP | Ensembl ].

VAR_041977

Experimental info

Mutagenesis

159

1

S → A: No phenotype. Ref.48

Mutagenesis

159

1

S → T: Impaired p35/p25 (CDK5R1) binding. Ref.48

Secondary structure

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292

Helix Strand Turn

Details...

Beta strand

4 – 9

6

Beta strand

17 – 23

7

Turn

24 – 26

3

Beta strand

29 – 38

10

Beta strand

40 – 42

3

Helix

45 – 55

11

Beta strand

66 – 72

7

Beta strand

75 – 81

7

Beta strand

84 – 86

3

Helix

87 – 93

7

Turn

94 – 96

3

Helix

100 – 119

20

Helix

129 – 131

3

Beta strand

132 – 134

3

Beta strand

140 – 142

3

Helix

145 – 147

3

Helix

165 – 167

3

Helix

170 – 173

4

Helix

182 – 195

14

Turn

196 – 198

3

Helix

208 – 219

12

Turn

224 – 226

3

Helix

230 – 232

3

Turn

249 – 251

3

Helix

257 – 266

10

Helix

271 – 273

3

Helix

277 – 280

4

Helix

284 – 286

3

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified December 15, 1998. Version 3. Checksum: 54D10495F017D527	FASTA	292	33,304
	10 20 30 40 50 60 MQKYEKLEKI GEGTYGTVFK AKNRETHEIV ALKRVRLDDD DEGVPSSALR EICLLKELKH 70 80 90 100 110 120 KNIVRLHDVL HSDKKLTLVF EFCDQDLKKY FDSCNGDLDP EIVKSFLFQL LKGLGFCHSR 130 140 150 160 170 180 NVLHRDLKPQ NLLINRNGEL KLADFGLARA FGIPVRCYSA EVVTLWYRPP DVLFGAKLYS 190 200 210 220 230 240 TSIDMWSAGC IFAELANAGR PLFPGNDVDD QLKRIFRLLG TPTEEQWPSM TKLPDYKPYP 250 260 270 280 290 MYPATTSLVN VVPKLNATGR DLLQNLLKCN PVQRISAEEA LQHPYFSDFC PP
	Isoform 2 (CDK5-SV) [UniParc]. Checksum: 808E46028B657622	FASTA	260	29,544
	10 20 30 40 50 60 MQKYEKLEKI GEGTYGTVFK AKNRETHEIV ALKRVRLDDD DEGVPSSALR EICLLKELKH 70 80 90 100 110 120 KNIVRLHDVL HSDKKLTLVF EFCDQDLKKY FDSCNGDLDP EIVKNGELKL ADFGLARAFG 130 140 150 160 170 180 IPVRCYSAEV VTLWYRPPDV LFGAKLYSTS IDMWSAGCIF AELANAGRPL FPGNDVDDQL 190 200 210 220 230 240 KRIFRLLGTP TEEQWPSMTK LPDYKPYPMY PATTSLVNVV PKLNATGRDL LQNLLKCNPV 250 260 QRISAEEALQ HPYFSDFCPP

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"A family of human cdc2-related protein kinases." Meyerson M., Enders G.H., Wu C.-L., Su L.-K., Gorka C., Nelson C., Harlow E., Tsai L.-H. EMBO J. 11:2909-2917(1992) [PubMed: 1639063] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). Tissue: Fetal brain.
[2]	Meyerson M. Submitted (FEB-1993) to the EMBL/GenBank/DDBJ databases Cited for: SEQUENCE REVISION.
[3]	"Characterization of a novel human CDK5 splicing variant that inhibits Wnt/beta-catenin signaling." Li Q., Liu X., Zhang M., Ye G., Qiao Q., Ling Y., Wu Y., Zhang Y., Yu L. Mol. Biol. Rep. 37:2415-2421(2010) [PubMed: 19693690] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), SUBCELLULAR LOCATION, TISSUE SPECIFICITY, INTERACTION WITH CTNNB1, FUNCTION IN WNT/B-CATENIN SIGNALING PATHWAY. Tissue: Testis.
[4]	Hu X., Xu Y., Zhang B., Peng X., Yuan J., Qiang B. Submitted (JUL-2001) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[5]	"Cloning of human full-length CDSs in BD Creator(TM) system donor vector." Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A. Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
[6]	"The DNA sequence of human chromosome 7." Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H., Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R., Wylie K., Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E., Fewell G.A., Delehaunty K.D., Miner T.L. , Nash W.E., Cordes M., Du H., Sun H., Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A., Vanbrunt A., Nguyen C., Du F., Lamar B., Courtney L., Kalicki J., Ozersky P., Bielicki L., Scott K., Holmes A., Harkins R., Harris A., Strong C.M., Hou S., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Leonard S., Rohlfing T., Rock S.M., Tin-Wollam A.-M., Abbott A., Minx P., Maupin R., Strowmatt C., Latreille P., Miller N., Johnson D., Murray J., Woessner J.P., Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W., Spieth J., Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E., Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Bedell J.A., Mardis E.R., Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E., Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K., Simms E., Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S., Baertsch R.A., Brent M.R., Keibler E., Flicek P., Bork P., Suyama M., Bailey J.A., Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R., Eddy S.R., McPherson J.D., Olson M.V., Eichler E.E., Green E.D., Waterston R.H., Wilson R.K. Nature 424:157-164(2003) [PubMed: 12853948] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). Tissue: Lung.
[8]	"Biochemical and cellular effects of roscovitine, a potent and selective inhibitor of the cyclin-dependent kinases cdc2, cdk2 and cdk5." Meijer L., Borgne A., Mulner O., Chong J.P.J., Blow J.J., Inagaki N., Inagaki M., Delcros J.-G., Moulinoux J.-P. Eur. J. Biochem. 243:527-536(1997) [PubMed: 9030781] [Abstract] Cited for: ENZYME REGULATION BY ROSCOVITINE AND OLOMOUCINE.
[9]	"Evidence for the participation of the neuron-specific CDK5 activator P35 during laminin-enhanced axonal growth." Paglini G., Pigino G., Kunda P., Morfini G., Maccioni R., Quiroga S., Ferreira A., Caceres A. J. Neurosci. 18:9858-9869(1998) [PubMed: 9822744] [Abstract] Cited for: FUNCTION IN AXON GROWTH.
[10]	"Influence of phosphorylation of p35, an activator of cyclin-dependent kinase 5 (cdk5), on the proteolysis of p35." Kerokoski P., Suuronen T., Salminen A., Soininen H., Pirttilae T. Brain Res. Mol. Brain Res. 106:50-56(2002) [PubMed: 12393264] [Abstract] Cited for: FUNCTION AS P35/CDK5R1 KINASE.
[11]	"Apoptosis-associated tyrosine kinase is a Cdk5 activator p35 binding protein." Honma N., Asada A., Takeshita S., Enomoto M., Yamakawa E., Tsutsumi K., Saito T., Satoh T., Itoh H., Kaziro Y., Kishimoto T., Hisanaga S. Biochem. Biophys. Res. Commun. 310:398-404(2003) [PubMed: 14521924] [Abstract] Cited for: INTERACTION WITH AATK.
[12]	"Cdk5-mediated inhibition of the protective effects of transcription factor MEF2 in neurotoxicity-induced apoptosis." Gong X., Tang X., Wiedmann M., Wang X., Peng J., Zheng D., Blair L.A.C., Marshall J., Mao Z. Neuron 38:33-46(2003) [PubMed: 12691662] [Abstract] Cited for: FUNCTION AS MEF2A KINASE, ENZYME REGULATION, SUBCELLULAR LOCATION.
[13]	"Activation of latent cyclin-dependent kinase 5 (Cdk5)-p35 complexes by membrane dissociation." Zhu Y.-S., Saito T., Asada A., Maekawa S., Hisanaga S. J. Neurochem. 94:1535-1545(2005) [PubMed: 15992363] [Abstract] Cited for: FUNCTION AS P35 KINASE, SUBCELLULAR LOCATION, ENZYME REGULATION.
[14]	"Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer." Rikova K., Guo A., Zeng Q., Possemato A., Yu J., Haack H., Nardone J., Lee K., Reeves C., Li Y., Hu Y., Tan Z., Stokes M., Sullivan L., Mitchell J., Wetzel R., Macneill J., Ren J.M. , Yuan J., Bakalarski C.E., Villen J., Kornhauser J.M., Smith B., Li D., Zhou X., Gygi S.P., Gu T.-L., Polakiewicz R.D., Rush J., Comb M.J. Cell 131:1190-1203(2007) [PubMed: 18083107] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-15, MASS SPECTROMETRY. Tissue: Lung carcinoma.
[15]	"Suppression of calpain-dependent cleavage of the CDK5 activator p35 to p25 by site-specific phosphorylation." Kamei H., Saito T., Ozawa M., Fujita Y., Asada A., Bibb J.A., Saido T.C., Sorimachi H., Hisanaga S. J. Biol. Chem. 282:1687-1694(2007) [PubMed: 17121855] [Abstract] Cited for: FUNCTION AS P35/CDK5R KINASE.
[16]	"cdk5 modulates beta- and delta-catenin/Pin1 interactions in neuronal cells." Munoz J.P., Huichalaf C.H., Orellana D., Maccioni R.B. J. Cell. Biochem. 100:738-749(2007) [PubMed: 17009320] [Abstract] Cited for: FUNCTION AS CTNNB1 AND CTNND2 KINASE, INTERACTION WITH CTNNB1 AND CTNND2, SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
[17]	"Stabilization and activation of p53 induced by Cdk5 contributes to neuronal cell death." Lee J.-H., Kim H.-S., Lee S.-J., Kim K.-T. J. Cell Sci. 120:2259-2271(2007) [PubMed: 17591690] [Abstract] Cited for: FUNCTION AS P53/TP53 KINASE, INTERACTION WITH P53/TP53, SUBCELLULAR LOCATION.
[18]	"Cdk5 regulates differentiation of oligodendrocyte precursor cells through the direct phosphorylation of paxillin." Miyamoto Y., Yamauchi J., Chan J.R., Okada A., Tomooka Y., Hisanaga S., Tanoue A. J. Cell Sci. 120:4355-4366(2007) [PubMed: 18042622] [Abstract] Cited for: FUNCTION AS PXN KINASE.
[19]	"Phosphorylation of huntingtin by cyclin-dependent kinase 5 is induced by DNA damage and regulates wild-type and mutant huntingtin toxicity in neurons." Anne S.L., Saudou F., Humbert S. J. Neurosci. 27:7318-7328(2007) [PubMed: 17611284] [Abstract] Cited for: FUNCTION AS HUNTINGTIN KINASE, ENZYME REGULATION BY ROSCOVITINE.
[20]	"Regulation of membrane association and kinase activity of Cdk5-p35 by phosphorylation of p35." Sato K., Zhu Y.-S., Saito T., Yotsumoto K., Asada A., Hasegawa M., Hisanaga S. J. Neurosci. Res. 85:3071-3078(2007) [PubMed: 17671990] [Abstract] Cited for: FUNCTION AS P35/CDK5R KINASE, INTERACTION WITH P35/CDK5R, SUBCELLULAR LOCATION.
[21]	"Cdk5 regulates EphA4-mediated dendritic spine retraction through an ephexin1-dependent mechanism." Fu W.Y., Chen Y., Sahin M., Zhao X.S., Shi L., Bikoff J.B., Lai K.O., Yung W.H., Fu A.K., Greenberg M.E., Ip N.Y. Nat. Neurosci. 10:67-76(2007) [PubMed: 17143272] [Abstract] Cited for: PHOSPHORYLATION BY EPHA4 AT TYR-15.
[22]	"Myristoylation of p39 and p35 is a determinant of cytoplasmic or nuclear localization of active cyclin-dependent kinase 5 complexes." Asada A., Yamamoto N., Gohda M., Saito T., Hayashi N., Hisanaga S. J. Neurochem. 106:1325-1336(2008) [PubMed: 18507738] [Abstract] Cited for: SUBCELLULAR LOCATION.
[23]	"Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle." Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., Greff Z., Keri G., Stemmann O., Mann M. Mol. Cell 31:438-448(2008) [PubMed: 18691976] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-15; THR-17 AND SER-72, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[24]	"Deregulation of HDAC1 by p25/Cdk5 in neurotoxicity." Kim D., Frank C.L., Dobbin M.M., Tsunemoto R.K., Tu W., Peng P.L., Guan J.S., Lee B.H., Moy L.Y., Giusti P., Broodie N., Mazitschek R., Delalle I., Haggarty S.J., Neve R.L., Lu Y., Tsai L.H. Neuron 60:803-817(2008) [PubMed: 19081376] [Abstract] Cited for: FUNCTION AS HDAC REGULATOR.
[25]	"Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach." Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S. Anal. Chem. 81:4493-4501(2009) [PubMed: 19413330] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-15, MASS SPECTROMETRY. Tissue: Embryonic kidney.
[26]	"An extensive survey of tyrosine phosphorylation revealing new sites in human mammary epithelial cells." Heibeck T.H., Ding S.-J., Opresko L.K., Zhao R., Schepmoes A.A., Yang F., Tolmachev A.V., Monroe M.E., Camp D.G. II, Smith R.D., Wiley H.S., Qian W.-J. J. Proteome Res. 8:3852-3861(2009) [PubMed: 19534553] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-15, MASS SPECTROMETRY. Tissue: Mammary epithelium.
[27]	"Large-scale proteomics analysis of the human kinome." Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G., Mann M., Daub H. Mol. Cell. Proteomics 8:1751-1764(2009) [PubMed: 19369195] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-14; TYR-15; THR-17; SER-46; SER-72 AND TYR-239, MASS SPECTROMETRY.
[28]	"Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions." Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., Rodionov V., Han D.K. Sci. Signal. 2:RA46-RA46(2009) [PubMed: 19690332] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-15, MASS SPECTROMETRY. Tissue: Leukemic T-cell.
[29]	"Lysine acetylation targets protein complexes and co-regulates major cellular functions." Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T., Olsen J.V., Mann M. Science 325:834-840(2009) [PubMed: 19608861] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-56, MASS SPECTROMETRY.
[30]	"Cyclin-dependent kinase 5 regulates endothelial cell migration and angiogenesis." Liebl J., Weitensteiner S.B., Vereb G., Takacs L., Fuerst R., Vollmar A.M., Zahler S. J. Biol. Chem. 285:35932-35943(2010) [PubMed: 20826806] [Abstract] Cited for: FUNCTION IN ANGIOGENESIS.
[31]	"CDK5 phosphorylates eNOS at Ser-113 and regulates NO production." Lee C.-H., Wei Y.-W., Huang Y.-T., Lin Y.-T., Lee Y.-C., Lee K.-H., Lu P.-J. J. Cell. Biochem. 110:112-117(2010) [PubMed: 20213743] [Abstract] Cited for: FUNCTION AS NOS3 KINASE.
[32]	"Design, synthesis, and testing of an 6-O-linked series of benzimidazole based inhibitors of CDK5/p25." Jain P., Flaherty P.T., Yi S., Chopra I., Bleasdell G., Lipay J., Ferandin Y., Meijer L., Madura J.D. Bioorg. Med. Chem. 19:359-373(2011) [PubMed: 21144757] [Abstract] Cited for: INHIBITORS.
[33]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed: 21269460] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[34]	"Cdk5 targets active Src for ubiquitin-dependent degradation by phosphorylating Src(S75)." Pan Q., Qiao F., Gao C., Norman B., Optican L., Zelenka P.S. Cell. Mol. Life Sci. 68:3425-3436(2011) [PubMed: 21442427] [Abstract] Cited for: FUNCTION AS SRC KINASE.
[35]	"Cdk5 mediates vimentin Ser56 phosphorylation during GTP-induced secretion by neutrophils." Lee K.Y., Liu L., Jin Y., Fu S.B., Rosales J.L. J. Cell. Physiol. 227:739-750(2012) [PubMed: 21465480] [Abstract] Cited for: FUNCTION AS VIM KINASE, SUBCELLULAR LOCATION.
[36]	"Glutathione-S-transferase P1 is a critical regulator of Cdk5 kinase activity." Sun K.H., Chang K.H., Clawson S., Ghosh S., Mirzaei H., Regnier F., Shah K. J. Neurochem. 118:902-914(2011) [PubMed: 21668448] [Abstract] Cited for: ENZYME REGULATION, INTERACTION WITH GSTP1.
[37]	"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." Gallazzini M., Heussler G.E., Kunin M., Izumi Y., Burg M.B., Ferraris J.D. Mol. Biol. Cell 22:703-714(2011) [PubMed: 21209322] [Abstract] Cited for: FUNCTION AS TONEBP/NFAT5 KINASE.
[38]	"Cdk5-mediated phosphorylation of endophilin B1 is required for induced autophagy in models of Parkinson's disease." Wong A.S., Lee R.H., Cheung A.Y., Yeung P.K., Chung S.K., Cheung Z.H., Ip N.Y. Nat. Cell Biol. 13:568-579(2011) [PubMed: 21499257] [Abstract] Cited for: FUNCTION AS SH3GLB1 KINASE.
[39]	"Phosphorylation of glutamyl-prolyl tRNA synthetase by cyclin-dependent kinase 5 dictates transcript-selective translational control." Arif A., Jia J., Moodt R.A., DiCorleto P.E., Fox P.L. Proc. Natl. Acad. Sci. U.S.A. 108:1415-1420(2011) [PubMed: 21220307] [Abstract] Cited for: FUNCTION AS EPRS KINASE.
[40]	"A decade of CDK5." Dhavan R., Tsai L.H. Nat. Rev. Mol. Cell Biol. 2:749-759(2001) [PubMed: 11584302] [Abstract] Cited for: REVIEW.
[41]	"Cell cycle, CDKs and cancer: a changing paradigm." Malumbres M., Barbacid M. Nat. Rev. Cancer 9:153-166(2009) [PubMed: 19238148] [Abstract] Cited for: REVIEW ON INHIBITORS, GENE FAMILY.
[42]	"Making a neuron: Cdk5 in embryonic and adult neurogenesis." Jessberger S., Gage F.H., Eisch A.J., Lagace D.C. Trends Neurosci. 32:575-582(2009) [PubMed: 19782409] [Abstract] Cited for: REVIEW ON NEURONAL PHYSIOLOGY.
[43]	"Cdk5, the multifunctional surveyor." Lalioti V., Pulido D., Sandoval I.V. Cell Cycle 9:284-311(2010) [PubMed: 20061803] [Abstract] Cited for: REVIEW ON VARIOUS FUNCTIONS.
[44]	"Regulation and role of cyclin-dependent kinase activity in neuronal survival and death." Hisanaga S., Endo R. J. Neurochem. 115:1309-1321(2010) [PubMed: 21044075] [Abstract] Cited for: REVIEW ON REGULATION.
[45]	"Nucleocytoplasmic Cdk5 is involved in neuronal cell cycle and death in post-mitotic neurons." Zhang J., Herrup K. Cell Cycle 10:1208-1214(2011) [PubMed: 21415596] [Abstract] Cited for: REVIEW ON NEURON DEVELOPMENT.
[46]	"Cdk5: Mediator of neuronal development, death and the response to DNA damage." Zhu J., Li W., Mao Z. Mech. Ageing Dev. 132:389-394(2011) [PubMed: 21600237] [Abstract] Cited for: REVIEW ON NEURON DEVELOPMENT.
[47]	"Cdk5: multitasking between physiological and pathological conditions." Lopes J.P., Agostinho P. Prog. Neurobiol. 94:49-63(2011) [PubMed: 21473899] [Abstract] Cited for: REVIEW ON NEURONS.
[48]	"Structure and regulation of the CDK5-p25(nck5a) complex." Tarricone C., Dhavan R., Peng J., Areces L.B., Tsai L.-H., Musacchio A. Mol. Cell 8:657-669(2001) [PubMed: 11583627] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.65 ANGSTROMS) IN COMPLEX WITH P25, MUTAGENESIS OF SER-159.
[49]	"Mechanism of CDK5/p25 binding by CDK inhibitors." Mapelli M., Massimiliano L., Crovace C., Seeliger M.A., Tsai L.H., Meijer L., Musacchio A. J. Med. Chem. 48:671-679(2005) [PubMed: 15689152] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.20 ANGSTROMS) IN COMPLEX WITH INHIBITORS AND P25.
[50]	"Patterns of somatic mutation in human cancer genomes." Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G. , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R. Nature 446:153-158(2007) [PubMed: 17344846] [Abstract] Cited for: VARIANT [LARGE SCALE ANALYSIS] ASP-225.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

X66364 mRNA. Translation: CAA47007.1.
DQ411039 mRNA. Translation: ABD66016.1.
AY049778 mRNA. Translation: AAL15435.1.
BT006680 mRNA. Translation: AAP35326.1.
AC010973 Genomic DNA. No translation available.
BC005115 mRNA. Translation: AAH05115.1.

IPI

IPI00023530.

PIR

S23386.

RefSeq

NP_001157882.1. NM_001164410.1.
NP_004926.1. NM_004935.3.

UniGene

Hs.647078.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1H4L	X-ray	2.65	A/B	1-292	[»]
1LFR	model	-	A	1-292	[»]
1UNG	X-ray	2.30	A/B	1-292	[»]
1UNH	X-ray	2.35	A/B	1-292	[»]
1UNL	X-ray	2.20	A/B	1-292	[»]
3O0G	X-ray	1.95	A/B	1-292	[»]

ProteinModelPortal

Q00535.

SMR

Q00535. Positions 1-292.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-24221N.

IntAct

Q00535. 11 interactions.

MINT

MINT-1037488.

STRING

Q00535.

PTM databases

PhosphoSite

Q00535.

Polymorphism databases

DMDM

4033704.

Proteomic databases

PRIDE

Q00535.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000297518; ENSP00000297518; ENSG00000164885.
ENST00000485972; ENSP00000419782; ENSG00000164885.

GeneID

1020.

KEGG

hsa:1020.

UCSC

uc003wir.1. human.

Organism-specific databases

CTD

1020.

GeneCards

GC07M150750.

H-InvDB

HIX0019667.

HGNC

HGNC:1774. CDK5.

HPA

CAB008909.
HPA018977.

MIM

123831. gene.

neXtProt

NX_Q00535.

PharmGKB

PA26310.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG04827.

GeneTree

ENSGT00600000083998.

HOGENOM

HBG755340.

HOVERGEN

HBG014652.

InParanoid

Q00535.

OMA

CIFAEIS.

OrthoDB

EOG4X6C8R.

PhylomeDB

Q00535.

Enzyme and pathway databases

BRENDA

2.7.11.22. 2681.

Pathway_Interaction_DB

epha_fwdpathway. EPHA forward signaling.
lis1pathway. Lissencephaly gene (LIS1) in neuronal migration and development.
reelinpathway. Reelin signaling pathway.
mapktrkpathway. Trk receptor signaling mediated by the MAPK pathway.

Reactome

REACT_111045. Developmental Biology.
REACT_111102. Signal Transduction.
REACT_604. Hemostasis.

Gene expression databases

ArrayExpress

Q00535.

Bgee

Q00535.

CleanEx

HS_CDK5.

Genevestigator

Q00535.

GermOnline

ENSG00000164885. Homo sapiens.

Family and domain databases

InterPro

IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_cat_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR017442. Se/Thr_kinase-like_dom.
IPR008271. Ser/Thr_kinase_AS.
IPR002290. Ser/Thr_kinase_dom.
[Graphical view]

KO

K02090.

Pfam

PF00069. Pkinase. 1 hit.
[Graphical view]

SMART

SM00220. S_TKc. 1 hit.
[Graphical view]

SUPFAM

SSF56112. Kinase_like. 1 hit.

PROSITE

PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

Q00535.

NextBio

4287.

SOURCE

Search...

Entry information

Entry name

CDK5_HUMAN

Accession

Primary (citable) accession number: Q00535
Secondary accession number(s): A1XKG3

Entry history

Integrated into UniProtKB/Swiss-Prot:	April 1, 1993
Last sequence update:	December 15, 1998
Last modified:	January 25, 2012
This is version 133 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.