Affinage

CDK5

Cyclin-dependent kinase 5 · UniProt Q00535

Length
292 aa
Mass
33.3 kDa
Annotated
2026-06-09
100 papers in source corpus 37 papers cited in narrative 37 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CDK5 is an atypical proline-directed serine/threonine kinase that, unlike conventional cyclin-dependent kinases, is activated by the neuron-enriched non-cyclin activator p35 (and its calpain product p25) without requiring T-loop phosphorylation, and was first identified as the catalytic subunit of tau protein kinase II (PMID:8253190, PMID:9552397). Through its activator complex, CDK5 governs neuronal migration and cytoskeletal dynamics by acting on multiple Rho-family GTPase regulatory nodes: it associates with Rac1 in growth cones to downregulate Pak1 (PMID:9744280), phosphorylates the RhoGEF Trio to drive Rac activation (PMID:15331630), activates Mst3 to suppress RhoA (PMID:24872548), relieves autoinhibition of the Rho-GAP DLC1 (PMID:25452387), and stabilizes p27kip1 to control cofilin/F-actin in migrating cortical neurons (PMID:16341208). CDK5 also regulates focal adhesion stability and migration by phosphorylating FAK and talin, the latter blocking Smurf1-mediated degradation (PMID:14712065, PMID:19363486), and controls axonal transport via a CDK5–PP1–GSK3–kinesin pathway (PMID:15152189). CDK5 phosphorylates a broad substrate repertoire that links it to apoptosis and DNA-damage signaling (p53, ATM-S794) (PMID:17591690, PMID:19151707), synaptic plasticity and cAMP signaling (Src–NR2B–AP2-mediated NMDA receptor endocytosis, and PDE/CREB control) (PMID:18184784, PMID:21984943), circadian timing (PER2-S394 to drive PER2–CRY1 nuclear entry) (PMID:31687929), mitochondrial fission (DRP1-S585) (PMID:26002103), and metabolic control of insulin sensitivity (PPARγ-S273 and MEK) (PMID:25409143). Beyond the nervous system, CDK5 enables IFN-γ-induced PD-L1 expression in tumors by relieving IRF2/IRF2BP2 repression (PMID:27463676) and promotes cancer cell proliferation through substrates including p21CIP1, TPX2, and the PRMT1–WDR24–mTORC1 axis (PMID:27909065, PMID:31272499, PMID:36995937). Pathological calpain conversion of p35 to p25 prolongs and deregulates CDK5 activity, and the p25 complex can be selectively disrupted by a peptide inhibitor to protect against neurodegenerative phenotypes (PMID:25331900, PMID:37043533).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1993 High

    Established CDK5 as a bona fide tau kinase by identifying it as the catalytic subunit of tau protein kinase II, framing its later role in cytoskeletal regulation and tauopathy.

    Evidence Amino acid sequencing, antibody cross-reactivity, and in vitro tau phosphorylation assay

    PMID:8253190

    Open questions at the time
    • Did not identify the physiological activator
    • In vitro phosphorylation does not establish cellular substrate selectivity
  2. 1996 High

    Resolved how CDK5 is activated, showing it requires the non-cyclin activator p35 and does not depend on T-loop phosphorylation, distinguishing it mechanistically from other CDKs.

    Evidence Biochemical purification, in vitro kinase assay, dominant-negative transfection

    PMID:9552397

    Open questions at the time
    • Structural basis of activator binding not defined
    • Did not address regulation by calpain cleavage to p25
  3. 1997 Medium

    Showed CDK5/p35 activity is not strictly neuron-restricted, extending its potential biological scope to non-neuronal tissues.

    Evidence RT-PCR, immunocytochemistry, co-IP, and in vitro histone H1 kinase assay in lens cells

    PMID:9216066

    Open questions at the time
    • No functional follow-up in lens cells
    • Single lab, no in vivo validation
  4. 2001 High

    Identified regulators and modulators of the CDK5/p35 complex (SET, C42) and a developmental signaling role at the NMJ, beginning to map the activator-complex interactome.

    Evidence Affinity isolation/MS, yeast two-hybrid, co-IP, reporter assay, kinase assays

    PMID:11276227 PMID:11278334 PMID:11741927 PMID:11882646

    Open questions at the time
    • SET/C42 physiological significance not established in vivo
    • Mechanism of NMJ ErbB activation incomplete
  5. 2005 High

    Defined CDK5 as a master regulator of neuronal migration and cytoskeletal dynamics by linking it to Rac/Pak1, FAK, p27kip1/cofilin, and axonal transport machinery.

    Evidence Co-IP, co-localization, in vitro kinase assays, in vivo RNAi, F-actin and cortical migration analysis

    PMID:14712065 PMID:15152189 PMID:15331630 PMID:16341208 PMID:9744280

    Open questions at the time
    • Relative contribution of each substrate to migration in vivo unresolved
    • Some Trio/peptide phosphorylation shown only in vitro
  6. 2009 High

    Extended CDK5 substrate control to adhesion stability and DNA-damage/apoptosis signaling, showing it phosphorylates talin to block its degradation and phosphorylates ATM-S794 and p53 to drive neuronal death.

    Evidence In vitro kinase assays, phospho-mutants, ubiquitylation assays, ATM kinase assay, cell death assays

    PMID:17591690 PMID:19151707 PMID:19363486

    Open questions at the time
    • Upstream signal coupling DNA damage to CDK5 activation not fully defined
    • Substrate redundancy with other CDKs/kinases not excluded
  7. 2010 High

    Revealed a kinase-independent function of the p35–CDK5 dimer in suppressing neuronal cell cycle re-entry by sequestering E2F1 from DP1, distinguishing scaffold from catalytic roles.

    Evidence Co-IP, kinase-dead mutant, promoter/ChIP binding assay, cell cycle re-entry assay

    PMID:20392944

    Open questions at the time
    • Activator specificity (p35 vs p25/p39) mechanism not structurally explained
    • Relevance to disease cell cycle re-entry untested
  8. 2011 High

    Connected CDK5 to synaptic plasticity and memory through cAMP/CREB signaling and NMDA receptor surface control, establishing a cognitive role.

    Evidence Conditional KO, behavioral assays, biochemistry, pharmacological rescue (rolipram), co-IP, phospho-specific antibodies

    PMID:18184784 PMID:21984943

    Open questions at the time
    • Direct CDK5 substrate controlling PDE levels not identified
    • NR2B endocytosis mechanism relies on inhibitor studies without reconstitution
  9. 2015 High

    Expanded CDK5 function into metabolism, immune checkpoint control, mitochondrial fission, and ciliogenesis, demonstrating systemic and non-neuronal roles.

    Evidence Conditional/adipose KO, proteomics, in vitro kinase assays, phospho-mutants, flow cytometry, T-cell killing, mitochondrial morphology, ciliary length, epistasis rescue

    PMID:25331900 PMID:25409143 PMID:25452387 PMID:26002103 PMID:26206584 PMID:27463676

    Open questions at the time
    • Tissue-specific activator partners not always defined
    • Crosstalk and substrate competition with ERK/GSK3 incompletely mapped
  10. 2023 Medium

    Identified additional disease-relevant substrates (PER2, Sirt1, PRMT1, TPX2) and a selective peptide that disrupts the Cdk5/p25 complex, advancing both mechanism and therapeutic targeting.

    Evidence In vivo knockdown, in vitro kinase assays, co-IP, methylation/localization assays, xenografts, binding affinity assays, TAT-peptide delivery

    PMID:31272499 PMID:31687929 PMID:32660255 PMID:36995937 PMID:37043533

    Open questions at the time
    • Structural basis of Cdk5i peptide disruption unresolved
    • Several substrate findings are single-lab without reciprocal validation

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CDK5 substrate selectivity is partitioned across its many activator complexes (p35 vs p25 vs p39) and tissues, and how Tyr15 phosphorylation versus calpain cleavage independently deregulate activity, remains unresolved.
  • No unified structural model linking activator identity to substrate choice
  • Quantitative contribution of each substrate to neurodegeneration in vivo undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 12 GO:0016740 transferase activity 4 GO:0098772 molecular function regulator activity 2
Localization
GO:0005634 nucleus 5 GO:0005829 cytosol 3 GO:0005815 microtubule organizing center 2
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 4 R-HSA-112316 Neuronal System 3 R-HSA-1640170 Cell Cycle 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-1430728 Metabolism 2 R-HSA-168256 Immune System 1 R-HSA-73894 DNA Repair 1 R-HSA-9909396 Circadian clock 1
Partners
CDK5R1GSK3BLRRK2P53PER2RAC1SETTPX2
Complex memberships
CDK5/p25CDK5/p35

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 CDK5 (PSSALRE) was identified as the 30 kDa catalytic subunit of tau protein kinase II (TPKII), a proline-directed kinase that phosphorylates tau at the same sites as cdc2 kinase, establishing CDK5 as a tau kinase. Amino acid sequencing, antibody cross-reactivity, in vitro phosphorylation assay FEBS letters High 8253190
1996 CDK5 kinase activity in neurons requires association with its neuron-specific activator p35 (Nck5a/p25/35); p35 activates CDK5 without requiring T-loop phosphorylation of CDK5, distinguishing it from cyclin-dependent activation of other CDKs. Biochemical purification, in vitro kinase assay, transfection with dominant-negative mutants Progress in cell cycle research High 9552397
1997 CDK5 and p35 form a complex in lens epithelial and fiber cells (non-neuronal), with immunoprecipitated Cdk5 showing kinase activity in vitro using histone H1 as substrate, demonstrating CDK5/p35 activity is not strictly neuron-restricted. RT-PCR, immunocytochemistry, co-immunoprecipitation, in vitro kinase assay Developmental genetics Medium 9216066
1998 The p35/Cdk5 kinase complex co-localizes with Rac1 in neuronal growth cones; p35 associates directly with Rac1 in a GTP-dependent manner, and active p35/Cdk5 causes Pak1 hyperphosphorylation in a Rac-dependent manner, resulting in down-regulation of Pak1 kinase activity, thereby regulating actin cytoskeletal dynamics for neuronal migration and neurite outgrowth. Co-immunoprecipitation, co-localization by immunofluorescence, in vitro kinase assay, Pak1 activity assay Nature High 9744280
2001 Cdk5/p35 is involved in neuregulin (NRG)-induced acetylcholine receptor (AChR) gene expression at the neuromuscular junction; Cdk5, p35, and ErbB receptors form a complex, and inhibition of Cdk5 activity blocks NRG-induced AChR transcription and attenuates ErbB activation. Co-immunoprecipitation, kinase activity assay, pharmacological inhibition, overexpression, reporter assay Nature neuroscience High 11276227
2001 Cdk5 phosphorylates protein phosphatase inhibitor-1 at Ser-67 in striatal brain tissue; this phosphorylation does not convert inhibitor-1 into a PP1 inhibitor but reduces its efficiency as a substrate for PKA, modulating cAMP signaling amplitude. In vitro kinase assay, phosphorylation state-specific antibodies, selective kinase inhibitors, in vivo brain tissue analysis The Journal of biological chemistry High 11278334
2001 The protein SET binds the Cdk5 activator p35 and modulates Cdk5/p35 activity; SET enhances Cdk5/p35 (but not Cdk5/p25) kinase activity through its acidic tail region, and SET co-localizes with Cdk5/p35 in the nucleus of cortical neurons. Affinity isolation from rat brain, mass spectrometry, co-immunoprecipitation, co-transfection, immunostaining, kinase assay The Journal of biological chemistry High 11741927
2002 Cdk5 phosphorylates p53 in vitro (Cdk5/p25), and increased Cdk5 activity in cells elevates p53 protein levels and increases expression of p53-responsive genes p21 and Bax, implicating Cdk5 in neuronal apoptosis via p53 modulation. In vitro kinase assay with recombinant p53, transient transfection, immunoblot, reporter/gene expression analysis Journal of neurochemistry Medium 12064478
2002 C42 (a p35-associated protein) specifically inhibits Cdk5 activation by p35 by forming a complex with p35; the inhibitory domain maps to a 135 amino acid region conserved in yeast Pho81. Yeast two-hybrid screen, co-immunoprecipitation, deletion analysis, kinase inhibition assay The Journal of biological chemistry Medium 11882646
2002 CDK5 increases cell adhesion to fibronectin and decreases migration of corneal epithelial cells in a kinase-activity-dependent manner; kinase-inactive CDK5-T33 mutant reduces adhesion and increases migration, demonstrating CDK5 kinase activity regulates adhesion/migration. Stable transfection, kinase-dead mutant, adhesion assay, in vitro wound migration assay Molecular cancer research Medium 12496365
2004 CDK5 defines a regulatory pathway in axons involving PP1 and GSK3: CDK5 inhibition leads to PP1 activation, which then activates GSK3, causing GSK3-mediated phosphorylation of kinesin light chains and detachment of kinesin from transported cargo, impairing axonal transport. Pharmacological inhibition, biochemical assays, in vivo axonal transport experiments The EMBO journal High 15152189
2004 Cdk5 phosphorylates focal adhesion kinase (FAK) at Serine 732 in vitro and in developing brain; S732 phosphorylation prevents FAK accumulation at the centrosome and regulates centrosome-associated microtubule structure to promote nuclear translocation during neuronal migration. In vitro kinase assay, phospho-specific antibody, S732A mutant FAK expression, immunostaining Cell cycle Medium 14712065
2004 Cdk5 regulates cortical actin and hormone exocytosis in pituitary cells; Cdk5 phosphorylates Trio (a RhoGEF) at Cdk5 consensus sites and is required for Trio-mediated activation of Rac, linking Cdk5 to cortical actin reorganization and secretory granule fusion. Pharmacological inhibition (roscovitine), in vitro peptide phosphorylation, Rac activation assay, ultrastructural analysis Journal of cell science Medium 15331630
2005 Cdk5 phosphorylates and stabilizes p27kip1 in post-mitotic neurons, maintaining p27 levels that promote cortical neuronal migration by activating cofilin and regulating F-actin in migrating neurons; in vivo RNAi knockdown of p27 inhibited cortical migration. In vitro kinase assay, in vivo RNAi, F-actin staining, cortical migration analysis Nature cell biology High 16341208
2006 In Drosophila, Abl kinase activation by amyloid-beta is necessary for Cdk5 binding, activation, and nuclear/subcellular translocalization; Abl and p35/p25 cooperate to promote Cdk5-pY15 phosphorylation, which deregulates Cdk5 activity and localization in neurodegeneration. Genetic epistasis (abl mutations), cell death assay, co-immunoprecipitation, pharmacological inhibition Cell death and differentiation Medium 16932754
2007 Cdk5 interacts with p53 and phosphorylates p53 at Ser15, Ser33, and Ser46 in vitro; increased Cdk5 activity in the nucleus promotes p53 stabilization by disrupting p53-Hdm2 interaction (preventing ubiquitylation), enhances p300-mediated acetylation, and drives pro-apoptotic gene expression and mitochondria-mediated apoptosis. In vitro kinase assay, co-immunoprecipitation, site-directed mutagenesis (implicitly), ubiquitylation assay, cell death assay Journal of cell science High 17591690
2008 Cdk5 inhibition increases Src binding to PSD-95 and thereby increases Src-mediated phosphorylation of NR2B at Tyr1472, which decreases NR2B binding to the clathrin adaptor AP-2 and blocks activity-dependent endocytosis of NMDA receptors, increasing surface NMDAR expression. Pharmacological inhibition, co-immunoprecipitation, phospho-specific antibody, surface receptor assay The Journal of neuroscience Medium 18184784
2009 Talin head is a substrate for Cdk5; Cdk5 phosphorylates talin head at Ser425, which inhibits binding of the E3 ubiquitin ligase Smurf1 to talin head, preventing talin head ubiquitylation and degradation, thereby stabilizing focal adhesions and inhibiting cell migration. In vitro kinase assay, co-immunoprecipitation, S425A phospho-mutant expression, ubiquitylation assay, cell migration assay Nature cell biology High 19363486
2009 DNA damage activates Cdk5, which directly phosphorylates ATM at Ser794 in post-mitotic neurons; this Cdk5-mediated phosphorylation is required for ATM autophosphorylation at Ser1981 and ATM kinase activation, thereby regulating downstream p53 and H2AX phosphorylation and neuronal cell death. In vitro kinase assay, site-directed mutagenesis (Ser794), dominant-negative Cdk5, ATM kinase assay, neuronal death assay Nature cell biology High 19151707
2010 Cdk5 suppresses neuronal cell cycle re-entry through a kinase-activity-independent mechanism: the p35-Cdk5 dimer forms a complex with E2F1, excluding the E2F1 cofactor DP1 and preventing E2F1 from binding cell cycle gene promoters. p39 and p25 cannot substitute for p35 in this function. Co-immunoprecipitation, kinase-dead mutant, ChIP/promoter binding assay, cell cycle re-entry assay The Journal of neuroscience High 20392944
2011 Cdk5 loss of function in hippocampal circuits results in aberrant increase in phosphodiesterase (PDE) proteins, causing reduced cAMP signaling, defective CREB phosphorylation, and impaired synaptic plasticity and memory; restoring cAMP with PDE4 inhibitor rolipram rescues these deficits. Conditional knockout, behavioral memory assays, biochemical analysis (PDE levels, CREB phosphorylation), pharmacological rescue PloS one High 21984943
2014 Cdk5 phosphorylates Mst3 at Ser79, activating Mst3 kinase activity; Mst3 in turn phosphorylates RhoA at Ser26, negatively regulating RhoA GTPase activity and actin cytoskeletal reorganization required for neuronal radial migration; RhoA knockdown rescues migration defect in Mst3-knockdown cortices. In utero electroporation, in vitro kinase assay, epistasis (rescue experiment), RhoA GTPase activity assay The Journal of neuroscience High 24872548
2014 CDK5 phosphorylates PPARγ at serine 273 to stimulate diabetogenic gene expression in adipose tissue; Cdk5 also phosphorylates a novel site in MEK to suppress ERK activity; when adipose Cdk5 is ablated, ERK compensates by phosphorylating PPARγ-Ser273, worsening insulin resistance. Adipose-specific Cdk5 knockout, unbiased proteomics, in vitro kinase assay, MEK/ERK pharmacological inhibition, insulin resistance measurement Nature High 25409143
2014 p25 (calpain cleavage product of p35) preferentially binds and activates GSK3β in addition to Cdk5; GSK3β outcompetes Cdk5 for p25 binding when GSK3β is overexpressed; p25 alters GSK3β substrate specificity (enhancing tau phosphorylation, decreasing β-catenin phosphorylation) by occupying the AXIN-binding domain of GSK3β. Co-immunoprecipitation, FRET analysis, in silico docking, in vitro phosphorylation, siRNA knockdown PNAS High 25331900
2014 CDK5 phosphorylates four serines N-terminal to the Rho-GAP domain of the tumor suppressor DLC1; unphosphorylated N-terminal region functions as an autoinhibitory domain binding the Rho-GAP domain in a closed conformation; CDK5 phosphorylation relieves autoinhibition, activating DLC1 Rho-GAP activity, focal adhesion localization, and tensin/talin binding. In vitro kinase assay, phospho-mutant analysis, co-immunoprecipitation, Rho-GAP activity assay, focal adhesion localization The Journal of cell biology High 25452387
2015 CDK5 phosphorylates DRP1 at Ser585, promoting mitochondrial fission; CDK5-mediated DRP1-S585 phosphorylation is elevated at mitochondria following NMDA-induced injury; expression of DRP1-S585D increases fragmentation while S585A and dominant-negative cytoplasmic Cdk5 cause elongated mitochondria; conditional CDK5 deletion attenuates DRP1-S585 phosphorylation and rescues fission defects. In vitro kinase assay, phospho-site mutagenesis (S585D/S585A), conditional Cdk5 knockout, pharmacological inhibition (roscovitine), mitochondrial morphology analysis Human molecular genetics High 26002103
2015 CDK5 activity is required for IFN-γ-induced PD-L1 upregulation on medulloblastoma cells; disruption of Cdk5 results in persistent expression of PD-L1 transcriptional repressors IRF2 and IRF2BP2, reducing PD-L1 surface expression and enabling CD4+ T cell-mediated tumor rejection. Cdk5 conditional disruption in mouse model, flow cytometry for PD-L1, T cell killing assay, IRF2/IRF2BP2 expression analysis Science High 27463676
2015 CDK5 primes NDE1 for ubiquitylation by the E3 ligase FBW7 during G1/G0; CDK5-mediated phosphorylation of NDE1 enables FBW7 recognition and degradation of NDE1; depletion of either FBW7 or CDK5 elevates NDE1 levels and reduces ciliary length, which is rescued by co-depletion of NDE1. Genetic depletion (siRNA/shRNA), epistasis rescue experiment, co-immunoprecipitation, ciliary length measurement, cell cycle synchronization The EMBO journal High 26206584
2016 Cdk5 phosphorylates p21CIP1 at S130, triggering proteasome-dependent degradation of nuclear p21CIP1; this Cdk5-driven p21CIP1 degradation occurs primarily in S-phase, promotes Cdk2 activation and its interaction with DNA polymerase δ, and drives cancer cell growth. In vitro kinase assay, S130A mutant expression, proteasome inhibition, co-immunoprecipitation, cell growth assay, in vivo xenograft Cancer research Medium 27909065
2016 LRRK2 R1628P mutation increases LRRK2 binding affinity for Cdk5 and creates a novel Cdk5 phosphorylation site at S1627 on LRRK2; Cdk5-mediated phosphorylation of LRRK2-S1627 upregulates LRRK2 kinase activity and increases neuronal sensitivity to MPP+ in a Cdk5-dependent manner. Co-immunoprecipitation, site-directed mutagenesis, in vitro kinase assay, neuronal toxicity assay PloS one Medium 26930193
2018 Zinc induces Cdk5-Tyr15 phosphorylation via Src kinase, which activates Cdk5 in a p35-cleavage-independent manner during brain ischemia; Src inhibition or Y15F-CDK5 mutation abolishes zinc-induced CDK5 activation and protects neurons from ischemic death. Site-directed mutagenesis (Y15F), Src kinase inhibition, phospho-specific antibody, in vivo ischemia model, zinc chelation Cell death & disease Medium 30158515
2019 CDK5 phosphorylates the microtubule-associated spindle protein TPX2 at Ser486, promoting TPX2 protein stability; TPX2 silencing restores cell migration capability that was enhanced by CDK5 overexpression, placing TPX2 downstream of CDK5 in hepatocellular carcinoma. Comparative phosphoproteomic screening, in vitro/in vivo kinase assay, siRNA knockdown, xenograft model, diethylnitrosamine HCC model Journal of experimental & clinical cancer research Medium 31272499
2019 CDK5 regulates the circadian clock by phosphorylating PER2 at Ser394 in a diurnal fashion; this phosphorylation facilitates PER2 interaction with CRY1 and nuclear entry of the PER2-CRY1 complex, setting circadian period length; CDK5 knockdown in the SCN shortens the free-running period. In vivo Cdk5 knockdown in SCN, circadian period measurement, in vitro kinase assay, co-immunoprecipitation, nuclear localization assay eLife High 31687929
2020 Cdk5 phosphorylates Sirt1 at S47 in podocytes under diabetic conditions; Cdk5-mediated S47 phosphorylation decreases Sirt1 activity, leading to mitochondrial dysfunction (increased ROS, cytochrome c release, decreased ATP); S47A nonphosphorylatable mutant attenuates podocyte injury in vivo and in vitro. Roscovitine inhibition, dominant-negative Cdk5, phospho-S47 antibody, S47A mutant, in vitro and in vivo diabetic models, mitochondrial function assays Antioxidants & redox signaling Medium 32660255
2021 Cdk5 and GSK3β are negative regulators of FEME (Fast Endophilin-Mediated Endocytosis); they antagonize the binding of Endophilin to Dynamin-1 and CRMP4, and GSK3β binds directly to Endophilin to locally suppress FEME; this control is required for proper axon elongation, branching, and growth cone formation. Chemical and genetic inhibition, co-immunoprecipitation (GSK3β-Endophilin), axon morphology analysis in hippocampal neurons Nature communications Medium 33893293
2023 CDK5 phosphorylates PRMT1 at S307 in response to amino acids, promoting PRMT1 translocation from nucleus to cytoplasm/lysosome; cytoplasmic PRMT1 then methylates WDR24 (a GATOR2 component), activating mTORC1 signaling; disruption of the CDK5-PRMT1-WDR24 axis suppresses HCC cell proliferation and xenograft tumor growth. In vitro kinase assay, co-immunoprecipitation, methylation assay, subcellular fractionation, shRNA knockdown, xenograft tumor model Cell reports High 36995937
2023 A 12-amino-acid peptide (Cdk5i) derived from Cdk5 binds the Cdk5/p25 complex with high affinity, disrupts the Cdk5-p25 interaction, and reduces Cdk5/p25 kinase activity; when tagged with TAT for cell penetration, Cdk5i protects against neurodegenerative phenotypes associated with Cdk5 hyperactivity in cell and mouse models. Binding affinity assay, in vitro kinase assay, cell/mouse models of neurodegeneration, FITC-TAT peptide cell/brain penetration assay PNAS Medium 37043533

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 A decade of CDK5. Nature reviews. Molecular cell biology 935 11584302
1998 The p35/Cdk5 kinase is a neuron-specific Rac effector that inhibits Pak1 activity. Nature 335 9744280
2016 Cdk5 disruption attenuates tumor PD-L1 expression and promotes antitumor immunity. Science (New York, N.Y.) 275 27463676
2014 An ERK/Cdk5 axis controls the diabetogenic actions of PPARγ. Nature 261 25409143
2014 Physiological and pathological phosphorylation of tau by Cdk5. Frontiers in molecular neuroscience 239 25076872
2005 Cdk5 phosphorylates and stabilizes p27kip1 contributing to actin organization and cortical neuronal migration. Nature cell biology 235 16341208
2004 A novel CDK5-dependent pathway for regulating GSK3 activity and kinesin-driven motility in neurons. The EMBO journal 234 15152189
1993 A cdc2-related kinase PSSALRE/cdk5 is homologous with the 30 kDa subunit of tau protein kinase II, a proline-directed protein kinase associated with microtubule. FEBS letters 211 8253190
2015 The Role of Cdk5 in Alzheimer's Disease. Molecular neurobiology 204 26227906
2011 Cdk5: a multifaceted kinase in neurodegenerative diseases. Trends in cell biology 198 22189166
2009 Talin phosphorylation by Cdk5 regulates Smurf1-mediated talin head ubiquitylation and cell migration. Nature cell biology 173 19363486
2012 Deregulated Cdk5 activity is involved in inducing Alzheimer's disease. Archives of medical research 159 23142263
2014 Cdk5 activity in the brain - multiple paths of regulation. Journal of cell science 156 24879856
2001 Cdk5 is involved in neuregulin-induced AChR expression at the neuromuscular junction. Nature neuroscience 148 11276227
2009 Phosphorylation of ATM by Cdk5 mediates DNA damage signalling and regulates neuronal death. Nature cell biology 147 19151707
2008 An unusual member of the Cdk family: Cdk5. Cellular and molecular neurobiology 146 18183483
2002 Cdk5 behind the wheel: a role in trafficking and transport? Trends in cell biology 146 11854007
2016 The Emerging Role of Cdk5 in Cancer. Trends in cancer 142 27917404
2008 Cdk5 regulates the phosphorylation of tyrosine 1472 NR2B and the surface expression of NMDA receptors. The Journal of neuroscience : the official journal of the Society for Neuroscience 133 18184784
2021 Three decades of Cdk5. Journal of biomedical science 131 34814918
2004 A Jekyll and Hyde kinase: roles for Cdk5 in brain development and disease. Current opinion in neurobiology 131 15194121
2008 Deregulated Cdk5 promotes oxidative stress and mitochondrial dysfunction. Journal of neurochemistry 112 18691386
2006 The role of CDK5/P25 formation/inhibition in neurodegeneration. Drug news & perspectives 108 17160145
2012 Cdk5/p25-induced cytosolic PLA2-mediated lysophosphatidylcholine production regulates neuroinflammation and triggers neurodegeneration. The Journal of neuroscience : the official journal of the Society for Neuroscience 107 22262900
2011 Cdk5: multitasking between physiological and pathological conditions. Progress in neurobiology 103 21473899
2001 Cdk5 on the brain. Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research 100 11432802
2001 Cyclin-dependent protein kinase 5 (Cdk5) and the regulation of neurofilament metabolism. European journal of biochemistry 99 11248670
1994 Expression of CDK5 (PSSALRE kinase), a neural cdc2-related protein kinase, in the mature and developing mouse central and peripheral nervous systems. Brain research 94 7834371
2007 Stabilization and activation of p53 induced by Cdk5 contributes to neuronal cell death. Journal of cell science 93 17591690
2002 Cdk5 phosphorylates p53 and regulates its activity. Journal of neurochemistry 88 12064478
2017 Biological functions of CDK5 and potential CDK5 targeted clinical treatments. Oncotarget 86 28077789
2014 Cdk5 regulates multiple cellular events in neural development, function and disease. Development, growth & differentiation 86 24844647
2003 Cdk5: one of the links between senile plaques and neurofibrillary tangles? Journal of Alzheimer's disease : JAD 86 12719630
2009 Making a neuron: Cdk5 in embryonic and adult neurogenesis. Trends in neurosciences 84 19782409
2010 Cdk5 suppresses the neuronal cell cycle by disrupting the E2F1-DP1 complex. The Journal of neuroscience : the official journal of the Society for Neuroscience 82 20392944
2015 CDK5 phosphorylates DRP1 and drives mitochondrial defects in NMDA-induced neuronal death. Human molecular genetics 81 26002103
2001 Phosphorylation of protein phosphatase inhibitor-1 by Cdk5. The Journal of biological chemistry 77 11278334
2009 Recent advances in understanding the roles of Cdk5 in synaptic plasticity. Biochimica et biophysica acta 76 19442718
2004 Cdk5: mediator of neuronal death and survival. Neuroscience letters 74 15135890
2015 Cell cycle-dependent ubiquitylation and destruction of NDE1 by CDK5-FBW7 regulates ciliary length. The EMBO journal 71 26206584
2020 Physiological and Pathological Roles of Cdk5: Potential Directions for Therapeutic Targeting in Neurodegenerative Disease. ACS chemical neuroscience 69 32286796
1997 Expression of Cdk5, p35, and Cdk5-associated kinase activity in the developing rat lens. Developmental genetics 67 9216066
2022 The role of Cdk5 in neurological disorders. Frontiers in cellular neuroscience 65 35966199
2020 Development of CDK2 and CDK5 Dual Degrader TMX-2172. Angewandte Chemie (International ed. in English) 63 32415712
2010 Cdk5, the multifunctional surveyor. Cell cycle (Georgetown, Tex.) 63 20061803
2003 Cyclin-dependent kinase 5 (CDK5) and neuronal cell death. Cell and tissue research 63 12684868
1996 Cyclin-dependent kinase 5 (Cdk5) and neuron-specific Cdk5 activators. Progress in cell cycle research 62 9552397
2015 CDK5 knockdown prevents hippocampal degeneration and cognitive dysfunction produced by cerebral ischemia. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 61 26104286
2014 CDK5 activator protein p25 preferentially binds and activates GSK3β. Proceedings of the National Academy of Sciences of the United States of America 60 25331900
2006 Cdk5: a new player in pain signaling. Cell cycle (Georgetown, Tex.) 59 16552189
2002 Identification of a neuronal Cdk5 activator-binding protein as Cdk5 inhibitor. The Journal of biological chemistry 59 11882646
2011 Cdk5 is required for memory function and hippocampal plasticity via the cAMP signaling pathway. PloS one 58 21984943
2015 TIGAR regulates DNA damage and repair through pentosephosphate pathway and Cdk5-ATM pathway. Scientific reports 57 25928429
2003 Role of cdk5 in the pathogenesis of Alzheimer's disease. Neuro-Signals 57 14673207
2001 The protein SET binds the neuronal Cdk5 activator p35nck5a and modulates Cdk5/p35nck5a activity. The Journal of biological chemistry 56 11741927
2014 Cdk5-dependent Mst3 phosphorylation and activity regulate neuronal migration through RhoA inhibition. The Journal of neuroscience : the official journal of the Society for Neuroscience 55 24872548
2015 Cdk5 at crossroads of protein oligomerization in neurodegenerative diseases: facts and hypotheses. Journal of neurochemistry 54 26376455
2006 Abl deregulates Cdk5 kinase activity and subcellular localization in Drosophila neurodegeneration. Cell death and differentiation 54 16932754
2019 CDK5: A Unique CDK and Its Multiple Roles in the Nervous System. Journal of Alzheimer's disease : JAD 51 30856110
2016 Neuroprotective Mechanisms Mediated by CDK5 Inhibition. Current pharmaceutical design 51 26601962
2014 CDK5 is a major regulator of the tumor suppressor DLC1. The Journal of cell biology 51 25452387
2019 CDK5: Key Regulator of Apoptosis and Cell Survival. Biomedicines 50 31698798
2017 Cdk5 links with DNA damage response and cancer. Molecular cancer 50 28288624
2010 The role of Cdk5 in cognition and neuropsychiatric and neurological pathology. Brain research bulletin 49 21145377
2004 Cdk5 and Trio modulate endocrine cell exocytosis. Journal of cell science 46 15331630
2018 Amyloid-ß promotes neurotoxicity by Cdk5-induced p53 stabilization. Neuropharmacology 45 30452955
2002 CDK5 regulates cell adhesion and migration in corneal epithelial cells. Molecular cancer research : MCR 45 12496365
2020 The Role of CDK5 in Tumours and Tumour Microenvironments. Cancers 44 33396266
2017 Inhibition of Cdk5 Promotes β-Cell Differentiation From Ductal Progenitors. Diabetes 43 28986398
1994 Chromosomal mapping of human CDK2, CDK4, and CDK5 cell cycle kinase genes. Cytogenetics and cell genetics 43 8275715
2019 Cyclin-dependent kinase 5 (CDK5) regulates the circadian clock. eLife 42 31687929
2007 Alternative roles for Cdk5 in learning and synaptic plasticity. Biotechnology journal 42 17597494
2020 A kinase of many talents: non-neuronal functions of CDK5 in development and disease. Open biology 41 31910742
2003 Role of Cdk5 in neuronal signaling, plasticity, and drug abuse. Neuro-Signals 41 14673205
2023 A Cdk5-derived peptide inhibits Cdk5/p25 activity and improves neurodegenerative phenotypes. Proceedings of the National Academy of Sciences of the United States of America 40 37043533
2011 Twice switched at birth: cell cycle-independent roles of the "neuron-specific" cyclin-dependent kinase 5 (Cdk5) in non-neuronal cells. Cellular signalling 40 21741478
2008 Cdk5 and the non-catalytic arrest of the neuronal cell cycle. Cell cycle (Georgetown, Tex.) 38 19001851
2003 Cdk5 in neuroskeletal dynamics. Neuro-Signals 37 14673211
2019 CDK5-mediated phosphorylation and stabilization of TPX2 promotes hepatocellular tumorigenesis. Journal of experimental & clinical cancer research : CR 36 31272499
2011 Cdk5: mediator of neuronal development, death and the response to DNA damage. Mechanisms of ageing and development 36 21600237
2021 Cdk5 and GSK3β inhibit fast endophilin-mediated endocytosis. Nature communications 35 33893293
2023 Cdk5 and aberrant cell cycle activation at the core of neurodegeneration. Neural regeneration research 34 36453392
2018 Zinc induces CDK5 activation and neuronal death through CDK5-Tyr15 phosphorylation in ischemic stroke. Cell death & disease 34 30158515
2003 Cdk5: a novel role in learning and memory. Neuro-Signals 34 14673206
2017 CDK5 in oncology: recent advances and future prospects. Future medicinal chemistry 33 29076761
2003 Cdk5 and the mystery of synaptic vesicle endocytosis. The Journal of cell biology 33 14638853
2016 Targeting CDK5 post-stroke provides long-term neuroprotection and rescues synaptic plasticity. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 32 27486045
2004 Cdk5 phosphorylation of FAK regulates centrosome-associated miocrotubules and neuronal migration. Cell cycle (Georgetown, Tex.) 32 14712065
2016 Parkinson-Related LRRK2 Mutation R1628P Enables Cdk5 Phosphorylation of LRRK2 and Upregulates Its Kinase Activity. PloS one 31 26930193
2016 Cdk5 Directly Targets Nuclear p21CIP1 and Promotes Cancer Cell Growth. Cancer research 31 27909065
2020 Cdk5-Mediated Phosphorylation of Sirt1 Contributes to Podocyte Mitochondrial Dysfunction in Diabetic Nephropathy. Antioxidants & redox signaling 30 32660255
2016 CDK5 downregulation enhances synaptic plasticity. Cellular and molecular life sciences : CMLS 29 27506619
2004 Co-purification and localization of Munc18-1 (p67) and Cdk5 with neuronal cytoskeletal proteins. Neurochemistry international 29 12963086
2023 CDK5-PRMT1-WDR24 signaling cascade promotes mTORC1 signaling and tumor growth. Cell reports 28 36995937
2019 Role of Cdk5 in Amyloid-beta Pathology of Alzheimer's Disease. Current Alzheimer research 28 31820699
2014 Cdk12 and Cdk13 regulate axonal elongation through a common signaling pathway that modulates Cdk5 expression. Experimental neurology 28 24999027
2007 New approaches to the discovery of cdk5 inhibitors. Current Alzheimer research 27 18220519
2003 Protein-protein interactions in Cdk5 regulation and function. Neuro-Signals 27 14673210
2014 Tolfenamic acid reduces tau and CDK5 levels: implications for dementia and tauopathies. Journal of neurochemistry 26 25279694
2007 Cerebral ischemia, cell cycle elements and Cdk5. Biotechnology journal 26 17619233

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