ID:CDK5_HUMAN DESCRIPTION: RecName: Full=Cyclin-dependent kinase 5; EC=2.7.11.22; AltName: Full=Cell division protein kinase 5; AltName: Full=Serine/threonine-protein kinase PSSALRE; AltName: Full=Tau protein kinase II catalytic subunit; Short=TPKII catalytic subunit; 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, oligodendrocytes differentiation, synaptic plasticity and neurotransmission, by phosphorylating key proteins. Activated by interaction with CDK5R1 (p35) and ATP6V0D1 (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 PCTAIRE 1/CDK16 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 elicites 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. CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein. 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 ATP6V0D1 (p39) during the development of the nervous system; degradation of CDK5R1 (p35) and ATP6V0D1 (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. SUBUNIT: 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 (By similarity). 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. Interacts with EPHA4; may mediate the activation of NGEF by EPHA4. Interacts with PTK2/FAK1 (By similarity). INTERACTION: Q15078:CDK5R1; NbExp=5; IntAct=EBI-1041567, EBI-746189; P38936:CDKN1A; NbExp=2; IntAct=EBI-1041567, EBI-375077; P46527:CDKN1B; NbExp=4; IntAct=EBI-1041567, EBI-519280; P37231-2:PPARG; NbExp=2; IntAct=EBI-1041567, EBI-781416; SUBCELLULAR LOCATION: Isoform 1: Cytoplasm. Cell membrane; Peripheral membrane protein. Perikaryon. Cell projection, lamellipodium (By similarity). Cell projection, growth cone (By similarity). Cell junction, synapse, postsynaptic cell membrane, postsynaptic density (By similarity). Note=In axonal growth cone with extension to the peripheral lamellipodia (By similarity). Under neurotoxic stress and neuronal injury conditions, CDK5R (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. Co-localizes 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. SUBCELLULAR LOCATION: Isoform 2: Nucleus. TISSUE SPECIFICITY: Isoform 1 is ubiquitously expressed. Accumulates in cortical neurons (at protein level). Isoform 2 has only been detected in testis, skeletal muscle, colon, bone marrow and ovary. PTM: 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. MISCELLANEOUS: Dysregulation of CDK5 is associated with neurodegenerative disorders such as Alzheimer, Parkinson, and Niemann-Pick type C diseases, ischemia, and amyotrophic lateral sclerosis. SIMILARITY: Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. CDC2/CDKX subfamily. SIMILARITY: Contains 1 protein kinase domain.
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on Q00535
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Biological Process: GO:0000226 microtubule cytoskeleton organization GO:0001764 neuron migration GO:0001934 positive regulation of protein phosphorylation GO:0001963 synaptic transmission, dopaminergic GO:0006468 protein phosphorylation GO:0006886 intracellular protein transport GO:0006887 exocytosis GO:0006913 nucleocytoplasmic transport GO:0006915 apoptotic process GO:0007005 mitochondrion organization GO:0007049 cell cycle GO:0007160 cell-matrix adhesion GO:0007268 chemical synaptic transmission GO:0007399 nervous system development GO:0007409 axonogenesis GO:0007416 synapse assembly GO:0007519 skeletal muscle tissue development GO:0008045 motor neuron axon guidance GO:0008283 cell proliferation GO:0008306 associative learning GO:0008542 visual learning GO:0009611 response to wounding GO:0014044 Schwann cell development GO:0016079 synaptic vesicle exocytosis GO:0016241 regulation of macroautophagy GO:0016310 phosphorylation GO:0016477 cell migration GO:0018105 peptidyl-serine phosphorylation GO:0018107 peptidyl-threonine phosphorylation GO:0019233 sensory perception of pain GO:0021537 telencephalon development GO:0021549 cerebellum development GO:0021695 cerebellar cortex development GO:0021697 cerebellar cortex formation GO:0021766 hippocampus development GO:0021819 layer formation in cerebral cortex GO:0021954 central nervous system neuron development GO:0021987 cerebral cortex development GO:0022038 corpus callosum development GO:0030182 neuron differentiation GO:0030334 regulation of cell migration GO:0030517 negative regulation of axon extension GO:0030866 cortical actin cytoskeleton organization GO:0030900 forebrain development GO:0031175 neuron projection development GO:0031397 negative regulation of protein ubiquitination GO:0031914 negative regulation of synaptic plasticity GO:0032092 positive regulation of protein binding GO:0032801 receptor catabolic process GO:0034352 positive regulation of glial cell apoptotic process GO:0035249 synaptic transmission, glutamatergic GO:0035418 protein localization to synapse GO:0042220 response to cocaine GO:0042501 serine phosphorylation of STAT protein GO:0042981 regulation of apoptotic process GO:0043113 receptor clustering GO:0043525 positive regulation of neuron apoptotic process GO:0045055 regulated exocytosis GO:0045786 negative regulation of cell cycle GO:0045860 positive regulation of protein kinase activity GO:0045861 negative regulation of proteolysis GO:0045892 negative regulation of transcription, DNA-templated GO:0045956 positive regulation of calcium ion-dependent exocytosis GO:0046777 protein autophosphorylation GO:0046826 negative regulation of protein export from nucleus GO:0048148 behavioral response to cocaine GO:0048167 regulation of synaptic plasticity GO:0048488 synaptic vesicle endocytosis GO:0048511 rhythmic process GO:0048675 axon extension GO:0048709 oligodendrocyte differentiation GO:0048812 neuron projection morphogenesis GO:0048813 dendrite morphogenesis GO:0051301 cell division GO:0051402 neuron apoptotic process GO:0051966 regulation of synaptic transmission, glutamatergic GO:0060078 regulation of postsynaptic membrane potential GO:0060079 excitatory postsynaptic potential GO:0061001 regulation of dendritic spine morphogenesis GO:0070509 calcium ion import GO:0071156 regulation of cell cycle arrest GO:0090314 positive regulation of protein targeting to membrane GO:1901215 negative regulation of neuron death GO:1901216 positive regulation of neuron death GO:1903076 regulation of protein localization to plasma membrane GO:1903421 regulation of synaptic vesicle recycling GO:1904646 cellular response to beta-amyloid GO:2000251 positive regulation of actin cytoskeleton reorganization GO:2000273 positive regulation of receptor activity
L04658 - Homo sapiens gene sequence. BC005115 - Homo sapiens cyclin-dependent kinase 5, mRNA (cDNA clone MGC:1469 IMAGE:3537202), complete cds. GQ900934 - Homo sapiens clone HEL-T-46 epididymis secretory sperm binding protein mRNA, complete cds. AK026533 - Homo sapiens cDNA: FLJ22880 fis, clone KAT03552, highly similar to HSSTHPKE Homo sapiens mRNA PSSALRE for serine/threonine protein kinase. AY927560 - Homo sapiens mRNA sequence. X66364 - H.sapiens mRNA PSSALRE for serine/threonine protein kinase. AY049778 - Homo sapiens cyclin-dependent kinase 5 (CDK5) mRNA, complete cds. BT006680 - Homo sapiens cyclin-dependent kinase 5 mRNA, complete cds. DQ411039 - Homo sapiens protein kinase CDK5 splicing variant mRNA, complete cds, alternatively spliced. KJ905165 - Synthetic construct Homo sapiens clone ccsbBroadEn_14575 CDK5 gene, encodes complete protein. KJ890884 - Synthetic construct Homo sapiens clone ccsbBroadEn_00278 CDK5 gene, encodes complete protein. CU674995 - Synthetic construct Homo sapiens gateway clone IMAGE:100016981 5' read CDK5 mRNA. KU177968 - Homo sapiens cyclin-dependent kinase 5 isoform 1 (CDK5) mRNA, partial cds. KU177969 - Homo sapiens cyclin-dependent kinase 5 isoform 2 (CDK5) mRNA, partial cds. AB463550 - Synthetic construct DNA, clone: pF1KB8207, Homo sapiens CDK5 gene for cyclin-dependent kinase 5, without stop codon, in Flexi system. CR457041 - Homo sapiens full open reading frame cDNA clone RZPDo834B0318D for gene CDK5, cyclin-dependent kinase 5; complete cds, incl. stopcodon.
Biochemical and Signaling Pathways
BioCarta from NCI Cancer Genome Anatomy Project h_fosbPathway - FOSB gene expression and drug abuse h_p35alzheimersPathway - Deregulation of CDK5 in Alzheimers Disease h_cdk5Pathway - Phosphorylation of MEK1 by cdk5/p35 down regulates the MAP kinase pathway h_rac1Pathway - Rac 1 cell motility signaling pathway h_biopeptidesPathway - Bioactive Peptide Induced Signaling Pathway h_EfpPathway - Estrogen-responsive protein Efp controls cell cycle and breast tumors growth h_reelinPathway - Reelin Signaling Pathway h_Lis1Pathway - Lissencephaly gene (LIS1) in neuronal migration and development h_ck1Pathway - Regulation of ck1/cdk5 by type 1 glutamate receptors
Reactome (by CSHL, EBI, and GO)
Protein Q00535 (Reactome details) participates in the following event(s):
US Server
Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
