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Information on EC 2.7.11.22 - cyclin-dependent kinase and Organism(s) Mus musculus and UniProt Accession Q04859
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2.7.11.22 cyclin-dependent kinaseIUBMB Comments
Activation of cyclin-dependent kinases requires association of the enzyme with a regulatory subunit referred to as a cyclin. It is the sequential activation and inactivation of cyclin-dependent kinases, through the periodic synthesis and destruction of cyclins, that provides the primary means of cell-cycle regulation.
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Word Map
- 2.7.11.22
- cyclins
- p27kip1
- retinoblastoma
-
mitosis
-
cell-cycle
-
checkpoint
- histone
- tumorigenesis
- tumour
- bcl-2
- p16ink4a
-
s-phase
-
hyperphosphorylation
- leukemia
- prostate
- chromatin
- epidermal
-
exit
-
antiproliferative
- mapks
- caspase-3
-
mitogen
- tau
- xenopus
- spindle
- c-myc
-
interphase
-
quiescent
- oocyte
- pcna
-
fission
- alzheimer
- proteasome
- microtubule
- analysis
- medicine
- cdc25c
- pharmacology
- letrozole
-
cycle-dependent
-
polo-like
- chk1
-
p53-independent
- drug development
-
cytokinesis
- centrosome
-
prophase
-
postmitotic
-
receptor-positive
-
cycle-related
-
anaphase
-
aurora
-
metaphase
-
her2-negative
The taxonomic range for the selected organisms is: Mus musculus
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Reaction Schemes
+
a [protein]-(L-serine/L-threonine)
=
+
a [protein]-(L-serine/L-threonine) phosphate
Synonyms
cyclin-dependent kinase, cdk, p34cdc2, cdkl5, cdc2 kinase, cyclin-dependent kinase 5, cyclin-dependent kinase 2, cdc28, cyclin-dependent kinase 4, cyclin-dependent kinase 1, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
CDK
CDK2
Cdk5
cyclin-dependent kinase 5
cyclin-dependent kinase 7
as part of the CDK-activating kinase complex, CDK7 is a component of the basal transcription factor TFIIH
Cyclin-dependent kinase pef1
-
-
-
-
PHO85 homolog
-
-
-
-
additional information
Cdk5
-
-
cyclin-dependent kinase 5
-
-
additional information
-
CDK5 is a unique member of the CDK family, see also EC 2.7.11.26
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
phospho group transfer
-
-
-
-
SYSTEMATIC NAME
IUBMB Comments
ATP:cyclin phosphotransferase
Activation of cyclin-dependent kinases requires association of the enzyme with a regulatory subunit referred to as a cyclin. It is the sequential activation and inactivation of cyclin-dependent kinases, through the periodic synthesis and destruction of cyclins, that provides the primary means of cell-cycle regulation.
CAS REGISTRY NUMBER
COMMENTARY
150428-23-2
-
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
ATP + 1-(beta-D-ribofuranosyl)-nicotinamide
ADP + beta-nicotinamide D-ribonucleotide
-
-
-
?
ATP + B-cell lymphoma protein 2
ADP + phosphorylated B-cell lymphoma protein 2
-
B-cell lymphoma protein 2 is phosphorylated at Ser70, Cdk5-mediated B-cell lymphoma protein 2 phosphorylation is pivotal for the antiapoptotic effect of Bcl-2 and contributes to the maintenance of neuronal survival by Cdk5
-
-
?
ATP + collapsing response mediator protein
ADP + phosphorylated collapsing response mediator protein
-
-
-
-
?
ATP + high-molecular-weight neurofilament
ADP + phosphorylated high-molecular-weight neurofilament
-
-
-
?
ATP + MEP50 protein
ADP + MEP50 phosphoprotein
-
a PRMT5 co-regulatory factor
-
-
?
ATP + microtubule-associated tau
ADP + phosphorylated microtubule-associated tau
-
-
-
?
ATP + neurofilament heavy chain
ADP + phosphorylated neurofilament heavy chain
-
-
-
-
?
ATP + pre-synaptic P/Q-type voltage-dependent calcium channel
ADP + phosphorylated pre-synaptic P/Q-type voltage-dependent calcium channel
-
-
-
?
ATP + Sept5 protein
ADP + phosphorylated Sept5 protein
-
Sept5 protein is phosphorylated at Ser17
-
-
?
ATP + septine 5
ADP + phosphorylated septine 5
-
Ser327 is the major phosphorylation site for Cdk5 in presence of activator p35
-
-
?
ATP + steroidogenic factor 1
ADP + phosphorylated steroidogenic factor 1
also known as Ad4BP, systematic name NR5A1, the phosphorylation site is at Ser203
-
-
?
ATP + [tau protein]
ADP + O-phospho-[tau-protein]
-
Cdk5-p25 or Cdk5-p35, see also EC 2.7.11.26
-
-
?
ATP + c-Jun N-terminal kinase 3
ADP + phosphorylated c-Jun N-terminal kinase 3
-
i.e. JNK3, phosphorylation inhibits JNK3 and leads to reduced phosphorylation of c-jun and to reduced apoptosis
-
-
?
ATP + c-Jun N-terminal kinase 3
ADP + phosphorylated c-Jun N-terminal kinase 3
-
i.e. JNK3, phosphorylation at Thr131
-
-
?
ATP + ErbB2
ADP + phosphorylated ErbB2
-
phosphorylation of the neuregulin receptor by Cdk5 is involved in regulation of neuregulin
-
-
?
ATP + ErbB3
ADP + phosphorylated ErbB3
-
phosphorylation of the neuregulin receptor by Cdk5 is involved in regulation of neuregulin
-
-
?
ATP + histone H1
ADP + phosphorylated histone H1
-
preferred substrate of cdk5 associated with p35
-
-
?
ATP + histone H1
ADP + phosphorylated histone H1
-
commercial substrate, Cdk5
-
-
?
ATP + huntingtin
ADP + phosphorylated huntingtin
-
huntingtin is phosphorylated by Cdk5 at Ser1181 and Ser1201
-
-
?
ATP + MEK1
ADP + phosphorylated MEK1
-
Cdk5 regulates the ERK1/2 pathway through phosphorylation of MEK1, overview
-
-
?
ATP + neuregulin receptor ErbB2
ADP + phosphorylated neuregulin receptor ErbB2
-
phosphorylation at Ser1176 by Cdk5
-
-
?
ATP + neuregulin receptor ErbB2
ADP + phosphorylated neuregulin receptor ErbB2
-
phosphorylation at Ser1176 in the sequence RPKTLSPGKN by Cdk5
-
-
?
ATP + neuregulin receptor ErbB3
ADP + phosphorylated neuregulin receptor ErbB3
-
phosphorylation at Thr871 and Ser1120 in the consensus sequence RSRSPR by Cdk5, Cdk5 associates with Erb3 in vivo
-
-
?
ATP + neuregulin receptor ErbB3
ADP + phosphorylated neuregulin receptor ErbB3
-
phosphorylation at Thr871 in the sequence AKTPIKWAL and Ser1120 in the consensus sequence RSRSPR by Cdk5, weak phosphorylation of Ser1204 in the proline-rich sequence RRGSPPRPPR
-
-
?
ATP + NF-H
ADP + phosphorylated NF-H
-
neurofilament protein that correlates neurit outgrowth, phosphorylation at the KSP repeats, regulated by the myelin-associate glycoprotein
-
-
?
ATP + NF-H
ADP + phosphorylated NF-H
-
neurofilament protein, phosphorylation at the KSP repeats
-
-
?
ATP + NF-M
ADP + phosphorylated NF-M
-
neurofilament protein, phosphorylation at the KSP repeats, regulated by the myelin-associate glycoprotein
-
-
?
ATP + NF-M
ADP + phosphorylated NF-M
-
neurofilament protein, phosphorylation at the KSP repeats
-
-
?
ATP + pocket protein p107
ADP + phosphorylated pocket protein 107
-
hyperphosphorylation by CDK/cyclin contributes to the transactivation of genes with functional E2F-binding sites, including growth and cell-cycle regulators, i.e. c-myc, Rb protein, cdc2, cyclin E, and cyclin A, and genes encoding proteins required for nucleotide and DNA biosynthesis
-
-
?
ATP + pocket protein p107
ADP + phosphorylated pocket protein 107
-
hyperphosphorylation by CDK/cyclin
-
-
?
ATP + pocket protein p130
ADP + phosphorylated pocket protein 130
-
hyperphosphorylation by CDK/cyclin contributes to the transactivation of genes with functional E2F-binding sites, including growth and cell-cycle regulators, i.e. c-myc, Rb protein, cdc2, cyclin E, and cyclin A, and genes encoding proteins required for nucleotide and DNA biosynthesis
-
-
?
ATP + pocket protein p130
ADP + phosphorylated pocket protein 130
-
hyperphosphorylation by CDK/cyclin
-
-
?
ATP + protein
ADP + phosphoprotein
serine/threonine-specific protein kinase
-
-
?
ATP + protein
ADP + phosphoprotein
receptor protein tyrosine kinase
-
-
?
ATP + retinoblastoma protein
ADP + phosphorylated retinoblastoma protein
-
i.e. Rb protein, hyperphosphorylation by CDK/cyclin contributes to the transactivation of genes with functional E2F-binding sites, including growth and cell-cycle regulators, i.e. c-myc, Rb protein, cdc2, cyclin E, and cyclin A, and genes encoding proteins required for nucleotide and DNA biosynthesis
-
-
?
ATP + retinoblastoma protein
ADP + phosphorylated retinoblastoma protein
-
i.e. Rb protein, hyperphosphorylation by CDK/cyclin
-
-
?
ATP + retinoblastoma protein
ADP + phosphorylated retinoblastoma protein
the phosphorylation site is at Ser795
-
-
?
ATP + STAT3
ADP + phosphorylated STAT3
-
specific phosphorylation at Ser727 by CDK5-p35, CDK5 is involved in regulation of the signal transducer and transcription activator STAT3 in brain and muscle
-
-
?
ATP + STAT3
ADP + phosphorylated STAT3
-
specific phosphorylation at Ser727 by CDK5-p35
-
-
?
ATP + tau protein
ADP + phosphorylated tau protein
-
cdk5 substrate in brain, Cdk5-p25 or Cdk5-p35
-
-
?
ATP + tau protein
ADP + phosphorylated tau protein
-
hyperactivated Cdk5-p25
-
-
?
ATP + [tau protein]
ADP + [O-phospho-tau protein]
-
substrate of CDK5 in the central nervous system, see also EC 2.7.11.26, tau hyperphosphorylation is involved in neurodegeneration and Alzheimer's disease, tau protein phosphorylation by CDK5 is involved in apoptosis in cortical cells
-
-
?
ATP + [tau protein]
ADP + [O-phospho-tau protein]
-
substrate of CDK5 in the central nervous system, see also EC 2.7.11.26, phosphorylation at the PHF-1 epitope, not the Tau-1 epitope, of tau protein by CDK5-p25
-
-
?
ATP + [tau-protein]
ADP + O-phospho -[tau-protein]
-
cdk5 substrate in brain, cdk5 associated with p39, tau is a microtubule-associated and developmentally regulated protein involved in axonal development in neurons, tau phosphorylation by cyclin-dependent kinase 5/p39 during brain development reduces its affinity for microtubules, reaction of EC 2.7.11.26
-
-
?
ATP + [tau-protein]
ADP + O-phospho -[tau-protein]
-
preferred substrate of cdk5 associated with p39, recombinant bacterially expressed human tau protein as substrate, phosphorylation at Ser202 and Thr205, reaction of EC 2.7.11.26
-
-
?
ATP + [tau-protein]
ADP + O-phospho-[tau-protein]
-
activity in organisms with mutated APP and tau, not in wild-type, overview
-
-
?
ATP + [tau-protein]
ADP + O-phospho-[tau-protein]
-
hyperphosphorylation of tau by CDK5 is involved in apoptosis and neurodegeneration in Alzheimer's disease, overview
-
-
?
ATP + [tau-protein]
ADP + O-phospho-[tau-protein]
-
phosphorylation of the PHF-1 epitope at Ser396 and Ser404 by CDK5
-
-
?
additional information
?
-
the cdc2 protein kinase plays a role in transcriptional regulation
-
-
?
additional information
?
-
enzyme may have a critical function during normal embryonic development and continues to be expressed in differentiated adult tissues
-
-
?
additional information
?
-
-
enzyme may have a critical function during normal embryonic development and continues to be expressed in differentiated adult tissues
-
-
?
additional information
?
-
enzyme is involved in signal transduction process of pattern formation in the hindbrain
-
-
?
additional information
?
-
enzyme is involved in signal transduction process of pattern formation in the hindbrain
-
-
?
additional information
?
-
-
enzyme is involved in signal transduction process of pattern formation in the hindbrain
-
-
?
additional information
?
-
-
naturally occurring V717I mutation of the amyloid precursor protein APP in a CT100 fragment of mutants leads to augmented age-dependent tau phosphorylation, followed by increased activation status of mitogen-activated protein kinase family members, e.g. ERK1/2, p38, and c-Jun NH2-terminal kinase, compared to the wild-type organism, naturally occurring V337M mutation of tau protein of mutants leads to age-dependent memory deficits
-
-
?
additional information
?
-
-
cdk5 catalyzes tau phosphorylation in brain, but cyclin-dependent phosphorylation of other proteins, EC 2.7.11.22, in different tissues
-
-
?
additional information
?
-
-
CDK-cyclins and CDK inhibitory proteins are involved in the cell cycle regulation and of vascular cell proliferation and migration, as well as in the control of neointimal thickening, modeling, overview
-
-
?
additional information
?
-
-
Cdk5 regulates Akt activation and cell survival through the neuregulin-mediated PI 3-kinase signaling pathway, null mutants show lower phosphatidylinositol 3-kinase activity, Cdk5-p35 mediates neuroprotection
-
-
?
additional information
?
-
-
Cdk5 regulation, overview, Cdk5 is involved in neuronal migration and phosphorylation of neurofilaments and cytoskeletal proteins, and is critical for neuronal survival, deregulation of Cdk5 occurs in neurodegeneration
-
-
?
additional information
?
-
-
the CDKs are involved in regulation of cell cycle and neuronal differentiation, cleavage of p35 to p25 occurs in neurons undergoing induced cell death and in brains exposed to ischaemia
-
-
?
additional information
?
-
no detectable kinase activity towards CDKs, the Pol II carboxyl-terminal domain (CTD), histone H1 or myelin basic protein
-
-
?
additional information
?
-
-
the CDK2-cyclin E complex is a inducer of S-phase entry and key factor for the initiation of centrosome duplication, that CDK4/6-cyclin D are the proteins that compensates for the loss of CDK2 in the initiation of centrosome duplication
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
ATP + 1-(beta-D-ribofuranosyl)-nicotinamide
ADP + beta-nicotinamide D-ribonucleotide
-
-
-
?
ATP + c-Jun N-terminal kinase 3
ADP + phosphorylated c-Jun N-terminal kinase 3
-
i.e. JNK3, phosphorylation inhibits JNK3 and leads to reduced phosphorylation of c-jun and to reduced apoptosis
-
-
?
ATP + ErbB2
ADP + phosphorylated ErbB2
-
phosphorylation of the neuregulin receptor by Cdk5 is involved in regulation of neuregulin
-
-
?
ATP + ErbB3
ADP + phosphorylated ErbB3
-
phosphorylation of the neuregulin receptor by Cdk5 is involved in regulation of neuregulin
-
-
?
ATP + MEK1
ADP + phosphorylated MEK1
-
Cdk5 regulates the ERK1/2 pathway through phosphorylation of MEK1, overview
-
-
?
ATP + MEP50 protein
ADP + MEP50 phosphoprotein
-
a PRMT5 co-regulatory factor
-
-
?
ATP + neuregulin receptor ErbB2
ADP + phosphorylated neuregulin receptor ErbB2
-
phosphorylation at Ser1176 by Cdk5
-
-
?
ATP + neuregulin receptor ErbB3
ADP + phosphorylated neuregulin receptor ErbB3
-
phosphorylation at Thr871 and Ser1120 in the consensus sequence RSRSPR by Cdk5, Cdk5 associates with Erb3 in vivo
-
-
?
ATP + NF-H
ADP + phosphorylated NF-H
-
neurofilament protein that correlates neurit outgrowth, phosphorylation at the KSP repeats, regulated by the myelin-associate glycoprotein
-
-
?
ATP + NF-M
ADP + phosphorylated NF-M
-
neurofilament protein, phosphorylation at the KSP repeats, regulated by the myelin-associate glycoprotein
-
-
?
ATP + pocket protein p107
ADP + phosphorylated pocket protein 107
-
hyperphosphorylation by CDK/cyclin contributes to the transactivation of genes with functional E2F-binding sites, including growth and cell-cycle regulators, i.e. c-myc, Rb protein, cdc2, cyclin E, and cyclin A, and genes encoding proteins required for nucleotide and DNA biosynthesis
-
-
?
ATP + pocket protein p130
ADP + phosphorylated pocket protein 130
-
hyperphosphorylation by CDK/cyclin contributes to the transactivation of genes with functional E2F-binding sites, including growth and cell-cycle regulators, i.e. c-myc, Rb protein, cdc2, cyclin E, and cyclin A, and genes encoding proteins required for nucleotide and DNA biosynthesis
-
-
?
ATP + retinoblastoma protein
ADP + phosphorylated retinoblastoma protein
-
i.e. Rb protein, hyperphosphorylation by CDK/cyclin contributes to the transactivation of genes with functional E2F-binding sites, including growth and cell-cycle regulators, i.e. c-myc, Rb protein, cdc2, cyclin E, and cyclin A, and genes encoding proteins required for nucleotide and DNA biosynthesis
-
-
?
ATP + STAT3
ADP + phosphorylated STAT3
-
specific phosphorylation at Ser727 by CDK5-p35, CDK5 is involved in regulation of the signal transducer and transcription activator STAT3 in brain and muscle
-
-
?
ATP + [tau protein]
ADP + [O-phospho-tau protein]
-
substrate of CDK5 in the central nervous system, see also EC 2.7.11.26, tau hyperphosphorylation is involved in neurodegeneration and Alzheimer's disease, tau protein phosphorylation by CDK5 is involved in apoptosis in cortical cells
-
-
?
ATP + [tau-protein]
ADP + O-phospho -[tau-protein]
-
cdk5 substrate in brain, cdk5 associated with p39, tau is a microtubule-associated and developmentally regulated protein involved in axonal development in neurons, tau phosphorylation by cyclin-dependent kinase 5/p39 during brain development reduces its affinity for microtubules, reaction of EC 2.7.11.26
-
-
?
ATP + tau protein
ADP + phosphorylated tau protein
-
cdk5 substrate in brain, Cdk5-p25 or Cdk5-p35
-
-
?
ATP + tau protein
ADP + phosphorylated tau protein
-
hyperactivated Cdk5-p25
-
-
?
ATP + [tau-protein]
ADP + O-phospho-[tau-protein]
-
activity in organisms with mutated APP and tau, not in wild-type, overview
-
-
?
ATP + [tau-protein]
ADP + O-phospho-[tau-protein]
-
hyperphosphorylation of tau by CDK5 is involved in apoptosis and neurodegeneration in Alzheimer's disease, overview
-
-
?
additional information
?
-
the cdc2 protein kinase plays a role in transcriptional regulation
-
-
?
additional information
?
-
enzyme may have a critical function during normal embryonic development and continues to be expressed in differentiated adult tissues
-
-
?
additional information
?
-
-
enzyme may have a critical function during normal embryonic development and continues to be expressed in differentiated adult tissues
-
-
?
additional information
?
-
enzyme is involved in signal transduction process of pattern formation in the hindbrain
-
-
?
additional information
?
-
enzyme is involved in signal transduction process of pattern formation in the hindbrain
-
-
?
additional information
?
-
-
enzyme is involved in signal transduction process of pattern formation in the hindbrain
-
-
?
additional information
?
-
-
naturally occurring V717I mutation of the amyloid precursor protein APP in a CT100 fragment of mutants leads to augmented age-dependent tau phosphorylation, followed by increased activation status of mitogen-activated protein kinase family members, e.g. ERK1/2, p38, and c-Jun NH2-terminal kinase, compared to the wild-type organism, naturally occurring V337M mutation of tau protein of mutants leads to age-dependent memory deficits
-
-
?
additional information
?
-
-
CDK-cyclins and CDK inhibitory proteins are involved in the cell cycle regulation and of vascular cell proliferation and migration, as well as in the control of neointimal thickening, modeling, overview
-
-
?
additional information
?
-
-
Cdk5 regulates Akt activation and cell survival through the neuregulin-mediated PI 3-kinase signaling pathway, null mutants show lower phosphatidylinositol 3-kinase activity, Cdk5-p35 mediates neuroprotection
-
-
?
additional information
?
-
-
Cdk5 regulation, overview, Cdk5 is involved in neuronal migration and phosphorylation of neurofilaments and cytoskeletal proteins, and is critical for neuronal survival, deregulation of Cdk5 occurs in neurodegeneration
-
-
?
additional information
?
-
-
the CDKs are involved in regulation of cell cycle and neuronal differentiation, cleavage of p35 to p25 occurs in neurons undergoing induced cell death and in brains exposed to ischaemia
-
-
?
additional information
?
-
-
the CDK2-cyclin E complex is a inducer of S-phase entry and key factor for the initiation of centrosome duplication, that CDK4/6-cyclin D are the proteins that compensates for the loss of CDK2 in the initiation of centrosome duplication
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Ca2+
Ca2+
-
induces cleavage of p35 to p25 by calpains, which changes the localization of Cdk5 from the particluate to the soluble fraction
Ca2+
-
stimulates Cdk5, Ca2+/calmodulin induce the phosphorylation of p35 by Cdk5 after stimulation of the Ca2+-permeable cation channels NMDA receptor and kainate receptor, leading to cleavage of p35 to p25
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
CDK inhibitory proteins
-
members of the family of CDK inhibitory proteins, e.g. INK4 proteins, overview, CKIs may play a role as regulators in neointimal hyperplasia
-
NMDA
-
inactivates Cdk5 by modulation of Ser67 on the protein phosphatase inhibitor-I, overview
RNAi
depletion of PNQALRE by more than 80%, impairs cell proliferation, but fails to arrest the cell cycle at a discrete point
-
roscovitine
-
inhibits Cdk5 activity, including the p35 phosphorylation activity
additional information
-
enzyme cofactor p35 levels in primary embryonal cortical neurons are reduced by glutamate-induced stimulation of NMDA or kainate receptors through NMDA or kainate, p35 is reduced via proteasomal degradation, reduced p35 leads to inhibition of Cdk5, no inhibition by casein kinase inhibitor CKI-7
-
additional information
-
glutamate triggers the ubiquitination and subsequent degradation of p35 in neurons after autophosphorylation of Cdk5-p35 at p35
-
additional information
-
no effect by doxycycline on enzyme expression and activity
-
additional information
-
physiological effects of CDK inhibition, overview, CDKs are deactivated by dephosphorylation, protein p27Kip1 mediates CDK2 inhibition
-
additional information
-
after irridation of one- or two-cell embryos the cdk1/cyclin B1 complex is blocked
-
additional information
-
dysregulation of Cdk5 occurs with aging and concomitantly with an increase in DNA damage
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Calmodulin
-
Ca2+/calmodulin induce the phosphorylation of p35 by Cdk5 after stimulation of the Ca2+-permeable cation channels NMDA receptor and kainate receptor, leading to cleavage of p35 to p25
p25
-
cyclin activator, dependent on, over 10fold increase in activity of CDK5
-
p25
-
regulatory and activating subunit, soluble localization of enzyme complex
-
p25
-
regulatory subunit and activator of Cdk5, soluble, p35 is cleaved to p25 by calpain leading to hyperactivation of Cdk5
-
p35
-
tightly bound neuronal activators of cdk5, required for activity with regulatory function, p39 activates to a greater extent compared to p35 in vitro
-
p35
-
activation subunit, required, interacts with and activates Cdk5, laminin induces upregulation of p35, regulation of p35 expression, overview
-
p35
-
membrane-bound cofactor of Cdk5, levels in primary embryonal cortical neurons are reduced by glutamate-induced stimulation of NMDA or kainate receptors through NMDA or kainate, cleavage of p35 to p25, reduced p35 leads to inhibition of Cdk5
-
p35
-
regulatory and activating subunit, particulate localization of enzyme complex
-
p35
-
regulatory subunit and activator of Cdk5, membrane-bound, in neuronal growth cones, p35 is cleaved to p25 by calpain leading to hyperactivation of Cdk5
-
p35
-
p35 knockout mice (p35-/-), which exhibit significantly decreased Cdk5 activity, show delayed responses to painful thermal stimulation compared with wild-type controls. In contrast, mice overexpressing p35, which exhibit elevated levels of Cdk5 activity, are more sensitive to painful thermal stimuli than are controls
-
p35
-
activation of Cdk5 requires association with two noncyclin neural-specific activators p35 and p39
-
p39
-
tightly bound neuronal activators of cdk5, required for activity with regulatory function, p39 activates to a greater extent compared to p35 in vitro, p39 is the activator activator in vivo
-
p39
-
activation subunit, can substitute for p35, interacts with and activates Cdk5
-
p39
-
activation of Cdk5 requires association with two noncyclin neural-specific activators p35 and p39
-
p39
-
regulatory subunit, Mice lacking p39 display an apparently normal phenotype
-
additional information
activation of cyclin-dependent kinase 4 by mouse MO15-associated kinase
-
additional information
-
activation of cyclin-dependent kinase 4 by mouse MO15-associated kinase
-
additional information
-
thapsigargin-induced apoptosis might enhance the phosphorylation of the PHF-1 epitope of tau protein by CDK5-p25, no effect by doxycycline on enzyme expression and activity
-
additional information
cyclin H or cyclin H together with cyclin K do not activate PNQALRE
-
additional information
myocardial ischemia activates Cdk2 resulting in the phosphorylation and inactivation of the retinoblastoma gene product
-
additional information
-
Cdk5 Cdk5 requires the binding of p35, p25 (a C-terminal fragment of p35), or p39 as regulatory subunnits for activation, activation mechanism of Cdk5, overview
-
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
-
dorsal root ganglia and trigeminal ganglia, Cdk5 is colocalized with p35
-
in MII oocytes only the dephosphorylated active form of cdk1 present, just after fertilization, the amount of the dephosphorylated form decreases, whereas that of the phosphorylated form increases
p58 expression is elevated between day 14 and day 16 post coitus
enzyme is highly expressed in mature brain. Expression of CDK5 is already seen at embryonal 12.5 days, and it gradually increases through the embryonal stage. After birth, the expression is maintained at a high level to adulthood
p58 expression is elevated early in embryogenesis and then decreases dramatically
-
inactive and phosphorylated form of cdk1 present in G2 arrested one-cell embryos, while the active and dephosphorylated form of cdk1 present in dividing control and irradiated one-cell embryos
-
immortilized embryonic brain cortex cell line overexpressing the human tau protein
-
immortalized embryonic brain cortical cells, CN1.4 cells stably overexpressing human tau protein with four microtubule-binding repeats and no N-terminal inserts
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
additional information
-
Ca2+ induces cleavage of p35 to p25 by calpains, which changes the localization of Cdk5 from the particulate to the soluble fraction
-
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
-
cyclin-dependent kinase 5, Cdk5, is a member of the family of Cdks. Cdks are proline-directed Ser/Thr protein kinases that are activated by binding a regulatory subunit called cyclin, comparison of neuronal and cycling Cdks, overview. Cdk5 may have evolved from cycling Cdks to function in post-mitotic neurons
malfunction
metabolism
physiological function
malfunction
-
the inhibition of cdk-5 activity has neuroprotective effect on neurons in Niemann-Pick disease type C mice
malfunction
-
Cdk5 null mice exhibit perinatal lethality with abnormal positioning of neurons in the brain. Ballooned perikarya of large neurons in the brainstem and cytoplasmic vacuoles in brain nuclei are described for Cdk5 null mice. Similar phenotypes were also observed in the p35-/- p39-/- double null mutant
metabolism
-
cycling Cdks and neuronal Cdk5 are inversely expressed during neuronal differentiation. Upon neuronal differentiation, cycling Cdks, which are active in proliferating neuronal precursor cells, are down-regulated and Cdk5-p35 is upregulated
metabolism
-
the primary cellular mechanism that restricts cyclin D1/CDK4 activity is cytoplasmic, ubiquitin-mediated degradation of cyclin D1 during S-phase. Mutations that disrupt this event, via within the cyclin D1 degron or inactivating the cyclin D1 E3 ligase, Fbx4, directly contribute to neoplastic growth
physiological function
-
Cdk5 appears to be involved in the regulation of neuronal survival both during neuronal development and under stress conditions
physiological function
-
nuclear cyclin D1/CDK4-dependent repression of CUL4A and CUL4B, encoding scaffolding proteins for the E3 ligase that directs CDT1 degradation during S-phase, the repression requires S-phase accumulation of catalytically active cyclin D1/CDK4, molecular mechanism, overview. Phosphorylation of MEP50, a PRMT5 co-regulatory factor, by CDK4 increases PRMT5/MEP50 activity, and increased PRMT5 activity mediates key events associated with cyclin D1-dependent neoplastic growth including CUL4 repression, CDT1 overexpression, and DNA re-replication
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
phosphoprotein
proteolytic modification
-
p35 is degraded by the proteasome after stimulation of NMDA or kainate receptors and subsequent Ca2+/calmodulin-dependent phosphorylation of p35 by Cdk5, p35 is cleaved to p25, reduced p35 leads to inhibition of Cdk5, overview
additional information
-
p35 and cyclin B are ubiquitinated prior to degradation, proteasomal degradation of p35 is induced by phosphatase inhibitor okadaic acid, proteolytic patterns of p35 amd p39, overview
phosphoprotein
-
in S/G2 phase of the cell cycle, Cdk1/Cdc2, upon binding of cyclin B, is phosphorylated and inactivated at T14, Y15, and T161 by protein kinases Wee1 and CAK, to activate the enzyme T14 and Y15 are dephosphorylated by phosphatase Cde25, the active enzyme is only phosphorylated at T161, release of cyclin B results in complete dephosphorylation of Cdk1/Cdc2, overview, Cdk5 binds p35 and is then activated by phosphorylation at T14, Y15, and S519, the bound p35 is also autophosphorylated by Cdk5-p35 at a single site, which induces ubiquitination and subsequent degradation of p35 in neurons, release of p35 leads to dephosphorylation of Cdk5, overview, cyclin E is bound to and autophosphorylated by Cdk2 leading to its degradation
phosphoprotein
-
p35 is degraded by the proteasome after stimulation of NMDA or kainate receptors and subsequent Ca2+/calmodulin-dependent phosphorylation of p35 by Cdk5, reduced p35 leads to inhibition of Cdk5
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
S308D
the mutation mimicking the phosphorylated serine residue by aspartate substitution (S308D) changes CDKL5 localization to the cytosol
additional information
additional information
an isoleucine to valine change in the PSTAIR region, and a proline to serine change at the C-terminal region of the protein p34 cause the p34 protein kinase to become inactivated and degraded in FT210 cells at the restrictive temperature, 39°C
additional information
-
a cdk-deficient mouse mutant lacks tau phosphorylation activity
additional information
-
construction and expression of a dominant negative CDK5 mutant inhibiting CDK5 activity in C2C12 cells
additional information
-
construction of Cdk5-knockout mutant mice that are embryonically lethal with very few viable at birth dying a few hours postpartum, p35 and p39 double-knockout mutant mice show a similar phenotype, the KO mice show higher ERK1/2 activity and increased neurofilament phosphorylation
additional information
-
null mutant mice show lower phosphatidylinositol 3-kinase activity and phosphorylation of Akt in brain compared to wild-type mice
additional information
-
p35 null mutant mice have a longer threshold for long term potentiation, overview
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant GST-tagged CDK5 and p25 from Escherichia coli strain BL21 by glutathione affinity chromatography
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
full-length PNQALRE cDNA (splice variant 1) expressed in HEK 293, U2OS and HCT116 cells, PNQALRE and components of the CAK trimer coexpressed in insect Sf9 cells
isolation of cDNA
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
additional information
medicine
-
role for Cdk5/p35 activity in primary afferent nociceptive signaling, Cdk5/p35 may be a target for the development of analgesic drugs
medicine
Cdk2 signaling pathways are critical regulators of cardiac ischemia/reperfusion injury in vivo
medicine
cdk5 contributes to the pathobiology of focal cortical dysplasia
medicine
-
the p25/Cdk5 complex is an important mediator of dopamine and glutamate neurotoxicity associated to Huntigton's disease
additional information
-
cell-cycle effects in early embryos under normal conditions and after irridation are paralleled by changes in the activity of the central cell-cycle driving enzyme complex, the cdk1/cyclin B1 complex
additional information
no support of the proposed function of PNQALRE/CCRK in activating CDKs, but instead reinforcement of the notion that Cdk7 is the major, and to date the only, CAK in mammalian cells
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
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An Eph-related receptor protein tyrosine kinase gene segmentally expressed in the developing mouse hindbrain
Oncogene
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1992
Mus musculus (P30285), Mus musculus (Q03147), Mus musculus
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The FT210 cell line is a mouse G2 phase mutant with a temperature-sensitive CDC2 gene product
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63
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Mus musculus (P11440)
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Cloning of the mouse homologue of the yeast cell cycle control gene cdc2
DNA Seq.
1
49-54
1990
Mus musculus (P11440)
Cisek, L.J.; Corden, J.L.
Phosphorylation of RNA polymerase by the murine homologue of the cell-cycle control protein cdc2
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339
679-684
1989
Mus musculus (P11440)
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Regulated expression of a cell division control-related protein kinase during development
Cell Growth Differ.
2
85-93
1991
Mus musculus (P24788), Mus musculus
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Novel CDC2-related protein kinases produced in murine hematopoietic stem cells
Gene
124
305-306
1993
Mus musculus (P30285), Mus musculus (P49615), Mus musculus (Q03147)
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Mol. Cell. Biol.
14
2713-2721
1994
Mus musculus (P30285)
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Identification and properties of an atypical catalytic subunit (p34PSK-J3/cdk4) for mammalian D type G1 cyclins
Cell
71
323-334
1992
Mus musculus (P30285), Mus musculus
Ohshima, T.; Nagle, J.W.; Pant, H.C.; Joshi, J.B.; Kozak, C.A.; Brady, R.O.; Kulkarni, A.B.
Molecular cloning and chromosomal mapping of the mouse cyclin-dependent kinase 5 gene
Genomics
28
585-588
1995
Mus musculus (P49615), Mus musculus
Ino, H.; Ishizuka, T.; Chiba, T.; Tatibana, M.
Expression of CDK5 (PSSALRE kinase), a neural cdc2-related protein kinase, in the mature and developing mouse central and peripheral nervous systems
Brain Res.
661
196-206
1994
Mus musculus (P49615)
Stepanova, L.; Ershler, M.A.; Belyavsky, A.V.
Sequence of the cDNA encoding murine CRK4 protein kinase
Gene
149
321-324
1994
Mus musculus (Q03147), Mus musculus
Matsuoka, M.; Kato, J.Y.; Fisher, R.P.; Morgan, D.O.; Sherr, C.J.
Activation of cyclin-dependent kinase 4 (cdk4) by mouse MO15-associated kinase
Mol. Cell. Biol.
14
7265-7275
1994
Mus musculus (Q03147), Mus musculus
Ershler, M.A.; Nagorskaia, T.V.; Fisser Ia, V.; Beliavskii, A.V.
Identification of new protein kinase genes, similar to kinases of the cdc2 family and expressed in murine hematopoietic stem cells
Dokl. Akad. Nauk
324
893-897
1992
Mus musculus (Q03147)
Okuda, T.; Cleveland, J.L.; Downing, J.R.
PCTAIRE-1 and PCTAIRE-3, two members of a novel cdc2/CDC28-related protein kinase gene family
Oncogene
7
2249-2258
1992
Mus musculus (Q04735), Mus musculus (Q04899), Mus musculus
Bladt, F.; Birchmeier, C.
Characterization and expression analysis of the murine rck gene: a protein kinase with a potential function in sensory cells
Differentiation
53
115-122
1993
Mus musculus (Q04859)
Takahashi, S.; Saito, T.; Hisanaga, S.; Pant, H.C.; Kulkarni, A.B.
Tau phosphorylation by cyclin-dependent kinase 5/p39 during brain development reduces its affinity for microtubules
J. Biol. Chem.
278
10506-10515
2003
Mus musculus
Shelton, S.B.; Krishnamurthy, P.; Johnson, G.V.
Effects of cyclin-dependent kinase-5 activity on apoptosis and tau phosphorylation in immortalized mouse brain cortical cells
J. Neurosci. Res.
76
110-120
2004
Mus musculus
Lambourne, S.L.; Sellers, L.A.; Bush, T.G.; Choudhury, S.K.; Emson, P.C.; Suh, Y.H.; Wilkinson, L.S.
Increased tau phosphorylation on mitogen-activated protein kinase consensus sites and cognitive decline in transgenic models for Alzheimer's disease and FTDP-17: evidence for distinct molecular processes underlying tau abnormalities
Mol. Cell. Biol.
25
278-293
2005
Homo sapiens, Mus musculus
Kesavapany, S.; Li, B.S.; Amin, N.; Zheng, Y.L.; Grant, P.; Pant, H.C.
Neuronal cyclin-dependent kinase 5: role in nervous system function and its specific inhibition by the Cdk5 inhibitory peptide
Biochim. Biophys. Acta
1697
143-153
2004
Danio rerio, Saccharomyces cerevisiae, Caenorhabditis elegans, Canis lupus familiaris, Drosophila melanogaster, Homo sapiens, Doryteuthis pealeii, Mus musculus, Rattus norvegicus, Sus scrofa
Andres, V.
Control of vascular cell proliferation and migration by cyclin-dependent kinase signalling: new perspectives and therapeutic potential
Cardiovasc. Res.
63
11-21
2004
Homo sapiens, Mus musculus, Rattus norvegicus
Li, B.S.; Ma, W.; Jaffe, H.; Zheng, Y.; Takahashi, S.; Zhang, L.; Kulkarni, A.B.; Pant, H.C.
Cyclin-dependent kinase-5 is involved in neuregulin-dependent activation of phosphatidylinositol 3-kinase and Akt activity mediating neuronal survival
J. Biol. Chem.
278
35702-35709
2003
Mus musculus, Rattus norvegicus
Wei, F.Y.; Tomizawa, K.; Ohshima, T.; Asada, A.; Saito, T.; Nguyen, C.; Bibb, J.A.; Ishiguro, K.; Kulkarni, A.B.; Pant, H.C.; Mikoshiba, K.; Matsui, H.; Hisanaga, S.
Control of cyclin-dependent kinase 5 (Cdk5) activity by glutamatergic regulation of p35 stability
J. Neurochem.
93
502-512
2005
Mus musculus, Mus musculus ICR
Hisanaga, S.; Saito, T.
The regulation of cyclin-dependent kinase 5 activity through the metabolism of p35 or p39 Cdk5 activator
Neurosignals
12
221-229
2003
Homo sapiens, Mus musculus, Rattus norvegicus
Fu, A.K.; Fu, W.Y.; Ng, A.K.; Chien, W.W.; Ng, Y.P.; Wang, J.H.; Ip, N.Y.
Cyclin-dependent kinase 5 phosphorylates signal transducer and activator of transcription 3 and regulates its transcriptional activity
Proc. Natl. Acad. Sci. USA
101
6728-6733
2004
Mus musculus
Wohlbold, L.; Larochelle, S.; Liao, J.C.; Livshits, G.; Singer, J.; Shokat, K.M.; Fisher, R.P.
The cyclin-dependent kinase (CDK) family member PNQALRE/CCRK supports cell proliferation but has no intrinsic CDK-activating kinase (CAK) activity
Cell Cycle
5
546-554
2006
Mus musculus (Q9JHU3)
Baatout, S.; Mueller, W.; Michaux, A.; Buset, J.; Schoonjans, W.; Jacquet, P.
Histone H1 and cdk1 kinase activities in early embryos of four mouse strains after X-irradiation
In Vivo
21
571-582
2007
Mus musculus
Pareek, T.K.; Keller, J.; Kesavapany, S.; Pant, H.C.; Iadarola, M.J.; Brady, R.O.; Kulkarni, A.B.
Cyclin-dependent kinase 5 activity regulates pain signaling
Proc. Natl. Acad. Sci. USA
103
791-796
2006
Mus musculus, Rattus norvegicus
Fukasawa, K.
P53, cyclin-dependent kinase and abnormal amplification of centrosomes
Biochim. Biophys. Acta
1786
15-23
2008
Mus musculus
Cheung, Z.H.; Ip, N.Y.
The roles of cyclin-dependent kinase 5 in dendrite and synapse development
Biotechnol. J.
2
949-957
2007
Mus musculus
Sen, A.; Thom, M.; Nikolic, M.; Sisodiya, S.M.
The potential role of cyclin-dependent kinase 5 in focal cortical dysplasia
Dev. Neurosci.
30
96-104
2008
Mus musculus (P49615)
Taniguchi, M.; Taoka, M.; Itakura, M.; Asada, A.; Saito, T.; Kinoshita, M.; Takahashi, M.; Isobe, T.; Hisanaga, S.
Phosphorylation of adult type Sept5 (CDCrel-1) by cyclin-dependent kinase 5 inhibits interaction with syntaxin-1
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282
7869-7876
2007
Mus musculus
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Cyclin-dependent kinase 2 signaling regulates myocardial ischemia/reperfusion injury
J. Mol. Cell. Cardiol.
45
610-616
2008
Mus musculus (P97377)
Anne, S.L.; 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.
27
7318-7328
2007
Mus musculus, Rattus norvegicus
Paoletti, P.; Vila, I.; Rife, M.; Lizcano, J.M.; Alberch, J.; Gines, S.
Dopaminergic and glutamatergic signaling crosstalk in Huntingtons disease neurodegeneration: the role of p25/cyclin-dependent kinase 5
J. Neurosci.
28
10090-10101
2008
Mus musculus, Homo sapiens (Q00535), Homo sapiens
Amin, N.D.; Zheng, Y.L.; Kesavapany, S.; Kanungo, J.; Guszczynski, T.; Sihag, R.K.; Rudrabhatla, P.; Albers, W.; Grant, P.; Pant, H.C.
Cyclin-dependent kinase 5 phosphorylation of human septin SEPT5 (hCDCrel-1) modulates exocytosis
J. Neurosci.
28
3631-3643
2008
Mus musculus, Rattus norvegicus
Cheung, Z.H.; Gong, K.; Ip, N.Y.
Cyclin-dependent kinase 5 supports neuronal survival through phosphorylation of Bcl-2
J. Neurosci.
28
4872-4877
2008
Mus musculus
Lewis, A.E.; Rusten, M.; Hoivik, E.A.; Vikse, E.L.; Hansson, M.L.; Wallberg, A.E.; Bakke, M.
Phosphorylation of steroidogenic factor 1 is mediated by cyclin-dependent kinase 7
Mol. Endocrinol.
22
91-104
2008
Homo sapiens (P50613), Mus musculus (Q03147)
Lin, H.; Hu, G.X.; Dong, L.; Dong, Q.; Mukai, M.; Chen, B.B.; Holsberger, D.R.; Sottas, C.M.; Cooke, P.S.; Lian, Q.Q.; Li, X.K.; Ge, R.S.
Increased proliferation but decreased steroidogenic capacity in Leydig cells from mice lacking cyclin-dependent kinase inhibitor 1B
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80
1232-1238
2009
Mus musculus
Jhou, R.S.; Sun, K.H.; Sun, G.H.; Wang, H.H.; Chang, C.I.; Huang, H.C.; Lu, S.Y.; Tang, S.J.
Inhibition of cyclin-dependent kinases by olomoucine and roscovitine reduces lipopolysaccharide-induced inflammatory responses via down-regulation of nuclear factor kappaB
Cell Prolif.
42
141-149
2009
Mus musculus
Hao, Y.; Pan, D.; Zhang, M.; Xu, J.; Li, L.; Wei, J.; Wang, X.
The neuroprotective effects of cyclin-dependent kinase-5 inhibition in mice with Niemann-Pick disease type C
J. Huazhong Univ. Sci. Technol. Med. Sci.
29
324-329
2009
Mus musculus
Aggarwal, P.; Vaites, L.P.; Kim, J.K.; Mellert, H.; Gurung, B.; Nakagawa, H.; Herlyn, M.; Hua, X.; Rustgi, A.K.; McMahon, S.B.; Diehl, J.A.
Nuclear cyclin D1/CDK4 kinase regulates CUL4 expression and triggers neoplastic growth via activation of the PRMT5 methyltransferase
Cancer Cell
18
329-340
2010
Homo sapiens, Mus musculus
Hisanaga, S.; Endo, R.
Regulation and role of cyclin-dependent kinase activity in neuronal survival and death
J. Neurochem.
115
1309-1321
2010
Homo sapiens, Mus musculus
Oi, A.; Katayama, S.; Hatano, N.; Sugiyama, Y.; Kameshita, I.; Sueyoshi, N.
Subcellular distribution of cyclin-dependent kinase-like 5 (CDKL5) is regulated through phosphorylation by dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A)
Biochem. Biophys. Res. Commun.
482
239-245
2017
Mus musculus (Q3UTQ8), Mus musculus
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Transporter Classification Database (TCDB): 1.I.1.1.3
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