Molecular Target Synopsis
Overview
Domains and Structures
Drugs and Clinical Candidates
Druggability
Chemistry
Ligand Efficiency Plot
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Interaction Network
Gene Expression
Gene Copy Number Variation
RNAi
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Germline Genetics

CDK5 (Q00535) - Overview - Molecular Target Synopsis

Protein


CDK5, Cyclin-dependent-like kinase 5
Enzyme Classification 2.7.11.1
UniProt Q00535

Also Known as CDK5_HUMAN, CDK5, CDKN5

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 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). The complex p35/CDK5 interacts with CLOCK. Interacts with HTR6.

4AU8
CRYSTAL STRUCTURE OF COMPOUND 4A IN COMPLEX WITH CDK5, SHOWING AN UNUSUAL BINDING MODE TO THE HINGE REGION VIA A WATER MOLECULE
RCSB/PDB
Inspect Structure
See all 3D Structures for CDK5

Isoforms / Transcripts (Protein Coding)


Protein Length Ensembl Gene Ensembl Transcript Ensembl Protein Uniprot Isoform
292ENSG00000164885ENST00000485972ENSP00000419782Q00535-1
260ENSG00000164885ENST00000297518ENSP00000297518Q00535-2

Sub-cellular localization


UniProt: CDK5 is active in the following subcellular-locations: cell junction, cell membrane, cell projection, cytoplasm, growth cone, lamellipodium, nucleus, perikaryon, postsynaptic cell membrane, postsynaptic density, synapse.
GO terms: CDK5 is active in the following subcellular-locations: axon, cell junction, cytoplasm, cytosol, dendrite, filopodium, glutamatergic synapse, growth cone, lamellipodium, membrane, microtubule, neuromuscular junction, neuron projection, neuronal cell body, nucleoplasm, nucleus, perikaryon, plasma membrane, postsynaptic density, postsynaptic membrane, presynapse, protein kinase 5 complex, Schaffer collateral - CA1 synapse.



UniProt
GO terms

Gene Copy Number Variation


In COSMIC - Cell Lines Project CDK5 has gain in 4 cell-lines, loss in 5 cell-lines and no signal in 995 cell-lines. (see details)

Gene Expression


In NCI60, the highest expressing cell lines are: MDA_MB_435, MALME_3M, SK_MEL_2

In Array Express (RNA-seq of 675 commonly used human cancer cell lines), the highest expressing cell lines are: SK-N-FI, SK23, MKN-1

In Array Express (RNA-seq of long poly adenylated RNA and long non poly adenylated RNA from ENCODE cell lines), the highest expressing cell lines are: SK-N-SH, HeLa-S3, A549

(see details)

RNA Interference


CDK5 was reported in the following RNAI studies:

Cell - Large Scale Profiling of Kinase Dependencies in Cancer Cell Lines, the highest RNAi cell lines are: AC295, HEC1A. (see details)

3D Structures


For CDK5 there are:
6 structures (12 chains) solved
5 are solved in complex with at least one small molecule ligand



(see details)
Molecular Target 3D Synopsis

Screening and Chemistry


CDK5 has been screened with 2984 compounds (4259 bioactivities), 537 compounds have bioactivities that show binding affinity of <= 500nM (604 bioactivities). (see details)