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  7. CDK5 subfamily
  8. Cyclin-dependent-like kinase 5

Tchem Cyclin-dependent-like kinase 5

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.

This gene encodes a proline-directed serine/threonine kinase that is a member of the cyclin-dependent kinase family of proteins. Unlike other members of the family, the protein encoded by this gene does not directly control cell cycle regulation. Instead the protein, which is predominantly expressed at high levels in mammalian postmitotic central nervous system neurons, functions in diverse processes such as synaptic plasticity and neuronal migration through phosphorylation of proteins required for cytoskeletal organization, endocytosis and exocytosis, and apoptosis. In humans, an allelic variant of the gene that results in undetectable levels of the protein has been associated with lethal autosomal recessive lissencephaly-7. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2015]

 Comments

Property Summary

Ligand Count 38
NCBI Gene PubMed Count 262
PubMed Score 1238.43
PubTator Score 542.82

Knowledge Summary

Patent (42,088)

TINX Plot

  Disease (5)

Disease Target Count Z-score Confidence
Lissencephaly 7 with cerebellar hypoplasia 1 0.0 0.0
Tauopathies 3 0.0 0.0
Disease Target Count Z-score Confidence
Neurodegenerative disease 414 0.0 4.0

Expression

  Differential Expression (17)

Disease log2 FC p
adult high grade glioma -1.500 6.6e-05
astrocytic glioma -1.400 2.3e-03
Astrocytoma, Pilocytic -1.700 2.9e-08
atypical teratoid / rhabdoid tumor -1.600 3.3e-09
Breast cancer 1.500 9.4e-21
colon cancer 1.200 4.4e-02
ependymoma -1.700 8.0e-03
glioblastoma -1.300 1.8e-04
invasive ductal carcinoma 1.400 3.5e-03
lung cancer 1.800 6.6e-05
lung carcinoma 1.100 4.3e-20
malignant mesothelioma -1.300 6.1e-06
medulloblastoma -1.300 1.3e-04
medulloblastoma, large-cell -1.300 5.9e-04
oligodendroglioma -1.200 1.6e-02
Pick disease -1.100 1.0e-02
tuberculosis 1.500 1.5e-07

Synonym

Accession Q00535 A1XKG3
Symbols LIS7
PSSALRE

Gene

CDK5

PANTHER Protein Class (4)

  Ortholog (13)

Species Source Disease
Inparanoid OMA EggNOG
Inparanoid OMA EggNOG
Inparanoid OMA EggNOG
Inparanoid OMA EggNOG
Inparanoid OMA
Inparanoid OMA
OMA EggNOG
Inparanoid OMA EggNOG
Inparanoid OMA EggNOG
Inparanoid OMA
Inparanoid OMA EggNOG
Inparanoid OMA EggNOG
Inparanoid OMA EggNOG

 UniProt Keyword (27)

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 GO Function (13)

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 GO Component (20)

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 GO Process (66)

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 Compartment GO Term (73)

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 MGI Phenotype (7)

 HCA RNA Cell Line (56)

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Pathway (51)

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Protein-protein Interaction (8)

CDK3   CCNE1   C2CD5   CCNB1   CDKN1B   CABLES1   CDK20   CDK14  

PDB (7)

Ligand (38)

Structure of CHEMBL365855

CHEMBL365855
pIC50 7.60

Structure of CHEMBL3775677

CHEMBL3775677
pIC50 7.68

Structure of CHEMBL3775608

CHEMBL3775608
pIC50 7.77

Structure of CHEMBL186240

CHEMBL186240
pIC50 7.80

Structure of CHEMBL187903

CHEMBL187903
pIC50 7.89

Structure of CHEMBL184404

CHEMBL184404
pIC50 7.89

Structure of CHEMBL187256

CHEMBL187256
pIC50 7.89

Structure of CHEMBL191003

CHEMBL191003
pIC50 7.90

Structure of CHEMBL186470

CHEMBL186470
pIC50 7.92

Structure of CHEMBL363954

CHEMBL363954
pIC50 8.00

Structure of CHEMBL3774932

CHEMBL3774932
pIC50 8.05

Structure of CHEMBL3775470

CHEMBL3775470
pIC50 8.10

Structure of CHEMBL364213

CHEMBL364213
pIC50 8.10

Structure of CHEMBL384304

CHEMBL384304
pKd 8.13

Structure of CHEMBL186898

CHEMBL186898
pIC50 8.16

Structure of CHEMBL23254

CHEMBL23254
pIC50 8.22

Structure of CHEMBL3775509

CHEMBL3775509
pIC50 8.30

Structure of CHEMBL3774632

CHEMBL3774632
pIC50 8.30

Structure of CHEMBL362560

CHEMBL362560
pIC50 8.30

Structure of CHEMBL1241758

CHEMBL1241758
pIC50 8.30

Gene RIF (170)

AA Sequence 

MQKYEKLEKIGEGTYGTVFKAKNRETHEIVALKRVRLDDDDEGVPSSALREICLLKELKHKNIVRLHDVL      1 - 70
HSDKKLTLVFEFCDQDLKKYFDSCNGDLDPEIVKSFLFQLLKGLGFCHSRNVLHRDLKPQNLLINRNGEL     71 - 140
KLADFGLARAFGIPVRCYSAEVVTLWYRPPDVLFGAKLYSTSIDMWSAGCIFAELANAGRPLFPGNDVDD    141 - 210
QLKRIFRLLGTPTEEQWPSMTKLPDYKPYPMYPATTSLVNVVPKLNATGRDLLQNLLKCNPVQRISAEEA    211 - 280
LQHPYFSDFCPP                                                              281 - 292
//

Text Mined References (288)

PMID Year Title