CDK5
Entrez ID: 1020
Full name: cyclin dependent kinase 5
External links: HGNC UniprotKB Ensembl RefSeq COSMIC
Family: CMGC: CDK: CDK5
Chromosomal location: 7q36.1
Substructure location: Gatekeeper: 80 A-loop: 143...166 G-loop: 10...16 αC-helix: 46...55
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CDK5
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,...
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.
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GO - Biological processes (BP):
axon extension, axonogenesis, behavioral response to cocaine, calcium ion import, cell cycle, cell division, cell-matrix adhesion, cellular response to amyloid-beta, central nervous system neuron development, cerebellar cortex formation, chemical synaptic transmission, corpus callosum development, c...
axon extension, axonogenesis, behavioral response to cocaine, calcium ion import, cell cycle, cell division, cell-matrix adhesion, cellular response to amyloid-beta, central nervous system neuron development, cerebellar cortex formation, chemical synaptic transmission, corpus callosum development, cortical actin cytoskeleton organization, dendrite morphogenesis, excitatory postsynaptic potential, hippocampus development, histone phosphorylation, intracellular protein transport, layer formation in cerebral cortex, microtubule cytoskeleton organization, mitochondrion organization, motor neuron axon guidance, negative regulation of axon extension, negative regulation of cell cycle, negative regulation of neuron death, negative regulation of protein export from nucleus, negative regulation of protein ubiquitination, negative regulation of proteolysis, negative regulation of synaptic plasticity, negative regulation of transcription, DNA-templated, neuron apoptotic process, neuron differentiation, neuron migration, neuron projection development, nucleocytoplasmic transport, oligodendrocyte differentiation, peptidyl-serine phosphorylation, peptidyl-threonine phosphorylation, phosphorylation, positive regulation of actin cytoskeleton reorganization, positive regulation of calcium ion-dependent exocytosis, positive regulation of glial cell apoptotic process, positive regulation of neuron apoptotic process, positive regulation of protein binding, positive regulation of protein kinase activity, positive regulation of protein targeting to membrane, positive regulation of voltage-gated calcium channel activity, protein autophosphorylation, protein localization to synapse, protein phosphorylation, receptor catabolic process, receptor clustering, regulation of apoptotic process, regulation of cell cycle arrest, regulation of cell migration, regulation of dendritic spine morphogenesis, regulation of macroautophagy, regulation of protein localization to plasma membrane, regulation of signal transduction by p53 class mediator, regulation of synaptic plasticity, regulation of synaptic transmission, glutamatergic, regulation of synaptic vesicle recycling, response to wounding, rhythmic process, Schwann cell development, sensory perception of pain, serine phosphorylation of STAT protein, skeletal muscle tissue development, synapse assembly, synapse pruning, synaptic transmission, dopaminergic, synaptic transmission, glutamatergic, synaptic vesicle endocytosis, synaptic vesicle exocytosis, synaptic vesicle transport, visual learning
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GO - Molecular function (MF):
acetylcholine receptor activator activity, ATP binding, cyclin-dependent protein serine/threonine kinase activity, ephrin receptor binding, ErbB-2 class receptor binding, ErbB-3 class receptor binding, Hsp90 protein binding, kinase activity, p53 binding, protein kinase activity, protein kinase bindi...
acetylcholine receptor activator activity, ATP binding, cyclin-dependent protein serine/threonine kinase activity, ephrin receptor binding, ErbB-2 class receptor binding, ErbB-3 class receptor binding, Hsp90 protein binding, kinase activity, p53 binding, protein kinase activity, protein kinase binding, protein serine/threonine kinase activity, tau protein binding, tau-protein kinase activity, voltage-gated calcium channel activity involved in positive regulation of presynaptic cytosolic calcium levels
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GO - Cellular component (CC):
microtubule, cytosol, nucleoplasm, nucleus, plasma membrane, axon, cell, cell junction, cytoplasm, dendrite, filopodium, glutamatergic synapse, growth cone, lamellipodium, membrane, neuromuscular junction, neuron projection, neuronal cell body, perikaryon, postsynaptic density, presynapse, protein k...
microtubule, cytosol, nucleoplasm, nucleus, plasma membrane, axon, cell, cell junction, cytoplasm, dendrite, filopodium, glutamatergic synapse, growth cone, lamellipodium, membrane, neuromuscular junction, neuron projection, neuronal cell body, perikaryon, postsynaptic density, presynapse, protein kinase 5 complex, Schaffer collateral - CA1 synapse
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cyclin dependent kinase 5
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*NOTE: the Kaplan plots were collected from OncoLnc