Affinage

CDK5

Cyclin-dependent kinase 5 · UniProt Q00535

Length
292 aa
Mass
33.3 kDa
Annotated
2026-04-28
100 papers in source corpus 43 papers cited in narrative 43 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CDK5 is a proline-directed serine/threonine kinase that, upon activation by its non-cyclin cofactors p35 and p25, phosphorylates a remarkably diverse set of substrates to regulate neuronal migration, synaptic plasticity, axonal transport, circadian timing, DNA damage responses, and cell survival. In neurons, CDK5 phosphorylates DARPP-32 (Thr75) to modulate dopamine/PKA signaling (PMID:10604473), NR2B (Ser1116) and delta-catenin to control NMDA and AMPA receptor surface expression (PMID:24607229, PMID:20573893), DRP1 (Ser585) to drive mitochondrial fission (PMID:26002103), ATM (Ser794) to initiate the DNA damage checkpoint (PMID:19151707), PER2 (Ser394) and CLOCK to set circadian period (PMID:31687929, PMID:24235147), and p27/cofilin and FAK/talin to orchestrate cytoskeletal remodeling during cortical migration (PMID:16341208, PMID:19363486). Beyond neurons, CDK5 phosphorylates Rb to promote medullary thyroid carcinoma proliferation, controls PD-L1 expression through IRF2/IRF2BP2 repressor stability to modulate anti-tumor immunity, regulates Foxc2 in lymphatic valve morphogenesis, and suppresses the ERK-PPARγ diabetogenic axis in adipose tissue (PMID:24135281, PMID:27463676, PMID:26027726, PMID:25409143). Pathological conversion of p35 to the more stable p25 fragment leads to CDK5 hyperactivation, aberrant tau and CRMP2 hyperphosphorylation, oxidative stress, and neurodegeneration, which can be counteracted by a CDK5-derived peptide that selectively disrupts the CDK5-p25 interaction (PMID:18460467, PMID:37043533).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1999 High

    Establishing CDK5 as a signal integration node in dopamine signaling: CDK5 was shown to phosphorylate DARPP-32 at Thr75, converting it into a PKA inhibitor, revealing that CDK5 opposes cAMP/PKA signaling in striatal neurons.

    Evidence In vitro kinase assay, CDK5-specific inhibitor, genetically altered mice, striatal slice recordings

    PMID:10604473

    Open questions at the time
    • Upstream signals controlling CDK5 activity in dopamine neurons were unknown
    • Whether other CDK5 substrates contribute to dopaminergic signaling was unaddressed
  2. 2001 High

    Extending CDK5 function beyond neurons: CDK5/p35 was found necessary for neuregulin-induced AChR gene expression at the neuromuscular junction and shown to associate with ErbB receptors, and CDK5 was identified as the sole kinase phosphorylating protein phosphatase inhibitor-1 at Ser67 in striatum, broadening its role in signal modulation.

    Evidence Co-immunoprecipitation with ErbB, kinase assays, AChR promoter assay; phospho-specific antibodies and selective inhibitors in striatal tissue

    PMID:11276227 PMID:11278334

    Open questions at the time
    • Direct phosphorylation site on ErbB receptors was not identified
    • Whether I-1 Ser67 phosphorylation occurs outside striatum was untested
  3. 2002 High

    CDK5 was linked to p53 stabilization and apoptosis: nuclear CDK5 phosphorylates p53 at Ser15/33/46, disrupts p53-Hdm2 interaction, prevents ubiquitylation, and enhances p300-mediated acetylation, establishing CDK5 as a regulator of the DNA damage-apoptosis axis.

    Evidence In vitro kinase assay, co-immunoprecipitation, ubiquitylation assay, p53 reporter assay; confirmed in 2007 with apoptosis assays

    PMID:12064478 PMID:17591690

    Open questions at the time
    • Whether CDK5-p53 pathway operates in non-neuronal contexts was unclear
    • The relative contribution of each phosphosite to p53 stabilization was not dissected
  4. 2004 High

    CDK5 was established as a master regulator of neuronal migration and axonal transport through phosphorylation of FAK (Ser732), regulation of kinesin via a CDK5→PP1→GSK3 pathway, and Trio-dependent Rac activation for exocytosis.

    Evidence In vitro kinase assays, phospho-mutants, axonal perfusion, centrosome analysis, Rac activation assays

    PMID:14712065 PMID:15152189 PMID:15331630

    Open questions at the time
    • Whether CDK5 directly phosphorylates kinesin light chains or acts solely via GSK3 was unresolved
    • The specific CDK5 phosphorylation sites on Trio were mapped only on peptides
  5. 2005 High

    CDK5 was shown to phosphorylate and stabilize p27kip1 in post-mitotic neurons, activating a p27→cofilin pathway that drives actin reorganization essential for cortical neuronal migration.

    Evidence In vivo RNAi, in vitro kinase assay, F-actin measurement, cortical migration analysis

    PMID:16341208

    Open questions at the time
    • How CDK5-p27 stabilization avoids triggering cell cycle re-entry in post-mitotic neurons was unexplained
  6. 2008 High

    Multiple synaptic and stress-related CDK5 substrates were identified: CDK5 controls NMDA receptor endocytosis via Src-NR2B Tyr1472 phosphorylation, primes CRMP2 for sequential GSK3 phosphorylation relevant to Alzheimer's disease, phosphorylates Kalirin-7 (Thr1590) for dendritic spine morphogenesis, regulates CLOCK stability for circadian function, and inactivates peroxiredoxins to drive oxidative stress.

    Evidence Surface biotinylation, in vitro kinase/dephosphorylation assays, phosphomimic mutants, mutagenesis, subcellular fractionation, ROS measurements

    PMID:18184784 PMID:18460467 PMID:18628310 PMID:18691386 PMID:24235147

    Open questions at the time
    • Whether CRMP2 hyperphosphorylation is a cause or consequence of AD pathology remained debated
    • The relationship between CDK5-mediated peroxiredoxin inactivation and p25 generation was correlative
  7. 2009 High

    CDK5 was placed upstream of the DNA damage response: CDK5 phosphorylates ATM at Ser794, which is required for ATM autophosphorylation and downstream p53/H2AX signaling, explaining how post-mitotic neurons activate DNA damage checkpoints; separately, CDK5 phosphorylation of talin head at Ser425 protects it from Smurf1-mediated degradation, controlling focal adhesion turnover.

    Evidence In vitro kinase assays with mutagenesis, cell cycle re-entry assays, ubiquitylation assays, focal adhesion imaging

    PMID:19151707 PMID:19363486

    Open questions at the time
    • Whether CDK5 activates ATM in non-neuronal DNA damage contexts was untested
    • The stoichiometry of talin Ser425 phosphorylation in vivo was not measured
  8. 2010 High

    A kinase-independent function of CDK5 was discovered: the p35-CDK5 dimer sequesters E2F1 away from DP1, suppressing cell cycle gene transcription in neurons; CDK5 also phosphorylates STAT3 at Ser727 to promote DNA repair gene expression and delta-catenin to control AMPA receptor surface levels.

    Evidence Kinase-dead CDK5 mutants, E2F1 promoter assays, ChIP for STAT3, electrophysiology for AMPA/NMDA ratio

    PMID:20392944 PMID:20516069 PMID:20573893

    Open questions at the time
    • Whether p25 disrupts the E2F1 sequestration mechanism in disease was not tested
    • The STAT3-Eme1 pathway lacked independent replication
  9. 2011 High

    CDK5 was shown to regulate cAMP homeostasis and myoblast differentiation: hippocampal CDK5 loss increases PDE levels, disrupting CREB signaling and memory (rescued by PDE4 inhibition); nestin bidirectionally regulates CDK5 via p35-to-p25 cleavage control during myogenesis.

    Evidence Conditional knockout, cAMP/CREB assays, behavioral tests, rolipram rescue; RNAi/overexpression differentiation assays

    PMID:21346193 PMID:21984943

    Open questions at the time
    • The mechanism by which CDK5 suppresses PDE protein levels was unknown
    • Whether CDK5-nestin crosstalk operates in other muscle or stem cell contexts was untested
  10. 2013 High

    CDK5 was found to control presynaptic function by regulating Cav2.2 calcium channel-dependent exocytosis, with the CDK5/calcineurin balance determining the proportion of presynaptically silent terminals; separately, CDK5 was shown to drive medullary thyroid carcinoma via Rb Ser807/811 phosphorylation.

    Evidence Pharmacological dissection with Cav2.2-specific toxins and live terminal imaging; phosphoproteomics, conditional p25 mouse MTC model

    PMID:23699505 PMID:24135281

    Open questions at the time
    • The direct CDK5 substrate(s) at the presynaptic terminal governing Cav2.2 were not identified
    • Whether CDK5 phosphorylates Rb directly or via an intermediate kinase in MTC was not fully resolved
  11. 2014 High

    CDK5 substrate specificity was expanded to metabolic and migration signaling: CDK5 phosphorylates NR2B at Ser1116 to control surface expression and memory; Mst3 at Ser79 to inhibit RhoA during neuronal migration; and MEK to suppress ERK-mediated PPARγ Ser273 phosphorylation in adipose tissue, redefining CDK5's metabolic role.

    Evidence In vitro kinase assays, interfering peptide with in vivo behavioral rescue, in utero electroporation, adipose-specific KO with insulin clamp

    PMID:24607229 PMID:24872548 PMID:25409143

    Open questions at the time
    • The MEK phosphorylation site responsible for ERK suppression was not mapped
    • Whether CDK5 inhibition in adipose could be therapeutic without neurological side effects was unknown
  12. 2015 High

    CDK5 was connected to mitochondrial dynamics, ciliogenesis, lymphatic development, neuroprotection, and neuronal death: CDK5 phosphorylates DRP1 (Ser585) to promote fission, NDel1 to lock the Lis1/dynein complex and impair axonal transport, NDE1 to prime FBW7-mediated degradation for ciliogenesis, Foxc2 for lymphatic valve morphogenesis, Nrf2 for antioxidant gene induction in astrocytes, and CHIP (Ser20) to block tAIF degradation promoting cell death.

    Evidence Conditional KOs, phosphomimic/null mutants, ubiquitylation assays, organelle imaging, lymphatic phenotyping, co-culture neuroprotection

    PMID:25909891 PMID:26002103 PMID:26027726 PMID:26166569 PMID:26206088 PMID:26206584

    Open questions at the time
    • Whether DRP1 Ser585 phosphorylation is the sole CDK5-dependent mechanism for mitochondrial fission was unclear
    • The CDK5-NDE1-FBW7 pathway was not validated in primary ciliated tissues in vivo
  13. 2016 High

    CDK5 was established as a regulator of tumor immune evasion and angiogenesis: CDK5 disruption sustains IRF2/IRF2BP2 expression, suppressing PD-L1 and enabling T cell-mediated tumor rejection; endothelial CDK5 loss disrupts Notch signaling, causing aberrant angiogenesis that impairs tumor growth.

    Evidence CDK5 disruption in mouse medulloblastoma model with T cell depletion; endothelial-specific CDK5 KO with NICD measurement and tumor xenografts

    PMID:26755662 PMID:27463676

    Open questions at the time
    • The direct CDK5 substrate controlling IRF2/IRF2BP2 stability was not identified
    • The mechanism linking CDK5 to Notch cleavage (gamma-secretase regulation?) was indirect
  14. 2018 High

    A non-canonical CDK5 activation mechanism was identified: zinc-induced Src-mediated phosphorylation of CDK5 at Tyr15 activates CDK5 independently of p35-to-p25 cleavage, contributing to ischemic neuronal death.

    Evidence Y15F site-directed mutagenesis, Src inhibitor, CDK5 activity assay, rat MCAO ischemia model

    PMID:30158515

    Open questions at the time
    • Whether Tyr15 phosphorylation alters CDK5 substrate specificity or only activity level was unknown
    • The generality of p25-independent CDK5 activation in other pathological contexts was not explored
  15. 2019 High

    CDK5 was established as a circadian clock kinase: CDK5 phosphorylates PER2 at Ser394 in a diurnal fashion in the SCN, facilitating PER2-CRY1 complex formation and nuclear entry, thereby controlling circadian period length; CDK5 also stabilizes TPX2 to promote hepatocellular carcinoma.

    Evidence In vitro kinase assay, Co-IP, AAV-mediated CDK5 knockdown in SCN, free-running period measurement; phosphoproteomics, xenograft and DEN-HCC models

    PMID:31272499 PMID:31687929

    Open questions at the time
    • Whether CDK5 phosphorylates other clock proteins beyond CLOCK and PER2 was unknown
    • The mechanism linking TPX2 stabilization to mitotic fidelity in HCC was not dissected
  16. 2023 High

    A therapeutic strategy to selectively inhibit pathological CDK5 was demonstrated: a 12-amino-acid peptide (Cdk5i) derived from CDK5 itself disrupts the CDK5-p25 interaction, lowers hyperactivated CDK5/p25 kinase activity, and protects against neurodegeneration in mouse models.

    Evidence Binding affinity assay, in vitro CDK5/p25 kinase inhibition, TAT-peptide delivery, mouse model of p25-induced neurodegeneration

    PMID:37043533

    Open questions at the time
    • Whether Cdk5i spares CDK5/p35-dependent physiological functions was not rigorously assessed
    • Long-term safety and blood-brain barrier penetrance of the peptide were not established
    • Whether Cdk5i efficacy extends to sporadic Alzheimer's disease models was untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include: the full extent of CDK5's kinase-independent functions, the structural basis of p35 vs. p25 substrate selectivity, whether CDK5 directly phosphorylates substrates in the immune checkpoint and Notch pathways or acts through intermediates, and whether selective p25 inhibition can be achieved therapeutically without disrupting physiological CDK5/p35 activity.
  • No high-resolution structure of full-length CDK5-p35 vs CDK5-p25 with substrate peptide
  • Direct CDK5 substrates in PD-L1 regulation and Notch signaling remain unidentified
  • In vivo selectivity of Cdk5i peptide for p25 over p35 needs quantification

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 26 GO:0098772 molecular function regulator activity 2
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 2
Pathway
R-HSA-112316 Neuronal System 5 R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 4 R-HSA-1640170 Cell Cycle 3 R-HSA-1643685 Disease 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-73894 DNA Repair 2 R-HSA-9909396 Circadian clock 2 R-HSA-168256 Immune System 1
Partners
ATMCDK5R1CDK5R2DARPP32DPYSL2DRP1MAPTNR2B
Complex memberships
CDK5/p25CDK5/p35

Evidence

Reading pass · 43 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 CDK5 phosphorylates DARPP-32 at threonine 75 in vitro and in intact brain cells, converting DARPP-32 into an inhibitor of PKA by a competitive mechanism, thereby modulating dopamine signaling; conversely, PKA phosphorylates DARPP-32 at threonine 34 to inhibit protein phosphatase 1, making DARPP-32 a bifunctional signal transduction molecule. In vitro kinase assay, intact brain cell phosphorylation, Cdk5-specific inhibitor, genetically altered mice, striatal slice recordings Nature High 10604473
2001 CDK5/p35 is required for neuregulin-induced acetylcholine receptor (AChR) gene expression at the neuromuscular junction; neuregulin increases p35-associated Cdk5 kinase activity in the membrane fraction of myotubes, and Cdk5 associates with ErbB receptors via co-immunoprecipitation. Co-immunoprecipitation, kinase activity assay, Cdk5 inhibition, p35 overexpression, AChR promoter assay Nature neuroscience High 11276227
2002 CDK5 phosphorylates p53 at Ser15, Ser33, and Ser46 in vitro; increased nuclear Cdk5 activity promotes p53 stabilization by disrupting the p53-Hdm2 interaction, preventing Hdm2-induced p53 ubiquitylation, and enhancing p300-mediated acetylation of p53, leading to transcriptional activation of pro-apoptotic genes. In vitro kinase assay, co-immunoprecipitation, transfection of Cdk5/p25, p53 reporter assays, ubiquitylation assay Journal of neurochemistry High 12064478
2004 CDK5 defines a regulatory pathway controlling kinesin-driven axonal transport: CDK5 inhibition activates GSK3 via protein phosphatase 1 (PP1), GSK3 then phosphorylates kinesin light chains causing kinesin to detach from membrane-bounded organelle cargoes. Pharmacological, biochemical, and in vivo axonal perfusion experiments; kinase activity assays The EMBO journal High 15152189
2005 CDK5 phosphorylates and stabilizes the CDK inhibitor p27kip1 in post-mitotic neurons; the CDK5-p27 pathway activates cofilin, an actin-binding protein, promoting actin reorganization required for cortical neuronal migration. In vivo RNAi, in vitro kinase assay, F-actin measurement, cortical neuronal migration analysis Nature cell biology High 16341208
2007 CDK5 interacts with p53, phosphorylates it at Ser15, Ser33, and Ser46, disrupts the p53-Hdm2 interaction to prevent ubiquitylation and degradation, and enhances p300-mediated acetylation, resulting in nuclear p53 accumulation and mitochondria-mediated apoptosis in neurons under genotoxic/oxidative stress. Co-immunoprecipitation, in vitro kinase assay, ubiquitylation assay, nuclear fractionation, apoptosis assays Journal of cell science High 17591690
2008 Inhibition of CDK5 increases Src binding to PSD-95 and Src-mediated phosphorylation of NR2B at tyrosine 1472, which reduces NR2B binding to the clathrin adaptor AP-2 and blocks activity-dependent endocytosis of NMDA receptors, thereby regulating their surface expression. Pharmacological CDK5 inhibition, co-immunoprecipitation, surface biotinylation, synaptosome fractionation The Journal of neuroscience High 18184784
2008 Deregulated CDK5 inactivates peroxiredoxins I and II, causing reactive oxygen species accumulation; CDK5 dysregulation is upstream of mitochondrial dysfunction, establishing a feedback loop in neuronal oxidative stress. Chemical genetic screen, novel CDK5 modulators, ROS measurement, mitochondrial damage assays Journal of neurochemistry Medium 18691386
2008 CDK5 phosphorylates the CLOCK transcription factor at Thr-451 and Thr-461, regulating CLOCK stability and subcellular distribution, and thereby affecting circadian transcriptional activation. In vitro kinase assay, co-immunoprecipitation, mutagenesis of phosphorylation sites, subcellular fractionation The Journal of biological chemistry High 24235147
2009 CDK5 phosphorylates ATM at Ser794 in post-mitotic neurons following DNA damage; this phosphorylation precedes and is required for ATM autophosphorylation at Ser1981 and ATM kinase activation, and the CDK5-ATM pathway regulates p53 and H2AX phosphorylation, controlling neuronal cell cycle re-entry and expression of pro-apoptotic genes PUMA and Bax. In vitro kinase assay, site-directed mutagenesis, neuronal CDK5 pathway interruption, cell cycle and apoptosis assays Nature cell biology High 19151707
2009 CDK5 phosphorylates talin head at Ser425, inhibiting its binding to the E3 ubiquitin ligase Smurf1; without CDK5 phosphorylation, Smurf1 ubiquitylates and degrades talin head, promoting focal adhesion turnover and inhibiting cell migration. In vitro kinase assay, co-immunoprecipitation, mutagenesis (S425A), ubiquitylation assay, focal adhesion turnover imaging Nature cell biology High 19363486
2010 CDK5 suppresses the neuronal cell cycle through a kinase-independent mechanism: the p35-CDK5 dimer forms a complex with E2F1, excluding the E2F1 cofactor DP1 and thereby inhibiting E2F1-dependent transcription of cell cycle genes; p39 and p25 cannot substitute for p35 in this function. Co-immunoprecipitation, E2F1 promoter binding assays, kinase-dead CDK5 mutants, cell cycle analysis The Journal of neuroscience High 20392944
2010 CDK5 phosphorylates STAT3 at Ser727 upon topoisomerase I inhibition; CDK5 associates with the C-terminal activation domain of STAT3 (by Co-IP and pulldown), and the CDK5-STAT3 pathway promotes expression of the DNA repair endonuclease Eme1, reducing DNA damage. Co-immunoprecipitation, pulldown assay, ChIP, pharmacological CDK5 induction, STAT3 phosphorylation assay The Journal of biological chemistry Medium 20516069
2010 CDK5 phosphorylates delta-catenin at Ser300 and Ser357; loss of this phosphorylation increases delta-catenin membrane localization, increases dendritic protrusions, and increases GluR2 AMPA receptor membrane expression, raising the AMPA/NMDA ratio at synapses. Site-directed mutagenesis, subcellular fractionation, surface receptor assay, electrophysiology The Journal of neuroscience High 20573893
2011 CDK5 loss of function in hippocampus disrupts cAMP signaling by aberrantly increasing phosphodiesterase (PDE) protein levels, leading to defective CREB phosphorylation, disrupted synaptic protein composition, and memory impairment; PDE4 inhibitor rolipram rescues plasticity and memory in CDK5-deficient mice. Conditional knockout, cAMP assay, PDE biochemistry, CREB phosphorylation, behavioral memory tests, pharmacological rescue PloS one High 21984943
2011 Nestin, an intermediate filament protein, regulates CDK5 activity in myoblasts by controlling the calpain-mediated cleavage of the CDK5 activator p35 to its degradation-resistant form p25; CDK5 in turn regulates nestin organization and stability, creating a bidirectional CDK5-nestin cross-talk that sets the pace of myoblast differentiation. RNAi knockdown, overexpression, p35/p25 cleavage assay, differentiation marker analysis Molecular biology of the cell Medium 21346193
2012 p25/CDK5 induces cytosolic phospholipase A2 (cPLA2) upregulation, leading to production of lysophosphatidylcholine (LPC) from neurons; LPC acts as a soluble lipid mediator initiating astrogliosis, neuroinflammation, and neurodegeneration in a paracrine manner. Lipidomic mass spectrometry, in vitro coculture, conditioned media transfer, RT-PCR, gene silencing The Journal of neuroscience High 22262900
2013 CDK5 phosphorylates the calcineurin substrate-related balance at nerve terminals regulates single action potential-driven exocytosis almost entirely through Cav2.2 (N-type) voltage-gated calcium channels; the balance of CDK5 and calcineurin Aα activities determines the proportion of presynaptically silent terminals. Acute pharmacological inhibition of CDK5 and calcineurin, calcium imaging, peptide toxin block of Cav2.2, live terminal imaging The Journal of neuroscience High 23699505
2013 CDK5 and its cofactors p35/p25 are expressed in medullary thyroid carcinoma cells; CDK5 phosphorylates the retinoblastoma protein (Rb) at Ser807/Ser811, and prevention of this phosphorylation attenuates MTC proliferation; conditional p25 overexpression in C cells causes lethal MTC in mice. Comparative phosphoproteomic screen, conditional mouse model, Rb phosphorylation assay, proliferation assays Cancer cell High 24135281
2014 CDK5 phosphorylates PPARγ at Ser273 in adipose tissue, stimulating diabetogenic gene expression; adipose-specific CDK5 knockout paradoxically increases PPARγ Ser273 phosphorylation because CDK5 normally suppresses ERK by acting on a novel site in MEK, and ERK directly phosphorylates PPARγ Ser273. Adipose-specific CDK5 KO, unbiased proteomics, in vitro kinase assay, MEK/ERK pharmacological inhibition, insulin clamp studies Nature High 25409143
2014 CDK5 phosphorylates the NMDA receptor subunit NR2B at Ser1116; this phosphorylation is regulated by neuronal activity and controls NR2B surface expression; disrupting NR2B-CDK5 interaction with a small interfering peptide increases NR2B surface levels, facilitates synaptic transmission, and improves memory in vivo. In vitro kinase assay, surface receptor assay, small interfering peptide, electrophysiology, in vivo behavioral memory tests Neuron High 24607229
2014 CDK5 phosphorylates Mst3 at Ser79, activating Mst3 kinase activity; Mst3 in turn phosphorylates RhoA at Ser26, inhibiting RhoA GTPase activity and allowing actin cytoskeletal reorganization required for the multipolar-to-bipolar transition and radial neuronal migration in the neocortex. In utero electroporation RNAi, in vitro kinase assay, RhoA GTPase activity assay, rescue experiments The Journal of neuroscience High 24872548
2014 The CDK5 activator p25 (but not p35) directly binds and activates GSK3β; overexpressed GSK3β outcompetes CDK5 for p25 binding; the GSK3β:p25 interaction alters GSK3β substrate specificity, enhancing tau phosphorylation while inhibiting β-catenin phosphorylation by blocking the AXIN-binding domain of GSK3β. Co-immunoprecipitation, FRET analysis, in silico modeling, siRNA knockdown, substrate phosphorylation assays Proceedings of the National Academy of Sciences of the United States of America High 25331900
2015 CDK5 phosphorylates the mitochondrial fission protein DRP1 at Ser585; this phosphorylation promotes mitochondrial fission; conditional CDK5 deletion significantly attenuates DRP1 Ser585 phosphorylation and rescues mitochondrial fragmentation defects in neurons exposed to NMDA-induced excitotoxicity. In vitro kinase assay, DRP1-S585D/A mutants, conditional CDK5 knockout, roscovitine inhibition, mitochondrial morphology imaging Human molecular genetics High 26002103
2015 CDK5 phosphorylates NDel1, stabilizing the Lis1/Ndel1/dynein complex in a high-affinity state that blocks ATP-dependent dynein release from microtubules, inhibiting processive dynein-driven cargo transport and causing axonal transport defects under stress conditions. CDK5 activator p25 overexpression, organelle live imaging, mechanistic Lis1/Ndel1/dynein biochemistry, CDK5 inhibition rescue, ALS mouse model Cell reports High 26166569
2015 Active p35/CDK5 complex in astrocyte cytosol phosphorylates Nrf2 at Thr395, Ser433, and Thr439, promoting Nrf2 nuclear translocation and induction of antioxidant gene expression, which protects nearby neurons against oxidative damage; this is triggered by NMDAR-stimulated PKCδ-mediated p35 stabilization. In vitro kinase assay, site-directed mutagenesis of Nrf2, nuclear fractionation, antioxidant gene reporter assay, co-culture neuroprotection assay Cell death and differentiation High 25909891
2015 CDK5 phosphorylates NDE1, priming it for recognition and ubiquitin-mediated destruction by the E3 ligase FBW7 upon entry into G1; depletion of FBW7 or CDK5 increases NDE1 levels and reduces ciliary length, establishing a CDK5-FBW7-NDE1 pathway coupling cell cycle to ciliogenesis. Co-immunoprecipitation, ubiquitylation assay, CDK5 and FBW7 depletion, ciliary length measurement The EMBO journal High 26206584
2015 CDK5 phosphorylates CHIP (C-terminus of Hsc70-interacting protein) at Ser20, disrupting the interaction between CHIP and truncated apoptosis-inducing factor (tAIF) without affecting CHIP E3 ligase activity, resulting in inhibition of CHIP-mediated tAIF degradation and promotion of neuronal death. In vitro kinase assay, co-immunoprecipitation, ubiquitylation assay, lentiviral transduction KD, phospho-site mutagenesis Cell death and differentiation High 26206088
2015 CDK5 is an essential regulator of lymphatic vessel development; endothelial-specific CDK5 knockdown causes lymphatic dysfunction and lymphedema; CDK5 phosphorylates the transcription factor Foxc2, linking CDK5 to lymphatic valve morphogenesis. Endothelial-specific CDK5 knockdown mouse model, substrate phosphorylation assay, lymphatic phenotype analysis Nature communications High 26027726
2016 CDK5 activity is required for IFN-γ-induced PD-L1 up-regulation on medulloblastoma; CDK5 disruption results in persistent expression of PD-L1 transcriptional repressors IRF2 and IRF2BP2, reducing tumor PD-L1 expression and enabling CD4+ T cell-mediated tumor rejection. CDK5 disruption in mouse MB model, IFN-γ stimulation, IRF2/IRF2BP2 expression analysis, T cell depletion, tumor rejection assay Science High 27463676
2016 CDK5 inhibition in endothelial cells disrupts Notch signaling by reducing generation of the active Notch intracellular domain (NICD), causing excessive but non-productive angiogenesis and inhibiting tumor growth; endothelial-specific CDK5 KO in mice phenocopies this effect. Endothelial-specific CDK5 knockout mouse, NICD measurement, tumor xenograft models, endothelial sprouting assay Oncotarget Medium 26755662
2019 CDK5 phosphorylates PER2 at Ser394 in the suprachiasmatic nuclei in a diurnal fashion; this phosphorylation facilitates PER2 interaction with Cryptochrome 1 (CRY1) and promotes nuclear entry of the PER2-CRY1 complex, thereby controlling the circadian period length. In vitro kinase assay with site-directed mutagenesis (S394), Co-IP, CDK5 knockdown in SCN (AAV), free-running period measurement in mice eLife High 31687929
2019 CDK5 phosphorylates TPX2 at Ser486, promoting TPX2 protein stability; CDK5-mediated TPX2 stabilization promotes hepatocellular carcinoma cell proliferation and tumorigenicity. Comparative phosphoproteomic screen, in vitro kinase assay, mutagenesis, xenograft and DEN-induced HCC mouse models Journal of experimental & clinical cancer research High 31272499
2018 Zinc induces CDK5 Tyr15 phosphorylation by Src kinase, which activates CDK5 and promotes ischemic neuronal death independently of the canonical p35-to-p25 cleavage mechanism; expression of a Y15F-CDK5 mutant abolished Tyr15 phosphorylation and protected hippocampal neurons from ischemia. Site mutation (Y15F-CDK5), zinc and Src inhibitor treatment, CDK5 activity assay, rat MCAO model Cell death & disease High 30158515
2004 CDK5 phosphorylates focal adhesion kinase (FAK) at Ser732 in vitro and in the developing brain; S732 phosphorylation regulates a centrosome-associated microtubule structure to promote nuclear translocation during neuronal migration without directly affecting FAK kinase activity. In vitro kinase assay, phospho-specific antibody, S732A unphosphorylatable mutant FAK, centrosome localization analysis, neuronal migration assay Cell cycle High 14712065
2004 CDK5 regulates exocytosis in pituitary cells partly by phosphorylating Trio (a RhoGEF) at CDK5 consensus sites, and CDK5 inhibition blocks Trio-mediated Rac activation, leading to reorganization of cortical actin and preventing secretory granules from approaching the plasma membrane. Roscovitine pharmacological inhibition, actin reorganization imaging, ultrastructural analysis, Rac activation assay, in vitro phosphorylation of Trio peptides Journal of cell science Medium 15331630
2004 CDK5 regulates activation and localization of Src during corneal epithelial wound healing; CDK5 and Src co-immunoprecipitate; CDK5 inhibition increases active Src (pY416) at the cell periphery and enhances wound closure, while Src inhibition blocks CDK5-pY15 accumulation, suggesting Src-dependent CDK5 phosphorylation. Co-immunoprecipitation, transgenic CDK5 overexpression in cornea, olomoucine inhibition, dominant-negative Cdk5T33, Src inhibitor PP1, wound healing assay Journal of cell science Medium 15280426
2008 CRMP2 is sequentially phosphorylated first by CDK5 at Ser522, then by GSK3 at Ser518/Thr514/Thr509; the CDK5-phosphorylated site on CRMP2 is comparatively resistant to protein phosphatase treatment due to nearby basic residues, potentially contributing to CRMP2 and tau hyperphosphorylation in Alzheimer's disease. In vitro phosphorylation/dephosphorylation assays, selective kinase inhibitors (CT99021, purvalanol), phospho-specific antibodies, PP1 biochemistry, Pin1 transgenic mice The Journal of biological chemistry High 18460467
2008 CDK5 phosphorylates Kalirin-7 at Thr1590; this phosphorylation is required for Kalirin-7-induced extension of broad cytoplasmic protrusions (GEF-activity dependent) in PC12 cells; Ala1590 mutant retains GEF activity but fails to drive protrusion extension, while Asp1590 mutant bypasses dominant-negative CDK5 blockade; phosphorylation also modestly increases GEF activity and Kalirin-7 solubility. In vitro kinase assay, site-directed mutagenesis, dominant-negative CDK5, GEF activity assay, PC12 cell morphology analysis, cortical neuron dendritic spine analysis Journal of cell science High 18628310
2001 CDK5 phosphorylates protein phosphatase inhibitor-1 (I-1) at Ser67 in vitro; Cdk5 is the only kinase phosphorylating I-1 at Ser67 in intact striatal tissue (verified by phospho-specific antibodies and selective inhibitors); phospho-Ser67 I-1 is a less efficient substrate for PKA, modulating the amplitude of cAMP-dependent signaling events. In vitro kinase assay (Cdk1, Cdk5, MAPK), phospho-state-specific antibodies, selective kinase inhibitors, striatal tissue studies, in vitro dephosphorylation by PP2A/PP2B The Journal of biological chemistry High 11278334
2002 Pctaire1 (a CDK-related kinase) interacts with the CDK5 activator p35 both in vitro and by co-immunoprecipitation in myotubes; CDK5/p25 phosphorylates Pctaire1 at Ser95, and this phosphorylation increases Pctaire1 kinase activity; in CDK5 null mice, Pctaire1 activity is significantly reduced. In vitro binding assay, co-immunoprecipitation, in vitro kinase assay, Pctaire1 activity assay, CDK5 null mice The Journal of biological chemistry High 12084709
2006 In Drosophila, Abl kinase activity is required for beta-amyloid-triggered CDK5 binding, activation, and nuclear-to-cytoplasmic translocalization; CDK5 activation in this context is p25-independent; blocking Abl kinase suppresses CDK5 activity and rescues neurodegeneration in Drosophila eyes. Genetic Abl mutations, Abl kinase inhibitor, Drosophila eye neurodegeneration model, CDK5 activity assay, subcellular localization analysis Cell death and differentiation Medium 16932754
2023 A 12-amino-acid peptide (Cdk5i) derived from CDK5 binds the CDK5/p25 complex with high affinity, disrupts the CDK5-p25 interaction, and lowers CDK5/p25 kinase activity; when tagged with TAT for cell penetrance, it protects against neurodegenerative phenotypes in cell and mouse models of p25-induced neurodegeneration. Binding affinity assay, in vitro CDK5/p25 kinase activity assay, TAT-peptide cell penetrance assay, mouse model of CDK5 hyperactivity Proceedings of the National Academy of Sciences of the United States of America High 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 934 11584302
1999 Phosphorylation of DARPP-32 by Cdk5 modulates dopamine signalling in neurons. Nature 474 10604473
2016 Cdk5 disruption attenuates tumor PD-L1 expression and promotes antitumor immunity. Science (New York, N.Y.) 274 27463676
2014 An ERK/Cdk5 axis controls the diabetogenic actions of PPARγ. Nature 259 25409143
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