{"gene":"CDK5","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":1993,"finding":"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.","method":"Amino acid sequencing, antibody cross-reactivity, in vitro phosphorylation assay","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct biochemical identification by sequencing and in vitro kinase assay, foundational finding replicated across many subsequent studies","pmids":["8253190"],"is_preprint":false},{"year":1996,"finding":"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.","method":"Biochemical purification, in vitro kinase assay, transfection with dominant-negative mutants","journal":"Progress in cell cycle research","confidence":"High","confidence_rationale":"Tier 1 / Strong — biochemical reconstitution replicated extensively across many independent labs","pmids":["9552397"],"is_preprint":false},{"year":1997,"finding":"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.","method":"RT-PCR, immunocytochemistry, co-immunoprecipitation, in vitro kinase assay","journal":"Developmental genetics","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro kinase assay confirmed, but single lab with no functional follow-up","pmids":["9216066"],"is_preprint":false},{"year":1998,"finding":"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.","method":"Co-immunoprecipitation, co-localization by immunofluorescence, in vitro kinase assay, Pak1 activity assay","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, co-localization, and functional kinase assays in single rigorous study; findings widely cited and consistent with broader literature","pmids":["9744280"],"is_preprint":false},{"year":2001,"finding":"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.","method":"Co-immunoprecipitation, kinase activity assay, pharmacological inhibition, overexpression, reporter assay","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, functional inhibition, and reporter assay within one study; multiple orthogonal methods","pmids":["11276227"],"is_preprint":false},{"year":2001,"finding":"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.","method":"In vitro kinase assay, phosphorylation state-specific antibodies, selective kinase inhibitors, in vivo brain tissue analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay plus in vivo validation with phospho-specific antibodies and selective inhibitors; multiple orthogonal methods","pmids":["11278334"],"is_preprint":false},{"year":2001,"finding":"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.","method":"Affinity isolation from rat brain, mass spectrometry, co-immunoprecipitation, co-transfection, immunostaining, kinase assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — MS-identified interaction confirmed by co-IP, co-localization, and functional kinase assay; multiple orthogonal methods in one study","pmids":["11741927"],"is_preprint":false},{"year":2002,"finding":"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.","method":"In vitro kinase assay with recombinant p53, transient transfection, immunoblot, reporter/gene expression analysis","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro phosphorylation confirmed, but single lab with limited mechanistic depth","pmids":["12064478"],"is_preprint":false},{"year":2002,"finding":"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.","method":"Yeast two-hybrid screen, co-immunoprecipitation, deletion analysis, kinase inhibition assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — co-IP and functional kinase assay in single lab; single study","pmids":["11882646"],"is_preprint":false},{"year":2002,"finding":"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.","method":"Stable transfection, kinase-dead mutant, adhesion assay, in vitro wound migration assay","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — kinase-dead mutant epistasis plus functional cell assays, single lab","pmids":["12496365"],"is_preprint":false},{"year":2004,"finding":"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.","method":"Pharmacological inhibition, biochemical assays, in vivo axonal transport experiments","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — pharmacological, biochemical, and in vivo experiments combined; multiple orthogonal approaches","pmids":["15152189"],"is_preprint":false},{"year":2004,"finding":"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.","method":"In vitro kinase assay, phospho-specific antibody, S732A mutant FAK expression, immunostaining","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vitro phosphorylation, phospho-specific antibody, and unphosphorylatable mutant, single lab","pmids":["14712065"],"is_preprint":false},{"year":2004,"finding":"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.","method":"Pharmacological inhibition (roscovitine), in vitro peptide phosphorylation, Rac activation assay, ultrastructural analysis","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — multiple methods but single lab; Trio phosphorylation shown with peptides only","pmids":["15331630"],"is_preprint":false},{"year":2005,"finding":"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.","method":"In vitro kinase assay, in vivo RNAi, F-actin staining, cortical migration analysis","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vitro phosphorylation plus in vivo RNAi with defined phenotypic readout; multiple orthogonal methods","pmids":["16341208"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Genetic epistasis (abl mutations), cell death assay, co-immunoprecipitation, pharmacological inhibition","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genetic epistasis in Drosophila model plus biochemical assays; single lab","pmids":["16932754"],"is_preprint":false},{"year":2007,"finding":"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.","method":"In vitro kinase assay, co-immunoprecipitation, site-directed mutagenesis (implicitly), ubiquitylation assay, cell death assay","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal biochemical assays including in vitro phosphorylation, co-IP, ubiquitylation assay, and functional apoptosis readout","pmids":["17591690"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Pharmacological inhibition, co-immunoprecipitation, phospho-specific antibody, surface receptor assay","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — co-IP and pharmacological approach in single lab, no reconstitution","pmids":["18184784"],"is_preprint":false},{"year":2009,"finding":"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.","method":"In vitro kinase assay, co-immunoprecipitation, S425A phospho-mutant expression, ubiquitylation assay, cell migration assay","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay, phospho-mutant rescue, ubiquitylation assay, and functional migration readout; multiple orthogonal methods","pmids":["19363486"],"is_preprint":false},{"year":2009,"finding":"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.","method":"In vitro kinase assay, site-directed mutagenesis (Ser794), dominant-negative Cdk5, ATM kinase assay, neuronal death assay","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro phosphorylation, mutagenesis, and functional pathway analysis with multiple orthogonal methods in one study","pmids":["19151707"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Co-immunoprecipitation, kinase-dead mutant, ChIP/promoter binding assay, cell cycle re-entry assay","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, kinase-dead mutant, and promoter binding assay; multiple orthogonal methods in one study","pmids":["20392944"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Conditional knockout, behavioral memory assays, biochemical analysis (PDE levels, CREB phosphorylation), pharmacological rescue","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined molecular mechanism, rescue experiment, multiple readouts","pmids":["21984943"],"is_preprint":false},{"year":2014,"finding":"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.","method":"In utero electroporation, in vitro kinase assay, epistasis (rescue experiment), RhoA GTPase activity assay","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vitro phosphorylation, in vivo RNAi, epistasis rescue, and GTPase activity assay; multiple orthogonal methods","pmids":["24872548"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Adipose-specific Cdk5 knockout, unbiased proteomics, in vitro kinase assay, MEK/ERK pharmacological inhibition, insulin resistance measurement","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — conditional KO, in vitro kinase assay, proteomics, and pharmacological rescue; multiple orthogonal methods, published in Nature","pmids":["25409143"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Co-immunoprecipitation, FRET analysis, in silico docking, in vitro phosphorylation, siRNA knockdown","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 / Moderate — FRET, co-IP, structural modeling, and functional phosphorylation assays; multiple orthogonal methods","pmids":["25331900"],"is_preprint":false},{"year":2014,"finding":"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.","method":"In vitro kinase assay, phospho-mutant analysis, co-immunoprecipitation, Rho-GAP activity assay, focal adhesion localization","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro kinase assay, phospho-mutants, GAP activity assay, co-IP; multiple orthogonal methods","pmids":["25452387"],"is_preprint":false},{"year":2015,"finding":"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.","method":"In vitro kinase assay, phospho-site mutagenesis (S585D/S585A), conditional Cdk5 knockout, pharmacological inhibition (roscovitine), mitochondrial morphology analysis","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro phosphorylation, phospho-mutants, conditional KO, and morphological readout; multiple orthogonal methods","pmids":["26002103"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Cdk5 conditional disruption in mouse model, flow cytometry for PD-L1, T cell killing assay, IRF2/IRF2BP2 expression analysis","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic disruption in animal model with defined molecular intermediates and functional immune readout","pmids":["27463676"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Genetic depletion (siRNA/shRNA), epistasis rescue experiment, co-immunoprecipitation, ciliary length measurement, cell cycle synchronization","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — epistasis rescue, co-IP, and quantitative phenotypic readout; multiple orthogonal methods","pmids":["26206584"],"is_preprint":false},{"year":2016,"finding":"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.","method":"In vitro kinase assay, S130A mutant expression, proteasome inhibition, co-immunoprecipitation, cell growth assay, in vivo xenograft","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — phospho-mutant and functional assay, but kinase-dead vs active Cdk5 comparison not fully detailed in abstract; single lab","pmids":["27909065"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Co-immunoprecipitation, site-directed mutagenesis, in vitro kinase assay, neuronal toxicity assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — co-IP, mutagenesis, in vitro kinase assay; single lab, single study","pmids":["26930193"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Site-directed mutagenesis (Y15F), Src kinase inhibition, phospho-specific antibody, in vivo ischemia model, zinc chelation","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis, pharmacological inhibition, in vivo model, and phospho-specific antibody; multiple approaches","pmids":["30158515"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Comparative phosphoproteomic screening, in vitro/in vivo kinase assay, siRNA knockdown, xenograft model, diethylnitrosamine HCC model","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — phosphoproteomic substrate identification, functional rescue experiment; single lab","pmids":["31272499"],"is_preprint":false},{"year":2019,"finding":"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.","method":"In vivo Cdk5 knockdown in SCN, circadian period measurement, in vitro kinase assay, co-immunoprecipitation, nuclear localization assay","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo knockdown, in vitro phosphorylation, co-IP interaction assay, and functional period readout; multiple orthogonal methods","pmids":["31687929"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Roscovitine inhibition, dominant-negative Cdk5, phospho-S47 antibody, S47A mutant, in vitro and in vivo diabetic models, mitochondrial function assays","journal":"Antioxidants & redox signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — phospho-mutant and genetic/pharmacological inhibition, single lab","pmids":["32660255"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Chemical and genetic inhibition, co-immunoprecipitation (GSK3β-Endophilin), axon morphology analysis in hippocampal neurons","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — co-IP and genetic inhibition with functional readouts, but Cdk5 mechanism less directly shown than GSK3β; single study","pmids":["33893293"],"is_preprint":false},{"year":2023,"finding":"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.","method":"In vitro kinase assay, co-immunoprecipitation, methylation assay, subcellular fractionation, shRNA knockdown, xenograft tumor model","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vitro kinase assay, localization experiment, methylation assay, in vivo tumor model; multiple orthogonal methods","pmids":["36995937"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Binding affinity assay, in vitro kinase assay, cell/mouse models of neurodegeneration, FITC-TAT peptide cell/brain penetration assay","journal":"PNAS","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional in vitro and in vivo assays but mechanism of disruption not fully resolved by structure; single lab","pmids":["37043533"],"is_preprint":false}],"current_model":"CDK5 is an atypical proline-directed serine/threonine kinase that requires binding to non-cyclin activators (p35 or p39, or their calpain-cleaved products p25/p29) for activity; active CDK5 phosphorylates a wide range of substrates—including tau, neurofilaments, FAK, DRP1, PPARγ, ATM, p53, PER2, talin, DLC1, NDE1, PRMT1, and Sirt1—to regulate neuronal migration, axonal transport (via a CDK5-PP1-GSK3-kinesin pathway), cytoskeletal dynamics (through Rac-Pak1 and Mst3-RhoA axes), synaptic plasticity (modulating NMDA receptor surface expression via Src-NR2B-AP2 and cAMP-PDE pathways), circadian rhythm (phosphorylating PER2-S394 to drive nuclear entry of PER2-CRY1), DNA damage signaling (phosphorylating ATM-S794 to initiate ATM autophosphorylation), immune checkpoint control (enabling IFN-γ-induced PD-L1 expression), and metabolic regulation (phosphorylating PPARγ-S273 and MEK to control insulin sensitivity); pathological conversion of p35 to p25 by calpain prolongs and deregulates CDK5 activity, hyperphosphorylating tau and other substrates to drive neurodegeneration."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":1993,"claim":"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","pmids":["8253190"],"confidence":"High","gaps":["Did not identify the physiological activator","In vitro phosphorylation does not establish cellular substrate selectivity"]},{"year":1996,"claim":"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","pmids":["9552397"],"confidence":"High","gaps":["Structural basis of activator binding not defined","Did not address regulation by calpain cleavage to p25"]},{"year":1997,"claim":"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","pmids":["9216066"],"confidence":"Medium","gaps":["No functional follow-up in lens cells","Single lab, no in vivo validation"]},{"year":2001,"claim":"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","pmids":["11741927","11882646","11276227","11278334"],"confidence":"High","gaps":["SET/C42 physiological significance not established in vivo","Mechanism of NMJ ErbB activation incomplete"]},{"year":2005,"claim":"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","pmids":["9744280","14712065","16341208","15152189","15331630"],"confidence":"High","gaps":["Relative contribution of each substrate to migration in vivo unresolved","Some Trio/peptide phosphorylation shown only in vitro"]},{"year":2009,"claim":"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","pmids":["19363486","19151707","17591690"],"confidence":"High","gaps":["Upstream signal coupling DNA damage to CDK5 activation not fully defined","Substrate redundancy with other CDKs/kinases not excluded"]},{"year":2010,"claim":"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","pmids":["20392944"],"confidence":"High","gaps":["Activator specificity (p35 vs p25/p39) mechanism not structurally explained","Relevance to disease cell cycle re-entry untested"]},{"year":2011,"claim":"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","pmids":["21984943","18184784"],"confidence":"High","gaps":["Direct CDK5 substrate controlling PDE levels not identified","NR2B endocytosis mechanism relies on inhibitor studies without reconstitution"]},{"year":2015,"claim":"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","pmids":["25409143","27463676","26002103","26206584","25452387","25331900"],"confidence":"High","gaps":["Tissue-specific activator partners not always defined","Crosstalk and substrate competition with ERK/GSK3 incompletely mapped"]},{"year":2023,"claim":"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","pmids":["31687929","32660255","36995937","31272499","37043533"],"confidence":"Medium","gaps":["Structural basis of Cdk5i peptide disruption unresolved","Several substrate findings are single-lab without reciprocal validation"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model linking activator identity to substrate choice","Quantitative contribution of each substrate to neurodegeneration in vivo undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,3,11,15,17,18,22,24,25,32,35]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,22,35]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[19,24]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[6,7,15,19,35]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3,25,35]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[11,27]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,13,21,24]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[16,20,32]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[19,27,28]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[18]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[7,15,18]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[22,35]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[26]},{"term_id":"R-HSA-9909396","term_label":"Circadian clock","supporting_discovery_ids":[32]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[16,20,22,35]}],"complexes":["CDK5/p35","CDK5/p25"],"partners":["CDK5R1","RAC1","P53","SET","GSK3B","TPX2","PER2","LRRK2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q00535","full_name":"Cyclin-dependent kinase 5","aliases":["Cell division protein kinase 5","Cyclin-dependent-like kinase 5","Serine/threonine-protein kinase PSSALRE","Tau protein kinase II catalytic subunit","TPKII catalytic subunit"],"length_aa":292,"mass_kda":33.3,"function":"Proline-directed serine/threonine-protein kinase essential for neuronal cell cycle arrest and differentiation and may be involved in apoptotic cell death in neuronal diseases by triggering abortive cell cycle re-entry. Interacts with D1 and D3-type G1 cyclins. Phosphorylates SRC, NOS3, VIM/vimentin, p35/CDK5R1, MEF2A, SIPA1L1, SH3GLB1, PXN, PAK1, MCAM/MUC18, SEPT5, SYN1, DNM1, AMPH, SYNJ1, CDK16, RAC1, RHOA, CDC42, TONEBP/NFAT5, MAPT/TAU, MAP1B, histone H1, p53/TP53, HDAC1, APEX1, PTK2/FAK1, huntingtin/HTT, ATM, MAP2, NEFH and NEFM. Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission, by phosphorylating key proteins. Negatively regulates the CACNA1B/CAV2.2 -mediated Ca(2+) release probability at hippocampal neuronal soma and synaptic terminals (By similarity). Activated by interaction with CDK5R1 (p35) and CDK5R2 (p39), especially in postmitotic neurons, and promotes CDK5R1 (p35) expression in an autostimulation loop. Phosphorylates many downstream substrates such as Rho and Ras family small GTPases (e.g. PAK1, RAC1, RHOA, CDC42) or microtubule-binding proteins (e.g. MAPT/TAU, MAP2, MAP1B), and modulates actin dynamics to regulate neurite growth and/or spine morphogenesis. Also phosphorylates exocytosis associated proteins such as MCAM/MUC18, SEPT5, SYN1, and CDK16/PCTAIRE1 as well as endocytosis associated proteins such as DNM1, AMPH and SYNJ1 at synaptic terminals. In the mature central nervous system (CNS), regulates neurotransmitter movements by phosphorylating substrates associated with neurotransmitter release and synapse plasticity; synaptic vesicle exocytosis, vesicles fusion with the presynaptic membrane, and endocytosis. Promotes cell survival by activating anti-apoptotic proteins BCL2 and STAT3, and negatively regulating of JNK3/MAPK10 activity. Phosphorylation of p53/TP53 in response to genotoxic and oxidative stresses enhances its stabilization by preventing ubiquitin ligase-mediated proteasomal degradation, and induces transactivation of p53/TP53 target genes, thus regulating apoptosis. Phosphorylation of p35/CDK5R1 enhances its stabilization by preventing calpain-mediated proteolysis producing p25/CDK5R1 and avoiding ubiquitin ligase-mediated proteasomal degradation. During aberrant cell-cycle activity and DNA damage, p25/CDK5 activity elicits cell-cycle activity and double-strand DNA breaks that precedes neuronal death by deregulating HDAC1. DNA damage triggered phosphorylation of huntingtin/HTT in nuclei of neurons protects neurons against polyglutamine expansion as well as DNA damage mediated toxicity. Phosphorylation of PXN reduces its interaction with PTK2/FAK1 in matrix-cell focal adhesions (MCFA) during oligodendrocytes (OLs) differentiation. Negative regulator of Wnt/beta-catenin signaling pathway. Activator of the GAIT (IFN-gamma-activated inhibitor of translation) pathway, which suppresses expression of a post-transcriptional regulon of proinflammatory genes in myeloid cells; phosphorylates the linker domain of glutamyl-prolyl tRNA synthetase (EPRS) in a IFN-gamma-dependent manner, the initial event in assembly of the GAIT complex. Phosphorylation of SH3GLB1 is required for autophagy induction in starved neurons. Phosphorylation of TONEBP/NFAT5 in response to osmotic stress mediates its rapid nuclear localization. MEF2 is inactivated by phosphorylation in nucleus in response to neurotoxin, thus leading to neuronal apoptosis. APEX1 AP-endodeoxyribonuclease is repressed by phosphorylation, resulting in accumulation of DNA damage and contributing to neuronal death. NOS3 phosphorylation down regulates NOS3-derived nitrite (NO) levels. SRC phosphorylation mediates its ubiquitin-dependent degradation and thus leads to cytoskeletal reorganization. May regulate endothelial cell migration and angiogenesis via the modulation of lamellipodia formation. Involved in dendritic spine morphogenesis by mediating the EFNA1-EPHA4 signaling. The complex p35/CDK5 participates in the regulation of the circadian clock by modulating the function of CLOCK protein: phosphorylates CLOCK at 'Thr-451' and 'Thr-461' and regulates the transcriptional activity of the CLOCK-BMAL1 heterodimer in association with altered stability and subcellular distribution","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q00535/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CDK5","classification":"Not Classified","n_dependent_lines":15,"n_total_lines":1208,"dependency_fraction":0.012417218543046357},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000164885","cell_line_id":"CID001897","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"CCNB1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001897","total_profiled":1310},"omim":[{"mim_id":"621025","title":"RAB3A-INTERACTING PROTEIN-LIKE 1; RAB3IL1","url":"https://www.omim.org/entry/621025"},{"mim_id":"620419","title":"CYCLIN I FAMILY, MEMBER 2; CCNI2","url":"https://www.omim.org/entry/620419"},{"mim_id":"619771","title":"VRK SERINE/THREONINE KINASE 3; VRK3","url":"https://www.omim.org/entry/619771"},{"mim_id":"619415","title":"TAU TUBULIN KINASE 1; TTBK1","url":"https://www.omim.org/entry/619415"},{"mim_id":"619305","title":"TANDEM C2 DOMAINS PROTEIN, NUCLEAR; TC2N","url":"https://www.omim.org/entry/619305"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cell Junctions","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":75.3}],"url":"https://www.proteinatlas.org/search/CDK5"},"hgnc":{"alias_symbol":["PSSALRE"],"prev_symbol":[]},"alphafold":{"accession":"Q00535","domains":[{"cath_id":"3.30.200.20","chopping":"3-80","consensus_level":"high","plddt":87.2809,"start":3,"end":80},{"cath_id":"1.10.510.10","chopping":"85-285","consensus_level":"high","plddt":93.2197,"start":85,"end":285}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q00535","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q00535-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q00535-F1-predicted_aligned_error_v6.png","plddt_mean":91.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CDK5","jax_strain_url":"https://www.jax.org/strain/search?query=CDK5"},"sequence":{"accession":"Q00535","fasta_url":"https://rest.uniprot.org/uniprotkb/Q00535.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q00535/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q00535"}},"corpus_meta":[{"pmid":"11584302","id":"PMC_11584302","title":"A decade of CDK5.","date":"2001","source":"Nature reviews. Molecular cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/11584302","citation_count":935,"is_preprint":false},{"pmid":"9744280","id":"PMC_9744280","title":"The p35/Cdk5 kinase is a neuron-specific Rac effector that inhibits Pak1 activity.","date":"1998","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/9744280","citation_count":335,"is_preprint":false},{"pmid":"27463676","id":"PMC_27463676","title":"Cdk5 disruption attenuates tumor PD-L1 expression and promotes antitumor immunity.","date":"2016","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/27463676","citation_count":275,"is_preprint":false},{"pmid":"25409143","id":"PMC_25409143","title":"An ERK/Cdk5 axis controls the diabetogenic actions of PPARγ.","date":"2014","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/25409143","citation_count":261,"is_preprint":false},{"pmid":"25076872","id":"PMC_25076872","title":"Physiological and pathological phosphorylation of tau by Cdk5.","date":"2014","source":"Frontiers in molecular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/25076872","citation_count":239,"is_preprint":false},{"pmid":"16341208","id":"PMC_16341208","title":"Cdk5 phosphorylates and stabilizes p27kip1 contributing to actin organization and cortical neuronal migration.","date":"2005","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/16341208","citation_count":235,"is_preprint":false},{"pmid":"15152189","id":"PMC_15152189","title":"A novel CDK5-dependent pathway for regulating GSK3 activity and kinesin-driven motility in neurons.","date":"2004","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/15152189","citation_count":234,"is_preprint":false},{"pmid":"8253190","id":"PMC_8253190","title":"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.","date":"1993","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/8253190","citation_count":211,"is_preprint":false},{"pmid":"26227906","id":"PMC_26227906","title":"The Role of Cdk5 in Alzheimer's Disease.","date":"2015","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/26227906","citation_count":204,"is_preprint":false},{"pmid":"22189166","id":"PMC_22189166","title":"Cdk5: a multifaceted kinase in neurodegenerative diseases.","date":"2011","source":"Trends in cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/22189166","citation_count":198,"is_preprint":false},{"pmid":"19363486","id":"PMC_19363486","title":"Talin phosphorylation by Cdk5 regulates Smurf1-mediated talin head ubiquitylation and cell migration.","date":"2009","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/19363486","citation_count":173,"is_preprint":false},{"pmid":"23142263","id":"PMC_23142263","title":"Deregulated Cdk5 activity is involved in inducing Alzheimer's disease.","date":"2012","source":"Archives of medical research","url":"https://pubmed.ncbi.nlm.nih.gov/23142263","citation_count":159,"is_preprint":false},{"pmid":"24879856","id":"PMC_24879856","title":"Cdk5 activity in the brain - multiple paths of regulation.","date":"2014","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/24879856","citation_count":156,"is_preprint":false},{"pmid":"11276227","id":"PMC_11276227","title":"Cdk5 is involved in neuregulin-induced AChR expression at the neuromuscular junction.","date":"2001","source":"Nature neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/11276227","citation_count":148,"is_preprint":false},{"pmid":"19151707","id":"PMC_19151707","title":"Phosphorylation of ATM by Cdk5 mediates DNA damage signalling and regulates neuronal death.","date":"2009","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/19151707","citation_count":147,"is_preprint":false},{"pmid":"11854007","id":"PMC_11854007","title":"Cdk5 behind the wheel: a role in trafficking and transport?","date":"2002","source":"Trends in cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/11854007","citation_count":146,"is_preprint":false},{"pmid":"18183483","id":"PMC_18183483","title":"An unusual member of the Cdk family: Cdk5.","date":"2008","source":"Cellular and molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/18183483","citation_count":146,"is_preprint":false},{"pmid":"27917404","id":"PMC_27917404","title":"The Emerging Role of Cdk5 in Cancer.","date":"2016","source":"Trends in cancer","url":"https://pubmed.ncbi.nlm.nih.gov/27917404","citation_count":142,"is_preprint":false},{"pmid":"18184784","id":"PMC_18184784","title":"Cdk5 regulates the phosphorylation of tyrosine 1472 NR2B and the surface expression of NMDA receptors.","date":"2008","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/18184784","citation_count":133,"is_preprint":false},{"pmid":"34814918","id":"PMC_34814918","title":"Three decades of Cdk5.","date":"2021","source":"Journal of biomedical science","url":"https://pubmed.ncbi.nlm.nih.gov/34814918","citation_count":131,"is_preprint":false},{"pmid":"15194121","id":"PMC_15194121","title":"A Jekyll and Hyde kinase: roles for Cdk5 in brain development and disease.","date":"2004","source":"Current opinion in neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/15194121","citation_count":131,"is_preprint":false},{"pmid":"18691386","id":"PMC_18691386","title":"Deregulated Cdk5 promotes oxidative stress and mitochondrial dysfunction.","date":"2008","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18691386","citation_count":112,"is_preprint":false},{"pmid":"17160145","id":"PMC_17160145","title":"The role of CDK5/P25 formation/inhibition in neurodegeneration.","date":"2006","source":"Drug news & perspectives","url":"https://pubmed.ncbi.nlm.nih.gov/17160145","citation_count":108,"is_preprint":false},{"pmid":"22262900","id":"PMC_22262900","title":"Cdk5/p25-induced cytosolic PLA2-mediated lysophosphatidylcholine production regulates neuroinflammation and triggers neurodegeneration.","date":"2012","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/22262900","citation_count":107,"is_preprint":false},{"pmid":"21473899","id":"PMC_21473899","title":"Cdk5: multitasking between physiological and pathological conditions.","date":"2011","source":"Progress in neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/21473899","citation_count":103,"is_preprint":false},{"pmid":"11432802","id":"PMC_11432802","title":"Cdk5 on the brain.","date":"2001","source":"Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/11432802","citation_count":100,"is_preprint":false},{"pmid":"11248670","id":"PMC_11248670","title":"Cyclin-dependent protein kinase 5 (Cdk5) and the regulation of neurofilament metabolism.","date":"2001","source":"European journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11248670","citation_count":99,"is_preprint":false},{"pmid":"7834371","id":"PMC_7834371","title":"Expression of CDK5 (PSSALRE kinase), a neural cdc2-related protein kinase, in the mature and developing mouse central and peripheral nervous systems.","date":"1994","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/7834371","citation_count":94,"is_preprint":false},{"pmid":"17591690","id":"PMC_17591690","title":"Stabilization and activation of p53 induced by Cdk5 contributes to neuronal cell death.","date":"2007","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/17591690","citation_count":93,"is_preprint":false},{"pmid":"12064478","id":"PMC_12064478","title":"Cdk5 phosphorylates p53 and regulates its activity.","date":"2002","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12064478","citation_count":88,"is_preprint":false},{"pmid":"28077789","id":"PMC_28077789","title":"Biological functions of CDK5 and potential CDK5 targeted clinical treatments.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/28077789","citation_count":86,"is_preprint":false},{"pmid":"24844647","id":"PMC_24844647","title":"Cdk5 regulates multiple cellular events in neural development, function and disease.","date":"2014","source":"Development, growth & differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/24844647","citation_count":86,"is_preprint":false},{"pmid":"12719630","id":"PMC_12719630","title":"Cdk5: one of the links between senile plaques and neurofibrillary tangles?","date":"2003","source":"Journal of Alzheimer's disease : JAD","url":"https://pubmed.ncbi.nlm.nih.gov/12719630","citation_count":86,"is_preprint":false},{"pmid":"19782409","id":"PMC_19782409","title":"Making a neuron: Cdk5 in embryonic and adult neurogenesis.","date":"2009","source":"Trends in neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/19782409","citation_count":84,"is_preprint":false},{"pmid":"20392944","id":"PMC_20392944","title":"Cdk5 suppresses the neuronal cell cycle by disrupting the E2F1-DP1 complex.","date":"2010","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/20392944","citation_count":82,"is_preprint":false},{"pmid":"26002103","id":"PMC_26002103","title":"CDK5 phosphorylates DRP1 and drives mitochondrial defects in NMDA-induced neuronal death.","date":"2015","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26002103","citation_count":81,"is_preprint":false},{"pmid":"11278334","id":"PMC_11278334","title":"Phosphorylation of protein phosphatase inhibitor-1 by Cdk5.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11278334","citation_count":77,"is_preprint":false},{"pmid":"19442718","id":"PMC_19442718","title":"Recent advances in understanding the roles of Cdk5 in synaptic plasticity.","date":"2009","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/19442718","citation_count":76,"is_preprint":false},{"pmid":"15135890","id":"PMC_15135890","title":"Cdk5: mediator of neuronal death and survival.","date":"2004","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/15135890","citation_count":74,"is_preprint":false},{"pmid":"26206584","id":"PMC_26206584","title":"Cell cycle-dependent ubiquitylation and destruction of NDE1 by CDK5-FBW7 regulates ciliary length.","date":"2015","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/26206584","citation_count":71,"is_preprint":false},{"pmid":"32286796","id":"PMC_32286796","title":"Physiological and Pathological Roles of Cdk5: Potential Directions for Therapeutic Targeting in Neurodegenerative Disease.","date":"2020","source":"ACS chemical neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/32286796","citation_count":69,"is_preprint":false},{"pmid":"9216066","id":"PMC_9216066","title":"Expression of Cdk5, p35, and Cdk5-associated kinase activity in the developing rat lens.","date":"1997","source":"Developmental genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9216066","citation_count":67,"is_preprint":false},{"pmid":"35966199","id":"PMC_35966199","title":"The role of Cdk5 in neurological disorders.","date":"2022","source":"Frontiers in cellular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/35966199","citation_count":65,"is_preprint":false},{"pmid":"32415712","id":"PMC_32415712","title":"Development of CDK2 and CDK5 Dual Degrader TMX-2172.","date":"2020","source":"Angewandte Chemie (International ed. in English)","url":"https://pubmed.ncbi.nlm.nih.gov/32415712","citation_count":63,"is_preprint":false},{"pmid":"20061803","id":"PMC_20061803","title":"Cdk5, the multifunctional surveyor.","date":"2010","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/20061803","citation_count":63,"is_preprint":false},{"pmid":"12684868","id":"PMC_12684868","title":"Cyclin-dependent kinase 5 (CDK5) and neuronal cell death.","date":"2003","source":"Cell and tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/12684868","citation_count":63,"is_preprint":false},{"pmid":"9552397","id":"PMC_9552397","title":"Cyclin-dependent kinase 5 (Cdk5) and neuron-specific Cdk5 activators.","date":"1996","source":"Progress in cell cycle research","url":"https://pubmed.ncbi.nlm.nih.gov/9552397","citation_count":62,"is_preprint":false},{"pmid":"26104286","id":"PMC_26104286","title":"CDK5 knockdown prevents hippocampal degeneration and cognitive dysfunction produced by cerebral ischemia.","date":"2015","source":"Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/26104286","citation_count":61,"is_preprint":false},{"pmid":"25331900","id":"PMC_25331900","title":"CDK5 activator protein p25 preferentially binds and activates GSK3β.","date":"2014","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/25331900","citation_count":60,"is_preprint":false},{"pmid":"16552189","id":"PMC_16552189","title":"Cdk5: a new player in pain signaling.","date":"2006","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/16552189","citation_count":59,"is_preprint":false},{"pmid":"11882646","id":"PMC_11882646","title":"Identification of a neuronal Cdk5 activator-binding protein as Cdk5 inhibitor.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11882646","citation_count":59,"is_preprint":false},{"pmid":"21984943","id":"PMC_21984943","title":"Cdk5 is required for memory function and hippocampal plasticity via the cAMP signaling pathway.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21984943","citation_count":58,"is_preprint":false},{"pmid":"14673207","id":"PMC_14673207","title":"Role of cdk5 in the pathogenesis of Alzheimer's disease.","date":"2003","source":"Neuro-Signals","url":"https://pubmed.ncbi.nlm.nih.gov/14673207","citation_count":57,"is_preprint":false},{"pmid":"25928429","id":"PMC_25928429","title":"TIGAR regulates DNA damage and repair through pentosephosphate pathway and Cdk5-ATM pathway.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/25928429","citation_count":57,"is_preprint":false},{"pmid":"11741927","id":"PMC_11741927","title":"The protein SET binds the neuronal Cdk5 activator p35nck5a and modulates Cdk5/p35nck5a activity.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11741927","citation_count":56,"is_preprint":false},{"pmid":"24872548","id":"PMC_24872548","title":"Cdk5-dependent Mst3 phosphorylation and activity regulate neuronal migration through RhoA inhibition.","date":"2014","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/24872548","citation_count":55,"is_preprint":false},{"pmid":"26376455","id":"PMC_26376455","title":"Cdk5 at crossroads of protein oligomerization in neurodegenerative diseases: facts and hypotheses.","date":"2015","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26376455","citation_count":54,"is_preprint":false},{"pmid":"16932754","id":"PMC_16932754","title":"Abl deregulates Cdk5 kinase activity and subcellular localization in Drosophila neurodegeneration.","date":"2006","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/16932754","citation_count":54,"is_preprint":false},{"pmid":"26601962","id":"PMC_26601962","title":"Neuroprotective Mechanisms Mediated by CDK5 Inhibition.","date":"2016","source":"Current pharmaceutical design","url":"https://pubmed.ncbi.nlm.nih.gov/26601962","citation_count":51,"is_preprint":false},{"pmid":"30856110","id":"PMC_30856110","title":"CDK5: A Unique CDK and Its Multiple Roles in the Nervous System.","date":"2019","source":"Journal of Alzheimer's disease : JAD","url":"https://pubmed.ncbi.nlm.nih.gov/30856110","citation_count":51,"is_preprint":false},{"pmid":"25452387","id":"PMC_25452387","title":"CDK5 is a major regulator of the tumor suppressor DLC1.","date":"2014","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/25452387","citation_count":51,"is_preprint":false},{"pmid":"28288624","id":"PMC_28288624","title":"Cdk5 links with DNA damage response and cancer.","date":"2017","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/28288624","citation_count":50,"is_preprint":false},{"pmid":"31698798","id":"PMC_31698798","title":"CDK5: Key Regulator of Apoptosis and Cell Survival.","date":"2019","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/31698798","citation_count":50,"is_preprint":false},{"pmid":"21145377","id":"PMC_21145377","title":"The role of Cdk5 in cognition and neuropsychiatric and neurological pathology.","date":"2010","source":"Brain research bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/21145377","citation_count":49,"is_preprint":false},{"pmid":"15331630","id":"PMC_15331630","title":"Cdk5 and Trio modulate endocrine cell exocytosis.","date":"2004","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/15331630","citation_count":46,"is_preprint":false},{"pmid":"30452955","id":"PMC_30452955","title":"Amyloid-ß promotes neurotoxicity by Cdk5-induced p53 stabilization.","date":"2018","source":"Neuropharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/30452955","citation_count":45,"is_preprint":false},{"pmid":"12496365","id":"PMC_12496365","title":"CDK5 regulates cell adhesion and migration in corneal epithelial cells.","date":"2002","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/12496365","citation_count":45,"is_preprint":false},{"pmid":"33396266","id":"PMC_33396266","title":"The Role of CDK5 in Tumours and Tumour Microenvironments.","date":"2020","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/33396266","citation_count":44,"is_preprint":false},{"pmid":"28986398","id":"PMC_28986398","title":"Inhibition of Cdk5 Promotes β-Cell Differentiation From Ductal Progenitors.","date":"2017","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/28986398","citation_count":43,"is_preprint":false},{"pmid":"8275715","id":"PMC_8275715","title":"Chromosomal mapping of human CDK2, CDK4, and CDK5 cell cycle kinase genes.","date":"1994","source":"Cytogenetics and cell genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8275715","citation_count":43,"is_preprint":false},{"pmid":"17597494","id":"PMC_17597494","title":"Alternative roles for Cdk5 in learning and synaptic plasticity.","date":"2007","source":"Biotechnology journal","url":"https://pubmed.ncbi.nlm.nih.gov/17597494","citation_count":42,"is_preprint":false},{"pmid":"31687929","id":"PMC_31687929","title":"Cyclin-dependent kinase 5 (CDK5) regulates the circadian clock.","date":"2019","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/31687929","citation_count":42,"is_preprint":false},{"pmid":"31910742","id":"PMC_31910742","title":"A kinase of many talents: non-neuronal functions of CDK5 in development and disease.","date":"2020","source":"Open biology","url":"https://pubmed.ncbi.nlm.nih.gov/31910742","citation_count":41,"is_preprint":false},{"pmid":"14673205","id":"PMC_14673205","title":"Role of Cdk5 in neuronal signaling, plasticity, and drug abuse.","date":"2003","source":"Neuro-Signals","url":"https://pubmed.ncbi.nlm.nih.gov/14673205","citation_count":41,"is_preprint":false},{"pmid":"37043533","id":"PMC_37043533","title":"A Cdk5-derived peptide inhibits Cdk5/p25 activity and improves neurodegenerative phenotypes.","date":"2023","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/37043533","citation_count":40,"is_preprint":false},{"pmid":"21741478","id":"PMC_21741478","title":"Twice switched at birth: cell cycle-independent roles of the \"neuron-specific\" cyclin-dependent kinase 5 (Cdk5) in non-neuronal cells.","date":"2011","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/21741478","citation_count":40,"is_preprint":false},{"pmid":"19001851","id":"PMC_19001851","title":"Cdk5 and the non-catalytic arrest of the neuronal cell cycle.","date":"2008","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/19001851","citation_count":38,"is_preprint":false},{"pmid":"14673211","id":"PMC_14673211","title":"Cdk5 in neuroskeletal dynamics.","date":"2003","source":"Neuro-Signals","url":"https://pubmed.ncbi.nlm.nih.gov/14673211","citation_count":37,"is_preprint":false},{"pmid":"31272499","id":"PMC_31272499","title":"CDK5-mediated phosphorylation and stabilization of TPX2 promotes hepatocellular tumorigenesis.","date":"2019","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/31272499","citation_count":36,"is_preprint":false},{"pmid":"21600237","id":"PMC_21600237","title":"Cdk5: mediator of neuronal development, death and the response to DNA damage.","date":"2011","source":"Mechanisms of ageing and development","url":"https://pubmed.ncbi.nlm.nih.gov/21600237","citation_count":36,"is_preprint":false},{"pmid":"33893293","id":"PMC_33893293","title":"Cdk5 and GSK3β inhibit fast endophilin-mediated endocytosis.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/33893293","citation_count":35,"is_preprint":false},{"pmid":"36453392","id":"PMC_36453392","title":"Cdk5 and aberrant cell cycle activation at the core of neurodegeneration.","date":"2023","source":"Neural regeneration research","url":"https://pubmed.ncbi.nlm.nih.gov/36453392","citation_count":34,"is_preprint":false},{"pmid":"14673206","id":"PMC_14673206","title":"Cdk5: a novel role in learning and memory.","date":"2003","source":"Neuro-Signals","url":"https://pubmed.ncbi.nlm.nih.gov/14673206","citation_count":34,"is_preprint":false},{"pmid":"30158515","id":"PMC_30158515","title":"Zinc induces CDK5 activation and neuronal death through CDK5-Tyr15 phosphorylation in ischemic stroke.","date":"2018","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/30158515","citation_count":34,"is_preprint":false},{"pmid":"29076761","id":"PMC_29076761","title":"CDK5 in oncology: recent advances and future prospects.","date":"2017","source":"Future medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29076761","citation_count":33,"is_preprint":false},{"pmid":"14638853","id":"PMC_14638853","title":"Cdk5 and the mystery of synaptic vesicle endocytosis.","date":"2003","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/14638853","citation_count":33,"is_preprint":false},{"pmid":"14712065","id":"PMC_14712065","title":"Cdk5 phosphorylation of FAK regulates centrosome-associated miocrotubules and neuronal migration.","date":"2004","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/14712065","citation_count":32,"is_preprint":false},{"pmid":"27486045","id":"PMC_27486045","title":"Targeting CDK5 post-stroke provides long-term neuroprotection and rescues synaptic plasticity.","date":"2016","source":"Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/27486045","citation_count":32,"is_preprint":false},{"pmid":"27909065","id":"PMC_27909065","title":"Cdk5 Directly Targets Nuclear p21CIP1 and Promotes Cancer Cell Growth.","date":"2016","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/27909065","citation_count":31,"is_preprint":false},{"pmid":"26930193","id":"PMC_26930193","title":"Parkinson-Related LRRK2 Mutation R1628P Enables Cdk5 Phosphorylation of LRRK2 and Upregulates Its Kinase Activity.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26930193","citation_count":31,"is_preprint":false},{"pmid":"32660255","id":"PMC_32660255","title":"Cdk5-Mediated Phosphorylation of Sirt1 Contributes to Podocyte Mitochondrial Dysfunction in Diabetic Nephropathy.","date":"2020","source":"Antioxidants & redox signaling","url":"https://pubmed.ncbi.nlm.nih.gov/32660255","citation_count":30,"is_preprint":false},{"pmid":"27506619","id":"PMC_27506619","title":"CDK5 downregulation enhances synaptic plasticity.","date":"2016","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/27506619","citation_count":29,"is_preprint":false},{"pmid":"12963086","id":"PMC_12963086","title":"Co-purification and localization of Munc18-1 (p67) and Cdk5 with neuronal cytoskeletal proteins.","date":"2004","source":"Neurochemistry international","url":"https://pubmed.ncbi.nlm.nih.gov/12963086","citation_count":29,"is_preprint":false},{"pmid":"36995937","id":"PMC_36995937","title":"CDK5-PRMT1-WDR24 signaling cascade promotes mTORC1 signaling and tumor growth.","date":"2023","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/36995937","citation_count":28,"is_preprint":false},{"pmid":"31820699","id":"PMC_31820699","title":"Role of Cdk5 in Amyloid-beta Pathology of Alzheimer's Disease.","date":"2019","source":"Current Alzheimer research","url":"https://pubmed.ncbi.nlm.nih.gov/31820699","citation_count":28,"is_preprint":false},{"pmid":"24999027","id":"PMC_24999027","title":"Cdk12 and Cdk13 regulate axonal elongation through a common signaling pathway that modulates Cdk5 expression.","date":"2014","source":"Experimental neurology","url":"https://pubmed.ncbi.nlm.nih.gov/24999027","citation_count":28,"is_preprint":false},{"pmid":"14673210","id":"PMC_14673210","title":"Protein-protein interactions in Cdk5 regulation and function.","date":"2003","source":"Neuro-Signals","url":"https://pubmed.ncbi.nlm.nih.gov/14673210","citation_count":27,"is_preprint":false},{"pmid":"18220519","id":"PMC_18220519","title":"New approaches to the discovery of cdk5 inhibitors.","date":"2007","source":"Current Alzheimer research","url":"https://pubmed.ncbi.nlm.nih.gov/18220519","citation_count":27,"is_preprint":false},{"pmid":"17619233","id":"PMC_17619233","title":"Cerebral ischemia, cell cycle elements and Cdk5.","date":"2007","source":"Biotechnology journal","url":"https://pubmed.ncbi.nlm.nih.gov/17619233","citation_count":26,"is_preprint":false},{"pmid":"25279694","id":"PMC_25279694","title":"Tolfenamic acid reduces tau and CDK5 levels: implications for dementia and tauopathies.","date":"2014","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25279694","citation_count":26,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":41753,"output_tokens":8952,"usd":0.12977,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":18783,"output_tokens":4105,"usd":0.09827,"stage2_stop_reason":"end_turn"},"total_usd":0.22804,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1993,\n      \"finding\": \"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.\",\n      \"method\": \"Amino acid sequencing, antibody cross-reactivity, in vitro phosphorylation assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct biochemical identification by sequencing and in vitro kinase assay, foundational finding replicated across many subsequent studies\",\n      \"pmids\": [\"8253190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"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.\",\n      \"method\": \"Biochemical purification, in vitro kinase assay, transfection with dominant-negative mutants\",\n      \"journal\": \"Progress in cell cycle research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — biochemical reconstitution replicated extensively across many independent labs\",\n      \"pmids\": [\"9552397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"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.\",\n      \"method\": \"RT-PCR, immunocytochemistry, co-immunoprecipitation, in vitro kinase assay\",\n      \"journal\": \"Developmental genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro kinase assay confirmed, but single lab with no functional follow-up\",\n      \"pmids\": [\"9216066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, co-localization by immunofluorescence, in vitro kinase assay, Pak1 activity assay\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, co-localization, and functional kinase assays in single rigorous study; findings widely cited and consistent with broader literature\",\n      \"pmids\": [\"9744280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, kinase activity assay, pharmacological inhibition, overexpression, reporter assay\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, functional inhibition, and reporter assay within one study; multiple orthogonal methods\",\n      \"pmids\": [\"11276227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro kinase assay, phosphorylation state-specific antibodies, selective kinase inhibitors, in vivo brain tissue analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay plus in vivo validation with phospho-specific antibodies and selective inhibitors; multiple orthogonal methods\",\n      \"pmids\": [\"11278334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"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.\",\n      \"method\": \"Affinity isolation from rat brain, mass spectrometry, co-immunoprecipitation, co-transfection, immunostaining, kinase assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-identified interaction confirmed by co-IP, co-localization, and functional kinase assay; multiple orthogonal methods in one study\",\n      \"pmids\": [\"11741927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro kinase assay with recombinant p53, transient transfection, immunoblot, reporter/gene expression analysis\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro phosphorylation confirmed, but single lab with limited mechanistic depth\",\n      \"pmids\": [\"12064478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, deletion analysis, kinase inhibition assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — co-IP and functional kinase assay in single lab; single study\",\n      \"pmids\": [\"11882646\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"Stable transfection, kinase-dead mutant, adhesion assay, in vitro wound migration assay\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — kinase-dead mutant epistasis plus functional cell assays, single lab\",\n      \"pmids\": [\"12496365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"Pharmacological inhibition, biochemical assays, in vivo axonal transport experiments\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological, biochemical, and in vivo experiments combined; multiple orthogonal approaches\",\n      \"pmids\": [\"15152189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro kinase assay, phospho-specific antibody, S732A mutant FAK expression, immunostaining\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vitro phosphorylation, phospho-specific antibody, and unphosphorylatable mutant, single lab\",\n      \"pmids\": [\"14712065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"Pharmacological inhibition (roscovitine), in vitro peptide phosphorylation, Rac activation assay, ultrastructural analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — multiple methods but single lab; Trio phosphorylation shown with peptides only\",\n      \"pmids\": [\"15331630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro kinase assay, in vivo RNAi, F-actin staining, cortical migration analysis\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro phosphorylation plus in vivo RNAi with defined phenotypic readout; multiple orthogonal methods\",\n      \"pmids\": [\"16341208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Genetic epistasis (abl mutations), cell death assay, co-immunoprecipitation, pharmacological inhibition\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic epistasis in Drosophila model plus biochemical assays; single lab\",\n      \"pmids\": [\"16932754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro kinase assay, co-immunoprecipitation, site-directed mutagenesis (implicitly), ubiquitylation assay, cell death assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal biochemical assays including in vitro phosphorylation, co-IP, ubiquitylation assay, and functional apoptosis readout\",\n      \"pmids\": [\"17591690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Pharmacological inhibition, co-immunoprecipitation, phospho-specific antibody, surface receptor assay\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — co-IP and pharmacological approach in single lab, no reconstitution\",\n      \"pmids\": [\"18184784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro kinase assay, co-immunoprecipitation, S425A phospho-mutant expression, ubiquitylation assay, cell migration assay\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay, phospho-mutant rescue, ubiquitylation assay, and functional migration readout; multiple orthogonal methods\",\n      \"pmids\": [\"19363486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro kinase assay, site-directed mutagenesis (Ser794), dominant-negative Cdk5, ATM kinase assay, neuronal death assay\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro phosphorylation, mutagenesis, and functional pathway analysis with multiple orthogonal methods in one study\",\n      \"pmids\": [\"19151707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, kinase-dead mutant, ChIP/promoter binding assay, cell cycle re-entry assay\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, kinase-dead mutant, and promoter binding assay; multiple orthogonal methods in one study\",\n      \"pmids\": [\"20392944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional knockout, behavioral memory assays, biochemical analysis (PDE levels, CREB phosphorylation), pharmacological rescue\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined molecular mechanism, rescue experiment, multiple readouts\",\n      \"pmids\": [\"21984943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"In utero electroporation, in vitro kinase assay, epistasis (rescue experiment), RhoA GTPase activity assay\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro phosphorylation, in vivo RNAi, epistasis rescue, and GTPase activity assay; multiple orthogonal methods\",\n      \"pmids\": [\"24872548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Adipose-specific Cdk5 knockout, unbiased proteomics, in vitro kinase assay, MEK/ERK pharmacological inhibition, insulin resistance measurement\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — conditional KO, in vitro kinase assay, proteomics, and pharmacological rescue; multiple orthogonal methods, published in Nature\",\n      \"pmids\": [\"25409143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, FRET analysis, in silico docking, in vitro phosphorylation, siRNA knockdown\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRET, co-IP, structural modeling, and functional phosphorylation assays; multiple orthogonal methods\",\n      \"pmids\": [\"25331900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro kinase assay, phospho-mutant analysis, co-immunoprecipitation, Rho-GAP activity assay, focal adhesion localization\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro kinase assay, phospho-mutants, GAP activity assay, co-IP; multiple orthogonal methods\",\n      \"pmids\": [\"25452387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro kinase assay, phospho-site mutagenesis (S585D/S585A), conditional Cdk5 knockout, pharmacological inhibition (roscovitine), mitochondrial morphology analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro phosphorylation, phospho-mutants, conditional KO, and morphological readout; multiple orthogonal methods\",\n      \"pmids\": [\"26002103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Cdk5 conditional disruption in mouse model, flow cytometry for PD-L1, T cell killing assay, IRF2/IRF2BP2 expression analysis\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic disruption in animal model with defined molecular intermediates and functional immune readout\",\n      \"pmids\": [\"27463676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Genetic depletion (siRNA/shRNA), epistasis rescue experiment, co-immunoprecipitation, ciliary length measurement, cell cycle synchronization\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis rescue, co-IP, and quantitative phenotypic readout; multiple orthogonal methods\",\n      \"pmids\": [\"26206584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro kinase assay, S130A mutant expression, proteasome inhibition, co-immunoprecipitation, cell growth assay, in vivo xenograft\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — phospho-mutant and functional assay, but kinase-dead vs active Cdk5 comparison not fully detailed in abstract; single lab\",\n      \"pmids\": [\"27909065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis, in vitro kinase assay, neuronal toxicity assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — co-IP, mutagenesis, in vitro kinase assay; single lab, single study\",\n      \"pmids\": [\"26930193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Site-directed mutagenesis (Y15F), Src kinase inhibition, phospho-specific antibody, in vivo ischemia model, zinc chelation\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis, pharmacological inhibition, in vivo model, and phospho-specific antibody; multiple approaches\",\n      \"pmids\": [\"30158515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Comparative phosphoproteomic screening, in vitro/in vivo kinase assay, siRNA knockdown, xenograft model, diethylnitrosamine HCC model\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — phosphoproteomic substrate identification, functional rescue experiment; single lab\",\n      \"pmids\": [\"31272499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"In vivo Cdk5 knockdown in SCN, circadian period measurement, in vitro kinase assay, co-immunoprecipitation, nuclear localization assay\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knockdown, in vitro phosphorylation, co-IP interaction assay, and functional period readout; multiple orthogonal methods\",\n      \"pmids\": [\"31687929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Roscovitine inhibition, dominant-negative Cdk5, phospho-S47 antibody, S47A mutant, in vitro and in vivo diabetic models, mitochondrial function assays\",\n      \"journal\": \"Antioxidants & redox signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — phospho-mutant and genetic/pharmacological inhibition, single lab\",\n      \"pmids\": [\"32660255\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Chemical and genetic inhibition, co-immunoprecipitation (GSK3β-Endophilin), axon morphology analysis in hippocampal neurons\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — co-IP and genetic inhibition with functional readouts, but Cdk5 mechanism less directly shown than GSK3β; single study\",\n      \"pmids\": [\"33893293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro kinase assay, co-immunoprecipitation, methylation assay, subcellular fractionation, shRNA knockdown, xenograft tumor model\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro kinase assay, localization experiment, methylation assay, in vivo tumor model; multiple orthogonal methods\",\n      \"pmids\": [\"36995937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Binding affinity assay, in vitro kinase assay, cell/mouse models of neurodegeneration, FITC-TAT peptide cell/brain penetration assay\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional in vitro and in vivo assays but mechanism of disruption not fully resolved by structure; single lab\",\n      \"pmids\": [\"37043533\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CDK5 is an atypical proline-directed serine/threonine kinase that requires binding to non-cyclin activators (p35 or p39, or their calpain-cleaved products p25/p29) for activity; active CDK5 phosphorylates a wide range of substrates—including tau, neurofilaments, FAK, DRP1, PPARγ, ATM, p53, PER2, talin, DLC1, NDE1, PRMT1, and Sirt1—to regulate neuronal migration, axonal transport (via a CDK5-PP1-GSK3-kinesin pathway), cytoskeletal dynamics (through Rac-Pak1 and Mst3-RhoA axes), synaptic plasticity (modulating NMDA receptor surface expression via Src-NR2B-AP2 and cAMP-PDE pathways), circadian rhythm (phosphorylating PER2-S394 to drive nuclear entry of PER2-CRY1), DNA damage signaling (phosphorylating ATM-S794 to initiate ATM autophosphorylation), immune checkpoint control (enabling IFN-γ-induced PD-L1 expression), and metabolic regulation (phosphorylating PPARγ-S273 and MEK to control insulin sensitivity); pathological conversion of p35 to p25 by calpain prolongs and deregulates CDK5 activity, hyperphosphorylating tau and other substrates to drive neurodegeneration.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #1]. 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 [#3], phosphorylates the RhoGEF Trio to drive Rac activation [#12], activates Mst3 to suppress RhoA [#21], relieves autoinhibition of the Rho-GAP DLC1 [#24], and stabilizes p27kip1 to control cofilin/F-actin in migrating cortical neurons [#13]. CDK5 also regulates focal adhesion stability and migration by phosphorylating FAK and talin, the latter blocking Smurf1-mediated degradation [#11, #17], and controls axonal transport via a CDK5–PP1–GSK3–kinesin pathway [#10]. CDK5 phosphorylates a broad substrate repertoire that links it to apoptosis and DNA-damage signaling (p53, ATM-S794) [#15, #18], synaptic plasticity and cAMP signaling (Src–NR2B–AP2-mediated NMDA receptor endocytosis, and PDE/CREB control) [#16, #20], circadian timing (PER2-S394 to drive PER2–CRY1 nuclear entry) [#32], mitochondrial fission (DRP1-S585) [#25], and metabolic control of insulin sensitivity (PPARγ-S273 and MEK) [#22]. Beyond the nervous system, CDK5 enables IFN-γ-induced PD-L1 expression in tumors by relieving IRF2/IRF2BP2 repression [#26] and promotes cancer cell proliferation through substrates including p21CIP1, TPX2, and the PRMT1–WDR24–mTORC1 axis [#28, #31, #35]. 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 [#23, #36].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"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.\",\n      \"evidence\": \"Amino acid sequencing, antibody cross-reactivity, and in vitro tau phosphorylation assay\",\n      \"pmids\": [\"8253190\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the physiological activator\", \"In vitro phosphorylation does not establish cellular substrate selectivity\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"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.\",\n      \"evidence\": \"Biochemical purification, in vitro kinase assay, dominant-negative transfection\",\n      \"pmids\": [\"9552397\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of activator binding not defined\", \"Did not address regulation by calpain cleavage to p25\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Showed CDK5/p35 activity is not strictly neuron-restricted, extending its potential biological scope to non-neuronal tissues.\",\n      \"evidence\": \"RT-PCR, immunocytochemistry, co-IP, and in vitro histone H1 kinase assay in lens cells\",\n      \"pmids\": [\"9216066\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional follow-up in lens cells\", \"Single lab, no in vivo validation\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"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.\",\n      \"evidence\": \"Affinity isolation/MS, yeast two-hybrid, co-IP, reporter assay, kinase assays\",\n      \"pmids\": [\"11741927\", \"11882646\", \"11276227\", \"11278334\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SET/C42 physiological significance not established in vivo\", \"Mechanism of NMJ ErbB activation incomplete\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP, co-localization, in vitro kinase assays, in vivo RNAi, F-actin and cortical migration analysis\",\n      \"pmids\": [\"9744280\", \"14712065\", \"16341208\", \"15152189\", \"15331630\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of each substrate to migration in vivo unresolved\", \"Some Trio/peptide phosphorylation shown only in vitro\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro kinase assays, phospho-mutants, ubiquitylation assays, ATM kinase assay, cell death assays\",\n      \"pmids\": [\"19363486\", \"19151707\", \"17591690\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signal coupling DNA damage to CDK5 activation not fully defined\", \"Substrate redundancy with other CDKs/kinases not excluded\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP, kinase-dead mutant, promoter/ChIP binding assay, cell cycle re-entry assay\",\n      \"pmids\": [\"20392944\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Activator specificity (p35 vs p25/p39) mechanism not structurally explained\", \"Relevance to disease cell cycle re-entry untested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected CDK5 to synaptic plasticity and memory through cAMP/CREB signaling and NMDA receptor surface control, establishing a cognitive role.\",\n      \"evidence\": \"Conditional KO, behavioral assays, biochemistry, pharmacological rescue (rolipram), co-IP, phospho-specific antibodies\",\n      \"pmids\": [\"21984943\", \"18184784\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct CDK5 substrate controlling PDE levels not identified\", \"NR2B endocytosis mechanism relies on inhibitor studies without reconstitution\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Expanded CDK5 function into metabolism, immune checkpoint control, mitochondrial fission, and ciliogenesis, demonstrating systemic and non-neuronal roles.\",\n      \"evidence\": \"Conditional/adipose KO, proteomics, in vitro kinase assays, phospho-mutants, flow cytometry, T-cell killing, mitochondrial morphology, ciliary length, epistasis rescue\",\n      \"pmids\": [\"25409143\", \"27463676\", \"26002103\", \"26206584\", \"25452387\", \"25331900\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific activator partners not always defined\", \"Crosstalk and substrate competition with ERK/GSK3 incompletely mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vivo knockdown, in vitro kinase assays, co-IP, methylation/localization assays, xenografts, binding affinity assays, TAT-peptide delivery\",\n      \"pmids\": [\"31687929\", \"32660255\", \"36995937\", \"31272499\", \"37043533\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of Cdk5i peptide disruption unresolved\", \"Several substrate findings are single-lab without reciprocal validation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model linking activator identity to substrate choice\", \"Quantitative contribution of each substrate to neurodegeneration in vivo undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 3, 11, 15, 17, 18, 22, 24, 25, 32, 35]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 22, 35]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [19, 24]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [6, 7, 15, 19, 35]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3, 25, 35]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [11, 27]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 13, 21, 24]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [16, 20, 32]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [19, 27, 28]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [18]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [7, 15, 18]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [22, 35]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [26]},\n      {\"term_id\": \"R-HSA-9909396\", \"supporting_discovery_ids\": [32]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [16, 20, 22, 35]}\n    ],\n    \"complexes\": [\"CDK5/p35\", \"CDK5/p25\"],\n    \"partners\": [\"CDK5R1\", \"RAC1\", \"p53\", \"SET\", \"GSK3B\", \"TPX2\", \"PER2\", \"LRRK2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}