P49615 (CDK5_MOUSE) Reviewed, UniProtKB/Swiss-Prot
Last modified July 9, 2014. Version 144. History...
Names and origin
|Protein names||Recommended name:|
Cyclin-dependent kinase 5
CR6 protein kinase
Cell division protein kinase 5
Serine/threonine-protein kinase PSSALRE
Tau protein kinase II catalytic subunit
Short name=TPKII catalytic subunit
|Organism||Mus musculus (Mouse) [Reference proteome]|
|Taxonomic identifier||10090 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus|
|Sequence length||292 AA.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
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. 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-ARNTL/BMAL1 heterodimer in association with altered stability and subcellular distribution. Ref.9 Ref.12 Ref.13 Ref.14 Ref.15
ATP + a protein = ADP + a phosphoprotein.
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 CDK5R2 (p39) during the development of the nervous system; degradation of CDK5R1 (p35) and CDK5R2 (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 By similarity. Ref.6
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. 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 By similarity. Interacts with EPHA4; may mediate the activation of NGEF by EPHA4M. Interacts with PTK2/FAK1. The complex p35/CDK5 interacts with CLOCK By similarity. Ref.5 Ref.8 Ref.9 Ref.13 Ref.15
Nucleus By similarity. Cytoplasm. Cell membrane; Peripheral membrane protein By similarity. Perikaryon By similarity. Cell projection › lamellipodium. Cell projection › growth cone. Cell junction › synapse › postsynaptic cell membrane › postsynaptic density By similarity. Note: In axonal growth cone with extension to the peripheral lamellipodia. Under neurotoxic stress and neuronal injury conditions, CDK5R1 (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. Colocalizes 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 By similarity. Ref.6
Specifically expressed in post-mitotic neurons and postsynaptic muscle. Ref.10
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 By similarity.
Phosphorylation at Ser-159 is essential for maximal catalytic activity By similarity.
Perinatal mortality associated with severe disruption of the cytoarchitecture of the brain cortex as a result of defects in neuronal migration and cohesiveness, and degenerative changes in large neurons of the brain stem, such as motor neurons in the lower cranial nerve nuclei and spinal cord. Disruption of lamination in the cerebral cortex, hippocampus, and cerebellum. Hypomyelination caused by impaired differentiation of oligodendrocytes. Ref.6 Ref.7 Ref.10 Ref.14
Contains 1 protein kinase domain.
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Chain||1 – 292||292||Cyclin-dependent kinase 5||PRO_0000085785|
|Domain||4 – 286||283||Protein kinase|
|Nucleotide binding||10 – 18||9||ATP By similarity|
|Active site||126||1||Proton acceptor By similarity|
|Binding site||33||1||ATP By similarity|
Amino acid modifications
|Modified residue||15||1||Phosphotyrosine; by ABL1, EPHA4 and FYN Ref.5|
|Modified residue||56||1||N6-acetyllysine Ref.16|
|Modified residue||72||1||Phosphoserine By similarity|
|Modified residue||159||1||Phosphoserine By similarity|
|Mutagenesis||15||1||Y → F: Loss of tyrosine phosphorylations by CABLES1 and ABL1; decreased activity. Ref.5|
|||"Expression of CDK5 (PSSALRE kinase), a neural cdc2-related protein kinase, in the mature and developing mouse central and peripheral nervous systems."|
Ino H., Ishizuka T., Chiba T., Tatibana M.
Brain Res. 661:196-206(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
|||"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] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
|||"Novel CDC2-related protein kinases produced in murine hematopoietic stem cells."|
Ershler M.A., Nagorskaya T.V., Visser J.W.M., Belyavsky A.V.
Gene 124:305-306(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 130-165.
Tissue: Bone marrow.
|||"Molecular cloning and chromosomal mapping of the mouse cyclin-dependent kinase 5 gene."|
Ohshima T., Nagle J.W., Pant H.C., Joshi J.B., Kozak C.A., Brady R.O., Kulkarni A.B.
Genomics 28:585-588(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE OF 1-12.
|||"Cables links Cdk5 and c-Abl and facilitates Cdk5 tyrosine phosphorylation, kinase upregulation, and neurite outgrowth."|
Zukerberg L.R., Patrick G.N., Nikolic M., Humbert S., Wu C.-L., Lanier L.M., Gertler F.B., Vidal M., Van Etten R.A., Tsai L.-H.
Neuron 26:633-646(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION IN A TRIMOLECULAR COMPLEX WITH CABLES1 AND ABL1, INTERACTION WITH CABLES1, PHOSPHORYLATION AT TYR-15, MUTAGENESIS OF TYR-15.
|||"p35 and p39 are essential for cyclin-dependent kinase 5 function during neurodevelopment."|
Ko J., Humbert S., Bronson R.T., Takahashi S., Kulkarni A.B., Li E., Tsai L.H.
J. Neurosci. 21:6758-6771(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION, DISRUPTION PHENOTYPE, ENZYME REGULATION.
|||"Synergistic contributions of cyclin-dependant kinase 5/p35 and Reelin/Dab1 to the positioning of cortical neurons in the developing mouse brain."|
Ohshima T., Ogawa M., Veeranna A., Hirasawa M., Longenecker G., Ishiguro K., Pant H.C., Brady R.O., Kulkarni A.B., Mikoshiba K.
Proc. Natl. Acad. Sci. U.S.A. 98:2764-2769(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: DISRUPTION PHENOTYPE.
|||"Ik3-2, a relative to ik3-1/cables, is associated with cdk3, cdk5, and c-abl."|
Sato H., Nishimoto I., Matsuoka M.
Biochim. Biophys. Acta 1574:157-163(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH CABLES2.
|||"Serine 732 phosphorylation of FAK by Cdk5 is important for microtubule organization, nuclear movement, and neuronal migration."|
Xie Z., Sanada K., Samuels B.A., Shih H., Tsai L.H.
Cell 114:469-482(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH PTK2/FAK1.
|||"Aberrant motor axon projection, acetylcholine receptor clustering, and neurotransmission in cyclin-dependent kinase 5 null mice."|
Fu A.K.Y., Ip F.C.F., Fu W.-Y., Cheung J., Wang J.H., Yung W.-H., Ip N.Y.
Proc. Natl. Acad. Sci. U.S.A. 102:15224-15229(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: DISRUPTION PHENOTYPE, TISSUE SPECIFICITY.
|||"Comprehensive identification of phosphorylation sites in postsynaptic density preparations."|
Trinidad J.C., Specht C.G., Thalhammer A., Schoepfer R., Burlingame A.L.
Mol. Cell. Proteomics 5:914-922(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
|||"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] [Europe PMC] [Abstract]
Cited for: FUNCTION IN DENDRITIC SPINE MORPHOGENESIS.
|||"The role of Cdk5-mediated apurinic/apyrimidinic endonuclease 1 phosphorylation in neuronal death."|
Huang E., Qu D., Zhang Y., Venderova K., Haque M.E., Rousseaux M.W.C., Slack R.S., Woulfe J.M., Park D.S.
Nat. Cell Biol. 12:563-571(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION AS APEX1 KINASE, INTERACTION WITH APEX1.
|||"Hypomyelination Phenotype caused by impaired differentiation of oligodendrocytes in Emx1-cre mediated Cdk5 conditional knockout mice."|
He X., Takahashi S., Suzuki H., Hashikawa T., Kulkarni A.B., Mikoshiba K., Ohshima T.
Neurochem. Res. 36:1293-1303(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: DISRUPTION PHENOTYPE, FUNCTION IN OLIGODENDROCYTE DIFFERENTIATION.
|||"Cyclin-dependent kinase 5 (Cdk5) regulates the function of CLOCK protein by direct phosphorylation."|
Kwak Y., Jeong J., Lee S., Park Y.U., Lee S.A., Han D.H., Kim J.H., Ohshima T., Mikoshiba K., Suh Y.H., Cho S., Park S.K.
J. Biol. Chem. 288:36878-36889(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH CLOCK.
|||"SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways."|
Park J., Chen Y., Tishkoff D.X., Peng C., Tan M., Dai L., Xie Z., Zhang Y., Zwaans B.M., Skinner M.E., Lombard D.B., Zhao Y.
Mol. Cell 50:919-930(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-56, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Embryonic fibroblast.
|+||Additional computationally mapped references.|
|D29678 mRNA. Translation: BAA06148.1.|
BC052007 mRNA. Translation: AAH52007.1.
X64604 mRNA. Translation: CAA45888.1.
S80121 Genomic DNA. No translation available.
|RefSeq||NP_031694.1. NM_007668.3. |
3D structure databases
|SMR||P49615. Positions 1-292. |
Protein-protein interaction databases
|BioGrid||198646. 4 interactions.|
|IntAct||P49615. 5 interactions.|
Protocols and materials databases
Genome annotation databases
|Ensembl||ENSMUST00000030814; ENSMUSP00000030814; ENSMUSG00000028969. |
|UCSC||uc008wrl.1. mouse. |
|MGI||MGI:101765. Cdk5. |
Enzyme and pathway databases
|BRENDA||22.214.171.124. 3474. |
|Reactome||REACT_194409. Developmental Biology. |
Gene expression databases
Family and domain databases
|InterPro||IPR011009. Kinase-like_dom. |
|Pfam||PF00069. Pkinase. 1 hit. |
|SMART||SM00220. S_TKc. 1 hit. |
|SUPFAM||SSF56112. SSF56112. 1 hit. |
|PROSITE||PS00107. PROTEIN_KINASE_ATP. 1 hit. |
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
|ChiTaRS||CDK5. mouse. |
|Accession||Primary (citable) accession number: P49615|
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|