DegronMD - Q00535(CDK5)

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. 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. {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}. View more >>

GO - Biological processes (BP): axon extension [GO:0048675]; axonogenesis [GO:0007409]; behavioral response to cocaine [GO:0048148]; calcium ion import [GO:0070509]; cell division [GO:0051301]; cell-matrix adhesion [GO:0007160]; cellular response to amyloid-beta [GO:1904646]; central nervous system neuron development [GO:0021954]; cerebellar cortex formation [GO:0021697]; chemical synaptic transmission [GO:0007268]; corpus callosum development [GO:0022038]; cortical actin cytoskeleton organization [GO:0030866]; dendrite morphogenesis [GO:0048813]; excitatory postsynaptic potential [GO:0060079]; hippocampus development [GO:0021766]; histone phosphorylation [GO:0016572]; intracellular protein transport [GO:0006886]; layer formation in cerebral cortex [GO:0021819]; microtubule cytoskeleton organization [GO:0000226]; mitochondrion organization [GO:0007005]; motor neuron axon guidance [GO:0008045]; negative regulation of axon extension [GO:0030517]; negative regulation of cell cycle [GO:0045786]; negative regulation of neuron death [GO:1901215]; negative regulation of protein export from nucleus [GO:0046826]; negative regulation of protein ubiquitination [GO:0031397]; negative regulation of proteolysis [GO:0045861]; negative regulation of synaptic plasticity [GO:0031914]; negative regulation of transcription, DNA-templated [GO:0045892]; neuron apoptotic process [GO:0051402]; neuron differentiation [GO:0030182]; neuron migration [GO:0001764]; neuron projection development [GO:0031175]; nucleocytoplasmic transport [GO:0006913]; oligodendrocyte differentiation [GO:0048709]; peptidyl-serine phosphorylation [GO:0018105]; peptidyl-threonine phosphorylation [GO:0018107]; phosphorylation [GO:0016310]; positive regulation of actin cytoskeleton reorganization [GO:2000251]; positive regulation of calcium ion-dependent exocytosis [GO:0045956]; positive regulation of glial cell apoptotic process [GO:0034352]; positive regulation of neuron apoptotic process [GO:0043525]; positive regulation of protein binding [GO:0032092]; positive regulation of protein kinase activity [GO:0045860]; positive regulation of protein targeting to membrane [GO:0090314]; positive regulation of voltage-gated calcium channel activity [GO:1901387]; protein autophosphorylation [GO:0046777]; protein localization to synapse [GO:0035418]; protein phosphorylation [GO:0006468]; receptor catabolic process [GO:0032801]; receptor clustering [GO:0043113]; regulation of apoptotic process [GO:0042981]; regulation of cell cycle [GO:0051726]; regulation of cell migration [GO:0030334]; regulation of dendritic spine morphogenesis [GO:0061001]; regulation of macroautophagy [GO:0016241]; regulation of protein localization to plasma membrane [GO:1903076]; regulation of synaptic plasticity [GO:0048167]; regulation of synaptic transmission, glutamatergic [GO:0051966]; regulation of synaptic vesicle recycling [GO:1903421]; regulation of transcription involved in G1/S transition of mitotic cell cycle [GO:0000083]; response to wounding [GO:0009611]; rhythmic process [GO:0048511]; Schwann cell development [GO:0014044]; sensory perception of pain [GO:0019233]; serine phosphorylation of STAT protein [GO:0042501]; skeletal muscle tissue development [GO:0007519]; synapse assembly [GO:0007416]; synapse pruning [GO:0098883]; synaptic transmission, dopaminergic [GO:0001963]; synaptic transmission, glutamatergic [GO:0035249]; synaptic vesicle endocytosis [GO:0048488]; synaptic vesicle exocytosis [GO:0016079]; synaptic vesicle transport [GO:0048489]; visual learning [GO:0008542] View more >>

GO - Molecular function (MF): View more >>

GO - Cellular component (CC): View more >>

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Mutation	Sample	Cancer	Dataset	Degron hit	Class	Location	Type	Impact score
p.V249E	TCGA-55-8207	LUAD	TCGA	PATTS	DEG_SPOP_SBC_1	243:247	Mutation rewiring degron network	0.2778
p.V249E	DO45351	LUAD	ICGC	PATTS	DEG_SPOP_SBC_1	243:247	Mutation rewiring degron network	0.2778
p.R217Q	TCGA-AX-A1C9	UCEC	TCGA	LLGTPTEE	DEG_SCF_FBW7_2	218:225	Mutation rewiring degron network	0.3056
p.R217Q	DO43098	UCEC	ICGC	LLGTPTEE	DEG_SCF_FBW7_2	218:225	Mutation rewiring degron network	0.3056
p.A244T	TCGA-AX-A1CE	UCEC	TCGA	PATTS	DEG_SPOP_SBC_1	243:247	Mutation altering degron motif	0.6028
p.A244T	DO42280	UCEC	ICGC	PATTS	DEG_SPOP_SBC_1	243:247	Mutation altering degron motif	0.6028
p.T221M	TCGA-CG-4306	STAD	TCGA	LLGTPTEE	DEG_SCF_FBW7_2	218:225	Mutation altering degron motif	0.7423
p.T221M	DO233115	GACA	ICGC	LLGTPTEE	DEG_SCF_FBW7_2	218:225	Mutation altering degron motif	0.7423
p.T221M	DO38567	STAD	ICGC	LLGTPTEE	DEG_SCF_FBW7_2	218:225	Mutation altering degron motif	0.7423
p.P228L	TCGA-CV-7568	HNSC	TCGA	LLGTPTEE	DEG_SCF_FBW7_2	218:225	Mutation rewiring degron network	0.25
p.P228L	DO14160	HNSC	ICGC	LLGTPTEE	DEG_SCF_FBW7_2	218:225	Mutation rewiring degron network	0.25
p.P240L	TCGA-D3-A3ML	SKCM	TCGA	PATTS	DEG_SPOP_SBC_1	243:247	Mutation rewiring degron network	0.25
p.P240L	DO47413	SKCM	ICGC	PATTS	DEG_SPOP_SBC_1	243:247	Mutation rewiring degron network	0.25
p.P240L	ACH-000398	Lymphoma	CCLE	PATTS	DEG_SPOP_SBC_1	243:247	Mutation rewiring degron network	0.25
p.K237N	TCGA-EY-A215	UCEC	TCGA	PATTS	DEG_SPOP_SBC_1	243:247	Mutation blocking ubiquitination signal	0.6111
p.K237N	DO42665	UCEC	ICGC	PATTS	DEG_SPOP_SBC_1	243:247	Mutation blocking ubiquitination signal	0.6111
p.K213E	DO233773	GACA	ICGC	LLGTPTEE	DEG_SCF_FBW7_2	218:225	Mutation blocking ubiquitination signal	0.6389
p.EE224DK	DO222550	MELA	ICGC	LLGTPTEE	DEG_SCF_FBW7_2	218:225	Mutation altering degron motif	0.7022
p.D235G	DO233550	PRAD	ICGC	LLGTPTEE	DEG_SCF_FBW7_2	218:225	Mutation rewiring degron network	0.0556
p.D235G	DO233550	PRAD	ICGC	PATTS	DEG_SPOP_SBC_1	243:247	Mutation rewiring degron network	0.1111
p.T231A	SIDM00217	Colorectal Carcinoma	GDSC	LLGTPTEE	DEG_SCF_FBW7_2	218:225	Mutation blocking phosphorylation signal	0.6111
p.T231A	ACH-000999	Colon/Colorectal Cancer	CCLE	LLGTPTEE	DEG_SCF_FBW7_2	218:225	Mutation blocking phosphorylation signal	0.6111
p.T231A	SNU-1040	large intestine	COSMIC	LLGTPTEE	DEG_SCF_FBW7_2	218:225	Mutation blocking phosphorylation signal	0.6111
p.V252A	ACH-000591	Brain Cancer	CCLE	PATTS	DEG_SPOP_SBC_1	243:247	Mutation rewiring degron network	0.1944
p.A248T	Sarc9371	bone	COSMIC	PATTS	DEG_SPOP_SBC_1	243:247	Mutation rewiring degron network	0.3056

DegronMD: protein-targeted degradation, mutation and drug response to degrons

CDK5

UniProt ID: Q00535

Entrez ID: 1020

Protein name: Cyclin-dependent kinase 5 (EC 2.7.11.1) (Cell division protein kinase 5) (Cyclin-dependent-like kinase 5) (Serine/threonine-protein kinase PSSALRE) (Tau protein kinase II catalytic subunit) (TPKII catalytic subunit)

External links: UniprotKB HGNC RefSeq COSMIC

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Kaplan plot for CDK5 in