CDK5
entrez
1020
canonical
uniprot
Q00535
canonical
ensembl
ENSG00000164885
resolver
ensp
ENSP00000297518
resolver
ensp
ENSP00000419782
resolver
genesymbol
CDK5
resolver
genesymbol_syn
CDKN5
resolver
genesymbol_syn
PSSALRE
resolver
hgnc
HGNC:1774
resolver
uniprot
A0A090N7W4
resolver
uniprot
A0A0S2Z355
resolver
uniprot
A1XKG3
resolver
uniprot_entry
A0A090N7W4_HUMAN
resolver
uniprot_entry
A0A0S2Z355_HUMAN
resolver
uniprot_entry
CDK5_HUMAN
resolver
uniprot_sec
A1XKG3
resolver
activity_regulation
ACTIVITY 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. {ECO:0000269|PubMed:12691662, ECO:0000269|PubMed:15992363, ECO:0000269|PubMed:17611284, ECO:0000269|PubMed:21668448, ECO:0000269|PubMed:9030781}.
uniprot
proteins
amino_acid_sequence
MQKYEKLEKIGEGTYGTVFKAKNRETHEIVALKRVRLDDDDEGVPSSALREICLLKELKHKNIVRLHDVLHSDKKLTLVFEFCDQDLKKYFDSCNGDLDPEIVKSFLFQLLKGLGFCHSRNVLHRDLKPQNLLINRNGELKLADFGLARAFGIPVRCYSAEVVTLWYRPPDVLFGAKLYSTSIDMWSAGCIFAELANAGRPLFPGNDVDDQLKRIFRLLGTPTEEQWPSMTKLPDYKPYPMYPATTSLVNVVPKLNATGRDLLQNLLKCNPVQRISAEEALQHPYFSDFCPP
uniprot
proteins
disease_involvement
DISEASE: Lissencephaly 7, with cerebellar hypoplasia (LIS7) [MIM:616342]: A form of lissencephaly, a disorder of cortical development characterized by agyria or pachygyria and disorganization of the clear neuronal lamination of normal six-layered cortex. LIS7 patients manifest lack of psychomotor development, facial dysmorphism, arthrogryposis, and early-onset intractable seizures resulting in death in infancy. {ECO:0000269|PubMed:25560765}. Note=The disease is caused by variants affecting the gene represented in this entry.
uniprot
proteins
ec_number
2.7.11.1
uniprot
proteins
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. Negatively regulates the CACNA1B/CAV2.2 -mediated Ca(2+) release probability at hippocampal neuronal soma and synaptic terminals (By similarity). Activated by interaction with CDK5R1 (p35) and CDK5R2 (p39), especially in postmitotic 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. Also phosphorylates 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-BMAL1 heterodimer in association with altered stability and subcellular distribution. {ECO:0000250|UniProtKB:Q03114, ECO:0000269|PubMed:12393264, ECO:0000269|PubMed:12691662, ECO:0000269|PubMed:15992363, ECO:0000269|PubMed:17009320, ECO:0000269|PubMed:17121855, ECO:0000269|PubMed:17591690, ECO:0000269|PubMed:17611284, ECO:0000269|PubMed:17671990, ECO:0000269|PubMed:18042622, ECO:0000269|PubMed:19081376, ECO:0000269|PubMed:19693690, ECO:0000269|PubMed:20061803, ECO:0000269|PubMed:20213743, ECO:0000269|PubMed:20826806, ECO:0000269|PubMed:21209322, ECO:0000269|PubMed:21220307, ECO:0000269|PubMed:21442427, ECO:0000269|PubMed:21465480, ECO:0000269|PubMed:21499257, ECO:0000269|PubMed:24235147, ECO:0000269|PubMed:9822744}.
uniprot
proteins
mass_dalton
33304
uniprot
proteins
mutagenesis
MUTAGEN 159; /note="S->A: No phenotype."; /evidence="ECO:0000269|PubMed:11583627"; MUTAGEN 159; /note="S->T: Impaired p35/p25 (CDK5R1) binding."; /evidence="ECO:0000269|PubMed:11583627
uniprot
proteins
post_translational_modification
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. {ECO:0000269|PubMed:10500146, ECO:0000269|PubMed:15689152, ECO:0000269|PubMed:17143272}.; PTM: Phosphorylation at Ser-159 is essential for maximal catalytic activity. {ECO:0000269|PubMed:10500146}.
uniprot
proteins
protein_family
CDC2/CDKX subfamily
uniprot
proteins
protein_family
CMGC Ser/Thr protein kinase family
uniprot
proteins
protein_family
Protein kinase superfamily
uniprot
proteins
pubmed
10500146
uniprot
proteins
pubmed
11583627
uniprot
proteins
pubmed
11584302
uniprot
proteins
pubmed
12393264
uniprot
proteins
pubmed
12691662
uniprot
proteins
pubmed
12853948
uniprot
proteins
pubmed
14521924
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
15689152
uniprot
proteins
pubmed
15992363
uniprot
proteins
pubmed
16039528
uniprot
proteins
pubmed
1639063
uniprot
proteins
pubmed
17009320
uniprot
proteins
pubmed
17121855
uniprot
proteins
pubmed
17143272
uniprot
proteins
pubmed
17344846
uniprot
proteins
pubmed
17591690
uniprot
proteins
pubmed
17611284
uniprot
proteins
pubmed
17671990
uniprot
proteins
pubmed
18042622
uniprot
proteins
pubmed
18507738
uniprot
proteins
pubmed
18691976
uniprot
proteins
pubmed
19081376
uniprot
proteins
pubmed
19238148
uniprot
proteins
pubmed
19369195
uniprot
proteins
pubmed
19413330
uniprot
proteins
pubmed
19608861
uniprot
proteins
pubmed
19693690
uniprot
proteins
pubmed
19782409
uniprot
proteins
pubmed
20061803
uniprot
proteins
pubmed
20213743
uniprot
proteins
pubmed
20826806
uniprot
proteins
pubmed
21044075
uniprot
proteins
pubmed
21144757
uniprot
proteins
pubmed
21209322
uniprot
proteins
pubmed
21220307
uniprot
proteins
pubmed
21269460
uniprot
proteins
pubmed
21415596
uniprot
proteins
pubmed
21442427
uniprot
proteins
pubmed
21465480
uniprot
proteins
pubmed
21473899
uniprot
proteins
pubmed
21499257
uniprot
proteins
pubmed
21600237
uniprot
proteins
pubmed
21668448
uniprot
proteins
pubmed
23186163
uniprot
proteins
pubmed
24235147
uniprot
proteins
pubmed
25560765
uniprot
proteins
pubmed
9030781
uniprot
proteins
pubmed
9822744
uniprot
proteins
sequence_length
292
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: [Isoform 1]: Cytoplasm {ECO:0000269|PubMed:12691662}. Nucleus {ECO:0000269|PubMed:12691662}. Cell membrane {ECO:0000269|PubMed:17009320}; Peripheral membrane protein. Perikaryon. Cell projection, lamellipodium {ECO:0000250|UniProtKB:P49615}. Cell projection, growth cone {ECO:0000250|UniProtKB:P49615}. Postsynaptic density {ECO:0000250|UniProtKB:Q03114}. Synapse {ECO:0000250|UniProtKB:Q03114}. 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. Colocalizes 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. {ECO:0000250}.; SUBCELLULAR LOCATION: [Isoform 2]: Nucleus.
uniprot
proteins