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Names & Taxonomy

Uniprot ID:: Q00535
Entry Name:: CDK5_HUMAN
Status:: reviewed
Protein Names:: Cyclin-dependent-like kinase 5 (EC 2.7.11.1) (Cell division protein kinase 5) (Serine/threonine-protein kinase PSSALRE) (Tau protein kinase II catalytic subunit) (TPKII catalytic subunit)
Gene Names:: CDK5 CDKN5
Gene Names Primary:: CDK5
Organism:: Homo sapiens (Human)

Structure

Length:: 292
Sequence:: MQKYEKLEKIGEGTYGTVFKAKNRETHEIVALKRVRLDDDDEGVPSSALREICLLKELKHKNIVRLHDVLHSDKKLTLVFEFCDQDLKKYFDSCNGDLDPEIVKSFLFQLLKGLGFCHSRNVLHRDLKPQNLLINRNGELKLADFGLARAFGIPVRCYSAEVVTLWYRPPDVLFGAKLYSTSIDMWSAGCIFAELANAGRPLFPGNDVDDQLKRIFRLLGTPTEEQWPSMTKLPDYKPYPMYPATTSLVNVVPKLNATGRDLLQNLLKCNPVQRISAEEALQHPYFSDFCPP
Proteomes:: UP000005640

Subcellular location

Subcellular Location:: Isoform 1: Cytoplasm. Cell membrane; Peripheral membrane protein. Perikaryon. Cell projection, lamellipodium

Function

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, 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.
Catalytic Activity:: ATP + a protein = ADP + a phosphoprotein.
Enzyme Regulation:: 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 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.
Active Site:: ACT_SITE 126 126 Proton acceptor.
Gene Ontology Go:: axon
cell junction
cyclin-dependent protein kinase 5 holoenzyme complex
cytoplasm
cytoskeleton
cytosol
dendrite
filopodium
growth cone
lamellipodium
membrane
neuromuscular junction
neuronal cell body
nucleus
perikaryon
plasma membrane
postsynaptic density
postsynaptic membrane
presynapse
acetylcholine receptor activator activity
ATP binding
cyclin-dependent protein serine/threonine kinase activity
ErbB-2 class receptor binding
ErbB-3 class receptor binding
kinase activity
protein kinase activity
protein serine/threonine kinase activity
tau-protein kinase activity
axon extension
axon guidance
behavioral response to cocaine
blood coagulation
calcium ion import
cell cycle
cell division
cell proliferation
cell-matrix adhesion
central nervous system neuron development
cerebellar cortex formation
corpus callosum development
cortical actin cytoskeleton organization
dendrite morphogenesis
excitatory postsynaptic potential
hippocampus development
intracellular protein transport
layer formation in cerebral cortex
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 neuron apoptotic process
positive regulation of protein binding
positive regulation of protein kinase activity
positive regulation of protein targeting to membrane
protein autophosphorylation
protein localization to synapse
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 synaptic plasticity
regulation of synaptic vesicle recycling
rhythmic process
Schwann cell development
sensory perception of pain
serine phosphorylation of STAT3 protein
skeletal muscle tissue development
synapse assembly
synaptic transmission
synaptic transmission, dopaminergic
synaptic transmission, glutamatergic
synaptic vesicle endocytosis
synaptic vesicle exocytosis
visual learning
Gene Ontology Biological Process:: axon extension
axon guidance
behavioral response to cocaine
blood coagulation
calcium ion import
cell cycle
cell division
cell-matrix adhesion
cell proliferation
central nervous system neuron development
cerebellar cortex formation
corpus callosum development
cortical actin cytoskeleton organization
dendrite morphogenesis
excitatory postsynaptic potential
hippocampus development
intracellular protein transport
layer formation in cerebral cortex
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 neuron apoptotic process
positive regulation of protein binding
positive regulation of protein kinase activity
positive regulation of protein targeting to membrane
protein autophosphorylation
protein localization to synapse
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 synaptic plasticity
regulation of synaptic vesicle recycling
rhythmic process
Schwann cell development
sensory perception of pain
serine phosphorylation of STAT3 protein
skeletal muscle tissue development
synapse assembly
synaptic transmission
synaptic transmission, dopaminergic
synaptic transmission, glutamatergic
synaptic vesicle endocytosis
synaptic vesicle exocytosis
visual learning
Gene Ontology Molecular Function:: acetylcholine receptor activator activity
ATP binding
cyclin-dependent protein serine/threonine kinase activity
ErbB-2 class receptor binding
ErbB-3 class receptor binding
kinase activity
protein kinase activity
protein serine/threonine kinase activity
tau-protein kinase activity
Gene Ontology Cellular Component:: axon
cell junction
cyclin-dependent protein kinase 5 holoenzyme complex
cytoplasm
cytoskeleton
cytosol
dendrite
filopodium
growth cone
lamellipodium
membrane
neuromuscular junction
neuronal cell body
nucleus
perikaryon
plasma membrane
postsynaptic density
postsynaptic membrane
presynapse
Keywords:: 3D-structure
ATP-binding
Acetylation
Alternative splicing
Apoptosis
Biological rhythms
Cell cycle
Cell division
Cell junction
Cell membrane
Cell projection
Complete proteome
Cytoplasm
Kinase
Lissencephaly
Membrane
Neurodegeneration
Neurogenesis
Nucleotide-binding
Nucleus
Phosphoprotein
Polymorphism
Postsynaptic cell membrane
Reference proteome
Serine/threonine-protein kinase
Synapse
Transferase
Interacts With:: Q8TDN4; P24863; P30279; Q15078; P38936; P46527; P37231-2

Names & Taxonomy

Structure

Subcellular location

Function

Publication