Affinage

MARK4

MAP/microtubule affinity-regulating kinase 4 · UniProt Q96L34

Length
752 aa
Mass
82.5 kDa
Annotated
2026-06-10
73 papers in source corpus 30 papers cited in narrative 30 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MARK4 is a serine/threonine kinase of the AMPK-related family that controls microtubule dynamics and cell polarity by phosphorylating microtubule-associated proteins—tau, MAP2, and MAP4—within their microtubule-binding domains, and it localizes to centrosomes and the microtubule network, where overexpression remodels microtubules into thinned, bundled arrays (PMID:14594945, PMID:15009667). Through these substrates MARK4 acts as a central node linking the cytoskeleton to multiple signaling programs. It negatively regulates mTORC1 by phosphorylating Raptor to disrupt the Raptor–Rag interaction selectively on the amino-acid signaling branch (PMID:23184942), and it negatively regulates the Hippo cascade by binding and phosphorylating MST and SAV to impair MST/SAV–LATS complex formation, thereby driving nuclear YAP/TAZ activity and cancer cell proliferation and migration (PMID:28183853). MARK4 is required for ciliogenesis, where its kinase activity and interaction with the mother-centriole protein ODF2 license removal of the CP110–Cep97 inhibitory complex to initiate axoneme extension (PMID:23400999). In innate immunity it binds NLRP3 directly and transports it to the microtubule-organizing center to nucleate inflammasome assembly, a function that promotes atherosclerotic plaque formation in hematopoietic cells (PMID:28656979, PMID:31167564). In the heart, MARK4 phosphorylates MAP4 to grant vasohibin-2 access to microtubules for α-tubulin detyrosination, modulating cardiomyocyte contractility after myocardial infarction (PMID:34040253). MARK4 kinase activity is enhanced by Cdk5 phosphorylation in its spacer domain, and its expression is controlled by Sp1/Setd8 and by PPARγ (PMID:31174206, PMID:38301049, PMID:26888669). A germline gain-of-function variant (p.Phe202Leu) that elevates tau and S6 phosphorylation links MARK4 to a childhood-onset neurodevelopmental disorder (PMID:38041405), and genetic ablation of MARK4 ameliorates tau pathology in tauopathy mice, establishing it as a driver of pathological tau phosphorylation and aggregation (PMID:38712317).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2003 High

    Established MARK4 as a microtubule-associated protein kinase, defining its core substrates and subcellular sites of action.

    Evidence In vitro kinase assay on tau/MAP2/MAP4, tandem affinity purification recovering tubulins, and immunofluorescence in cultured cells

    PMID:14594945

    Open questions at the time
    • Catalytic requirement for phenotypes not yet tested with kinase-dead mutants
    • Physiological versus overexpression effects on microtubules not distinguished
  2. 2004 High

    Confirmed MARK4 as a catalytically active AMPK-family kinase and showed kinase activity is required for its cellular effects.

    Evidence In vitro kinase assay with cognate peptide and wild-type versus kinase-dead overexpression viability assay

    PMID:15009667

    Open questions at the time
    • Endogenous substrate spectrum beyond peptide not addressed
    • Mechanism of cytotoxicity not defined
  3. 2012 High

    Placed MARK4 in metabolic and growth signaling by linking its loss to enhanced insulin/AMPK signaling in vivo and identifying Raptor as a substrate that gates mTORC1.

    Evidence Mouse knockout metabolic phenotyping plus in vitro Raptor phosphorylation and Rag-versus-Rheb epistasis in S2 and mammalian cells

    PMID:22992738 PMID:23184942

    Open questions at the time
    • Direct Raptor phospho-site mapping in vivo not established
    • Tissue-specific contributions to whole-body metabolic phenotype unresolved
  4. 2013 High

    Defined a MARK4 requirement for early ciliogenesis through ODF2 interaction and CP110–Cep97 removal.

    Evidence RNAi, Co-IP with ODF2, ultrastructural analysis, and kinase-dead rescue

    PMID:23400999

    Open questions at the time
    • Direct kinase substrate driving CP110–Cep97 removal not identified
    • Whether ODF2 is phosphorylated by MARK4 not shown
  5. 2016 High

    Identified MARK4 as a negative regulator of the Hippo pathway and a downstream effector of miR-515-5p in cancer cell migration.

    Evidence Reciprocal Co-IP and kinase assay on MST/SAV with CRISPR KO; 3'UTR luciferase reporter, knockdown-rescue, and xenograft metastasis

    PMID:26882547 PMID:28183853

    Open questions at the time
    • MST/SAV phospho-sites not mapped
    • Relationship between Hippo and microtubule functions in tumors unresolved
  6. 2017 High

    Demonstrated MARK4 directly binds NLRP3 and spatially organizes inflammasome assembly at the MTOC.

    Evidence Reciprocal Co-IP, confocal imaging of NLRP3 positioning, siRNA, knockout mice, and interface disruption

    PMID:28656979

    Open questions at the time
    • Whether NLRP3 is a phosphorylation substrate not resolved
    • Microtubule motor dependence of transport not defined
  7. 2019 High

    Established Cdk5 as an upstream activator of MARK4 via spacer-domain phosphorylation, connecting two tau kinases in neurodegeneration.

    Evidence In vitro kinase assay mapping the spacer site, neuronal Cdk5 inhibition, co-expression, and Drosophila tauopathy genetics

    PMID:31174206

    Open questions at the time
    • Spacer phospho-site identity and structural mechanism of activation not fully defined
    • Other activation-loop kinases not excluded
  8. 2019 Medium

    Linked MARK4 to in vivo neuronal injury responses and tau aggregation.

    Evidence Mouse subcortical stroke model with retrograde tracing and RNA-seq plus tau biosensor aggregation assay

    PMID:31429800

    Open questions at the time
    • Causality of MARK4 upregulation for dendrite remodeling not tested by loss-of-function
    • Direct aggregation versus phosphorylation contributions unseparated
  9. 2021 High

    Defined a MARK4→MAP4→VASH2→detyrosination axis controlling cardiomyocyte contractility after infarction.

    Evidence Knockout mice, myocardial infarction model, MAP4 phosphorylation and tubulin detyrosination blots, echocardiography, and rescue

    PMID:34040253

    Open questions at the time
    • MAP4 phospho-site dependence of VASH2 access not finely mapped
    • Therapeutic window for MARK4 inhibition in heart undefined
  10. 2023 Medium

    Connected a germline gain-of-function MARK4 variant to human neurodevelopmental disease through elevated tau and mTORC1 readouts.

    Evidence In vitro tau phosphorylation with variant protein and S6 phosphorylation assay

    PMID:38041405

    Open questions at the time
    • Single variant; genotype-phenotype breadth unknown
    • In vivo modeling of the variant not performed
  11. 2023 Medium

    Expanded MARK4 functions to mitochondrial morphology and respiration via MFN2/Marf interaction.

    Evidence Co-IP, Drosophila epistasis, mitochondrial imaging, and Seahorse respirometry

    PMID:37550059

    Open questions at the time
    • Whether MFN2 is a MARK4 substrate not shown
    • Mechanism of respiratory rescue undefined
  12. 2024 High

    Provided in vivo genetic proof that MARK4 drives tau pathology and defined Sp1/Setd8 transcriptional control.

    Evidence Mark4 KO crossed into PS19 tauopathy mice with behavior/histology; ChIP and Co-IP for Sp1/Setd8 promoter regulation

    PMID:38301049 PMID:38712317

    Open questions at the time
    • Cell-type-specific contribution of MARK4 to tau pathology unresolved
    • Setd8 enzymatic role at the promoter not delineated
  13. 2025 Medium

    Identified MARK4 as a stress-granule component and an activator of FTO-dependent compartmentalized translation, extending its role to RNA-linked stress responses.

    Evidence SG colocalization with TIA1, domain/kinase-dead constructs, FTO T6 phosphorylation mapping, and HARP synthesis readouts across cancer lines (one finding a preprint)

    PMID:40540400 PMID:bio_10.1101_2025.04.30.651577

    Open questions at the time
    • Stress-granule findings remain in preprint form
    • Coupling between SG localization and FTO/HARP pathway not unified

Open questions

Synthesis pass · forward-looking unresolved questions
  • How MARK4 integrates its many substrate-specific activities (microtubule, mTORC1, Hippo, inflammasome, FTO) into context-dependent outputs, and which are direct versus indirect, remains unresolved.
  • No unified substrate-recruitment logic established
  • Structural basis of spacer-domain regulation incomplete
  • Selective inhibitor pharmacology in vivo not validated for any indication

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0016740 transferase activity 5 GO:0098772 molecular function regulator activity 3 GO:0008092 cytoskeletal protein binding 2
Localization
GO:0005815 microtubule organizing center 4 GO:0005856 cytoskeleton 3 GO:0005829 cytosol 1 GO:0005929 cilium 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 3 R-HSA-1852241 Organelle biogenesis and maintenance 1 R-HSA-9612973 Autophagy 1
Partners
FTOMFN2MSTNLRP3ODF2RAPTORSAVTIA1
Complex memberships
stress granule

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 MARK4 phosphorylates tau, MAP2, and MAP4 at serine motifs in their microtubule-binding domains; it colocalizes with centrosomes and microtubules; a tandem affinity-purified MARK4 complex contains α-, β-, and γ-tubulin; overexpression causes thinning and bundling of the microtubule network. In vitro kinase assay, tandem affinity purification, immunofluorescence colocalization, overexpression in cultured cells The Journal of biological chemistry High 14594945
2003 MARK4L isoform expression is restricted to undifferentiated neural progenitor/proliferating glial precursor cells and is downregulated upon glial differentiation; antisense knockdown of MARK4 in glioblastoma cell lines consistently decreased tumor cell proliferation. Expression profiling, antisense oligonucleotide knockdown, cell proliferation assay Oncogene Medium 12735302
2004 MARK4/MARKL1 is a functional serine-threonine protein kinase that phosphorylates a cognate AMP-kinase family peptide substrate; overexpression of kinase-active but not kinase-dead MARK4 decreases cell viability, establishing kinase activity as required for the cytotoxic effect. In vitro kinase assay with cognate peptide substrate, overexpression of wild-type vs. kinase-dead mutant, cell viability assay Journal of neurochemistry High 15009667
2012 MARK4 deficiency in mice causes hyperphagia, hyperactivity, and hypermetabolism, protecting from diet-induced obesity through upregulation of brown fat activity and dramatically enhanced insulin-stimulated AKT phosphorylation; MARK4 ablation also upregulates AMPK kinase activity and expression in metabolic tissues. Targeted gene knockout in mice, metabolic phenotyping, western blot for AKT phosphorylation and AMPK activity The Journal of biological chemistry High 22992738
2012 MARK4 is a negative regulator of mTORC1: it selectively inhibits mTORC1 activation by Rag GTPases (amino acid signaling branch) but not by Rheb; MARK4 phosphorylates Raptor, a key mTORC1 component, and this phosphorylation interferes with the Raptor–Rag interaction. siRNA knockdown and overexpression in Drosophila S2 and mammalian cells, in vitro kinase assay (Raptor phosphorylation), co-immunoprecipitation The Journal of biological chemistry High 23184942
2012 MARK4 is the predominant MARK family member in the rat testis and localizes to the apical and basal ectoplasmic specialization (ES) at the blood-testis barrier; it structurally associates with α-tubulin and desmosomal adaptor plakophilin-2 but not with actin-based BTB proteins; diminished MARK4 expression correlates with apical ES disruption and spermatid detachment. Immunofluorescence colocalization, co-immunoprecipitation/co-localization with junctional markers, stage-specific expression analysis in seminiferous epithelium Spermatogenesis Medium 22670221
2013 MARK4 associates with the basal body and ciliary axoneme and its kinase activity is required for initiation of axoneme extension during ciliogenesis; MARK4 interacts with the mother centriolar protein ODF2, and ODF2 localization to the centriole partially depends on MARK4; MARK4 or ODF2 knockdown arrests the ciliary program before removal of the CP110–Cep97 inhibitory complex from the mother centriole. RNAi screen, immunofluorescence, ultrastructural analysis, co-immunoprecipitation (MARK4-ODF2), kinase-dead mutant rescue The Journal of cell biology High 23400999
2014 MARK4 is expressed throughout the cell cycle and preferentially activated during mitosis; depletion of MARK4S affects fibroblast and glioma cell morphology, slows proliferation (reduces S/G2M fractions, increases G1), and alters centrosome cycle causing G1 arrest; overexpression of either isoform reduces microtubule network density; MARK4 co-localizes with vimentin. siRNA knockdown, cytofluorimetric cell cycle analysis, immunofluorescence, overexpression European journal of cell biology Medium 25123532
2014 MARK4 promotes adipogenesis in 3T3-L1 adipocytes by activating JNK1 and inhibiting p38MAPK pathways, and triggers apoptosis via JNK1 activation; MARK4 upregulates SREBP-1c, FAS, ACCα, PPARγ and reduces ATGL protein levels. Overexpression in 3T3-L1 cells, specific pathway inhibitors, TUNEL assay, western blot for lipogenic and apoptotic markers Biology of the cell Medium 24989893
2016 MARK4 acts as a negative regulator of the Hippo kinase cassette in breast cancer cells: MARK4 binds MST and SAV, phosphorylates them, and attenuates formation of the MST/SAV–LATS complex in a kinase-activity-dependent manner, thereby promoting nuclear YAP/TAZ activity and breast cancer cell proliferation and migration. Co-immunoprecipitation (MARK4-MST, MARK4-SAV), in vitro kinase assay, siRNA and CRISPR/Cas9 knockout, nuclear YAP/TAZ localization, proliferation and migration assays EMBO reports High 28183853
2016 miR-515-5p directly inhibits MARK4 via 3′ UTR interaction; MARK4 knockdown mimics the inhibitory effect of miR-515-5p on breast and lung cancer cell migration; MARK4 overexpression rescues the miR-515-5p-induced migration inhibition, placing MARK4 downstream of miR-515-5p in the control of cancer cell migration and metastasis. 3′ UTR luciferase reporter assay, RNA-seq, siRNA knockdown, overexpression rescue, in vivo xenograft metastasis model EMBO reports High 26882547
2016 Mark4 binds to PPARγ (co-immunoprecipitation); PPARγ binds to the Mark4 promoter and inhibits Mark4 expression (ChIP); Mark4 promotes oxidative stress and inflammation in adipocytes by activating the IKKα/NF-κB signaling pathway; PPARγ interaction with Mark4 inhibits Mark4's stimulatory effect on oxidative stress. Co-immunoprecipitation, chromatin immunoprecipitation, ROS measurement, NF-κB pathway inhibitor (PTDC), overexpression in 3T3-L1 adipocytes Scientific reports Medium 26888669
2016 Methylene blue inhibits MARK4 by two mechanisms: downregulation of MARK4 protein level through the ubiquitin-proteasome pathway, and direct inhibition of MARK4 kinase activity in vitro; MB decreased MARK4-mediated tau phosphorylation in 293T cells and partially rescued PAR-1-mediated synaptic toxicity in Drosophila. In vitro kinase assay, proteasome inhibitor rescue, cell-based tau phosphorylation assay, Drosophila genetic model Scientific reports Medium 27708431
2017 MARK4 binds directly to NLRP3 (co-immunoprecipitation) and drives NLRP3 to the microtubule-organizing centre (MTOC), enabling formation of one large inflammasome speck per cell; MARK4 knockdown/knockout or disruption of the MARK4–NLRP3 interaction impairs NLRP3 spatial arrangement and limits NLRP3 inflammasome activation (IL-1β, caspase-1 output). Co-immunoprecipitation, confocal microscopy of NLRP3 positioning, siRNA knockdown, knockout mice, disruption of MARK4-NLRP3 interface Nature communications High 28656979
2019 Cdk5 phosphorylates MARK4 in the spacer domain (not the activation loop) and thereby increases MARK4 kinase activity; combined Cdk5 and MARK4 co-expression synergistically elevates tau phosphorylation at both Cdk5 SP/TP sites and MARK4 Ser262 targets, as well as total tau levels; in a Drosophila tauopathy model, Cdk5 promotes tau accumulation and neurodegeneration via MARK/Par-1-mediated Ser262 phosphorylation. In vitro kinase assay, Cdk5 inhibitor treatment in neurons, co-expression in mammalian cells, Drosophila genetics, phospho-specific western blot Human molecular genetics High 31174206
2019 Mark4 upregulation after subcortical stroke in Layer 5 cortical neurons is associated with selective apical dendrite remodeling and tau phosphorylation in vivo; in a cell-based tau biosensor assay, Mark4 promotes aggregation of human tau in vitro. In vivo mouse stroke model with retrograde neuronal tracing and RNA-seq, phospho-tau western blot, tau biosensor cell aggregation assay Acta neuropathologica communications Medium 31429800
2019 MARK4-dependent NLRP3 inflammasome activation in hematopoietic cells promotes atherosclerotic plaque formation; bone-marrow transplant of Mark4-deficient cells into Ldlr-/- mice significantly reduced lesion size and circulating IL-18/IFN-γ; Mark4-deficient macrophages showed reduced caspase-1 activity and IL-1β/IL-18 production upon cholesterol crystal stimulation. Bone marrow transplantation in Ldlr-/- mice, primary macrophage NLRP3 inflammasome assay, caspase-1 activity measurement, cytokine ELISA Arteriosclerosis, thrombosis, and vascular biology High 31167564
2020 Rosmarinic acid (RA) binds to the active site of MARK4 (binding constant ~10^7 M-1) and inhibits its kinase activity (IC50 = 6.204 µM), reducing tau phosphorylation in cell-based assays and inhibiting cancer cell growth with induction of apoptosis. Fluorescence binding assay, in vitro kinase inhibition assay, cell-based tau phosphorylation assay, molecular docking and MD simulation Scientific reports Medium 32587267
2020 Mark4 promotes autophagy in adipocytes by activating the AMPK pathway and inhibiting AKT/mTOR signaling, thereby increasing LC3A-to-LC3B-II conversion; this autophagy induction by Mark4 decreases thermogenesis gene expression and inhibits browning of white adipose tissue. Overexpression in adipocytes, serum starvation and rapamycin autophagy models, western blot for autophagy markers (Beclin1, ATG7, P62, LC3), pathway inhibitors International journal of molecular sciences Medium 32326642
2021 MARK4 regulates cardiomyocyte contractility by phosphorylating MAP4, which facilitates access of vasohibin-2 (VASH2) tubulin carboxypeptidase to microtubules for α-tubulin detyrosination; MARK4 deficiency substantially limits reduction of left ventricular ejection fraction after acute myocardial infarction in mice without affecting infarct size. MARK4 knockout mice, myocardial infarction model, western blot for MAP4 phosphorylation and tubulin detyrosination, cardiac echocardiography, mechanistic rescue experiments Nature High 34040253
2021 SET8 suppresses MARK4 expression and thereby inhibits the MARK4/NLRP3 inflammasome pathway; SET8 deficiency increases MARK4 and NLRP3 inflammasome activation; MARK4 siRNA knockdown inhibits hypoxia/reoxygenation-induced NLRP3 inflammasome activation. siRNA knockdown, western blot for NLRP3 pathway components, mouse hepatic ischemia-reperfusion model Life sciences Medium 33662429
2022 MARK2 and MARK4 knockdown in Sertoli cells impairs the tight junction-permeability barrier at the blood-testis barrier and disrupts microtubule and actin cytoskeletal organization; loss of MARK4 causes MTs to retract from the cell edge (more severe than MARK2 loss), demonstrating distinct functional roles for each isoform. siRNA knockdown in Sertoli cells, TJ-permeability assay, immunofluorescence of microtubule organization Endocrinology Medium 35971301
2023 MARK4 interacts with MFN2/Marf (mitofusin); loss of MARK4/PAR-1 alleviates synaptic bouton defects and mitochondrial hyperfusion caused by MFN2/Marf overexpression in Drosophila muscles and cultured cells; MARK4/PAR-1 knockdown also rescues respiratory dysfunction of mitochondria induced by MFN2/Marf overexpression in mammalian cells. Co-immunoprecipitation (MFN2-MARK4), Drosophila genetics (epistasis), mitochondrial morphology imaging, Seahorse respirometry in mammalian cells eNeuro Medium 37550059
2023 A gain-of-function missense variant in the MARK4 catalytic domain (p.Phe202Leu) increases MARK4-mediated phosphorylation of tau isoforms and phosphorylation of ribosomal protein S6 (indicating upregulation of mTORC1 pathway) without altering protein expression levels, linking a germline MARK4 variant to childhood-onset neurodevelopmental disorder. In vitro tau phosphorylation assay with variant protein, S6 phosphorylation assay (mTORC1 readout), protein expression analysis HGG advances Medium 38041405
2023 A SARS-CoV-2 Orf9b-derived peptide (TAT-Orf9b10-18_78-95) allosterically inhibits MARK4 kinase activity without inhibiting MARK2; it suppresses tau phosphorylation at microtubule-binding repeats in primary neurons and Drosophila, and suppresses tau-induced neurodegeneration in a fly tauopathy model. In vitro kinase assay (MARK4 vs MARK2), primary neuron phospho-tau western blot, Drosophila tauopathy genetic model, cell-permeable peptide delivery Neurobiology of disease High 37884211
2024 Mark4 deletion in PS19 tauopathy model mice ameliorates tau pathology: improved survival and memory, reduced neurodegeneration and astrogliosis, and decreased pathological tau phosphorylation (Ser356, AT8-positive tau, thioflavin S-positive tau aggregates). Genetic cross of Mark4 knockout with P301S tauopathy mice, behavioral testing, immunohistochemistry, western blot for phospho-tau species Brain communications High 38712317
2024 Sp1 transcription factor binds to the Mark4 promoter and activates Mark4 transcription; SET domain-containing protein Setd8 interacts with Sp1 and jointly regulates Mark4 transcription; Mark4 promotes vascular smooth muscle cell apoptosis and calcification by inhibiting Akt phosphorylation. ChIP (Sp1 on Mark4 promoter), co-immunoprecipitation (Setd8-Sp1), siRNA knockdown, rescue experiments, western blot for Akt phosphorylation Aging Medium 38301049
2024 MARK4 deficiency promotes myocardial lipid oxidation metabolism by downregulating ACSL4 expression, thereby reducing myocardial lipid accumulation in STZ-induced diabetic cardiomyopathy; MARK4 knockdown also reduces oxidative stress, apoptosis, and facilitates cardiomyocyte mitochondrial fusion. AAV9-shMARK4 in vivo knockdown, STZ/high-fat diet diabetic cardiomyopathy model, RNA-seq of differentially expressed genes, western blot Scientific reports Medium 38839927
2025 MARK4 is a component of stress granules (SGs) and co-localizes with TIA1 in SGs; MARK4 expression enhances hydrogen-peroxide-induced SG formation requiring its kinase activity and spacer domain for SG localization; MARK4 suppresses TIA1 dimerization induced by hydrogen peroxide; MARK4 and TIA1 synergistically promote tau accumulation in cultured cells, and knockdown of the Drosophila TIA1 homolog suppresses tau toxicity. Immunofluorescence (SG colocalization), domain deletion constructs, kinase-dead mutant, TIA1 dimerization assay, tau accumulation assay in cultured cells, Drosophila genetics bioRxiv (preprint)preprint Medium bio_10.1101_2025.04.30.651577
2025 MARK4 activates FTO by phosphorylating it at T6; activated FTO demethylates a translation-inhibiting m6A mRNA signature on HARP mRNAs at microtubule-associated translation microdomains (MATMs) on γ-tubulin, enabling compartmentalized stress-response protein synthesis in cancer cells; MARK4 inhibition suppresses HARP synthesis and increases cancer cell apoptosis after stress. Unbiased proteomics/transcriptomics, FTO phosphorylation (T6) identification, MARK4 inhibition with functional HARP synthesis readout, multiple cancer cell lines Cell reports Medium 40540400

Source papers

Stage 0 corpus · 73 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 MARK4 is a novel microtubule-associated proteins/microtubule affinity-regulating kinase that binds to the cellular microtubule network and to centrosomes. The Journal of biological chemistry 149 14594945
2019 LINC00673 is activated by YY1 and promotes the proliferation of breast cancer cells via the miR-515-5p/MARK4/Hippo signaling pathway. Journal of experimental & clinical cancer research : CR 136 31623640
2017 MARK4 regulates NLRP3 positioning and inflammasome activation through a microtubule-dependent mechanism. Nature communications 132 28656979
2020 Rosmarinic Acid Exhibits Anticancer Effects via MARK4 Inhibition. Scientific reports 120 32587267
2018 Identification and evaluation of bioactive natural products as potential inhibitors of human microtubule affinity-regulating kinase 4 (MARK4). Journal of biomolecular structure & dynamics 116 29683402
2017 MARK4 inhibits Hippo signaling to promote proliferation and migration of breast cancer cells. EMBO reports 105 28183853
2016 miR-515-5p controls cancer cell migration through MARK4 regulation. EMBO reports 96 26882547
2017 Investigation of molecular mechanism of recognition between citral and MARK4: A newer therapeutic approach to attenuate cancer cell progression. International journal of biological macromolecules 93 29079437
2014 MARK4 and MARK3 associate with early tau phosphorylation in Alzheimer's disease granulovacuolar degeneration bodies. Acta neuropathologica communications 90 24533944
2001 Isolation of a novel human gene, MARKL1, homologous to MARK3 and its involvement in hepatocellular carcinogenesis. Neoplasia (New York, N.Y.) 90 11326310
2020 MARK4 Inhibited by AChE Inhibitors, Donepezil and Rivastigmine Tartrate: Insights into Alzheimer's Disease Therapy. Biomolecules 82 32443670
2021 MARK4 controls ischaemic heart failure through microtubule detyrosination. Nature 79 34040253
2013 The microtubule affinity regulating kinase MARK4 promotes axoneme extension during early ciliogenesis. The Journal of cell biology 69 23400999
2003 The neural progenitor-restricted isoform of the MARK4 gene in 19q13.2 is upregulated in human gliomas and overexpressed in a subset of glioblastoma cell lines. Oncogene 69 12735302
2012 Inactivation of MARK4, an AMP-activated protein kinase (AMPK)-related kinase, leads to insulin hypersensitivity and resistance to diet-induced obesity. The Journal of biological chemistry 68 22992738
2012 Microtubule-associated protein/microtubule affinity-regulating kinase 4 (MARK4) is a negative regulator of the mammalian target of rapamycin complex 1 (mTORC1). The Journal of biological chemistry 59 23184942
2016 Mark4 promotes oxidative stress and inflammation via binding to PPARγ and activating NF-κB pathway in mice adipocytes. Scientific reports 57 26888669
2019 PCC0208017, a novel small-molecule inhibitor of MARK3/MARK4, suppresses glioma progression in vitro and in vivo. Acta pharmaceutica Sinica. B 53 32082974
2012 Microtubule affinity-regulating kinase 4 (MARK4) is a component of the ectoplasmic specialization in the rat testis. Spermatogenesis 53 22670221
2016 Attenuation of synaptic toxicity and MARK4/PAR1-mediated Tau phosphorylation by methylene blue for Alzheimer's disease treatment. Scientific reports 47 27708431
2021 Structure-based investigation of MARK4 inhibitory potential of Naringenin for therapeutic management of cancer and neurodegenerative diseases. Journal of cellular biochemistry 44 34121218
2015 Designing New Kinase Inhibitor Derivatives as Therapeutics Against Common Complex Diseases: Structural Basis of Microtubule Affinity-Regulating Kinase 4 (MARK4) Inhibition. Omics : a journal of integrative biology 44 26565604
2021 Myricetin inhibits breast and lung cancer cells proliferation via inhibiting MARK4. Journal of cellular biochemistry 40 34751461
2019 Cdk5 increases MARK4 activity and augments pathological tau accumulation and toxicity through tau phosphorylation at Ser262. Human molecular genetics 40 31174206
2014 Mark4 promotes adipogenesis and triggers apoptosis in 3T3-L1 adipocytes by activating JNK1 and inhibiting p38MAPK pathways. Biology of the cell 40 24989893
2004 Identification of regulated genes during permanent focal cerebral ischaemia: characterization of the protein kinase 9b5/MARKL1/MARK4. Journal of neurochemistry 40 15009667
2020 Structural and biochemical investigation of MARK4 inhibitory potential of cholic acid: Towards therapeutic implications in neurodegenerative diseases. International journal of biological macromolecules 39 32535203
2014 Microtubule-associated protein/microtubule affinity-regulating kinase 4 (MARK4) plays a role in cell cycle progression and cytoskeletal dynamics. European journal of cell biology 35 25123532
2014 The structural analysis of MARK4 and the exploration of specific inhibitors for the MARK family: a computational approach to obstruct the role of MARK4 in prostate cancer progression. Molecular bioSystems 34 24763618
2019 Ischemic axonal injury up-regulates MARK4 in cortical neurons and primes tau phosphorylation and aggregation. Acta neuropathologica communications 28 31429800
2016 Ubiquitin-associated domain of MARK4 provides stability at physiological pH. International journal of biological macromolecules 27 27677563
2021 SET8 mitigates hepatic ischemia/reperfusion injury in mice by suppressing MARK4/NLRP3 inflammasome pathway. Life sciences 24 33662429
2019 MARK4 (Microtubule Affinity-Regulating Kinase 4)-Dependent Inflammasome Activation Promotes Atherosclerosis-Brief Report. Arteriosclerosis, thrombosis, and vascular biology 22 31167564
2022 Inhibition of MARK4 by serotonin as an attractive therapeutic approach to combat Alzheimer's disease and neuroinflammation. RSC medicinal chemistry 21 35814926
2017 ssc-miR-7134-3p regulates fat accumulation in castrated male pigs by targeting MARK4 gene. International journal of biological sciences 21 28255271
2022 A Network-Guided Approach to Discover Phytochemical-Based Anticancer Therapy: Targeting MARK4 for Hepatocellular Carcinoma. Frontiers in oncology 20 35936719
2011 Differential signature of the centrosomal MARK4 isoforms in glioma. Analytical cellular pathology (Amsterdam) 20 22156016
2020 Mark4 Inhibited the Browning of White Adipose Tissue by Promoting Adipocytes Autophagy in Mice. International journal of molecular sciences 17 32326642
2023 Investigating MARK4 inhibitory potential of Bacopaside II: Targeting Alzheimer's disease. International journal of biological macromolecules 16 37315665
2020 Design and Development of Small-Molecule Arylaldoxime/5-Nitroimidazole Hybrids as Potent Inhibitors of MARK4: A Promising Approach for Target-Based Cancer Therapy. ACS omega 16 32954123
2022 MARK2 and MARK4 Regulate Sertoli Cell BTB Dynamics Through Microtubule and Actin Cytoskeletons. Endocrinology 13 35971301
2021 Long non-coding RNA DLGAP1-AS1 promotes the progression of gastric cancer via miR-515-5p/MARK4 axis. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas 12 34037089
2024 MARK4 aggravates cardiac dysfunction in mice with STZ-induced diabetic cardiomyopathy by regulating ACSL4-mediated myocardial lipid metabolism. Scientific reports 10 38839927
2024 Qingzhuan dark tea Theabrownin alleviates hippocampal injury in HFD-induced obese mice through the MARK4/NLRP3 pathway. Heliyon 9 38455533
2019 Structure and dynamics of inactive and active MARK4: conformational switching through the activation process. Journal of biomolecular structure & dynamics 9 31411112
2020 Correction to: LINC00673 is activated by YY1 and promotes the proliferation of breast cancer cells via the miR-515-5p/MARK4/Hippo signaling pathway. Journal of experimental & clinical cancer research : CR 8 32782003
2024 Interaction of Sp1 and Setd8 promotes vascular smooth muscle cells apoptosis by activating Mark4 in vascular calcification. Aging 7 38301049
2024 Ropinirole reverses the effects of neuroinflammation, and cellular demise by downregulating the MARK4-NFκβ signaling system in Alzheimer's disease. International journal of biological macromolecules 7 38759860
2012 Reduction of protein kinase MARK4 in the brains of experimental scrapie rodents and human prion disease correlates with deposits of PrP(Sc). International journal of molecular medicine 7 22692785
2024 MARK4 promotes the malignant phenotype of gastric cancer through the MAPK/ERK signaling pathway. Pathology, research and practice 6 39079384
2019 Differential Expression of MARK4 Protein and Related Perturbations in Females with Ovulatory PCOS. Endocrine, metabolic & immune disorders drug targets 6 31322078
2024 Vanillin-Isatin Hybrid-Induced MARK4 Inhibition As a Promising Therapeutic Strategy against Hepatocellular Carcinoma. ACS omega 5 38911744
2023 A Novel Interaction between MFN2/Marf and MARK4/PAR-1 Is Implicated in Synaptic Defects and Mitochondrial Dysfunction. eNeuro 5 37550059
2025 Apigenin-mediated MARK4 inhibition: a novel approach in advancing Alzheimer's disease therapeutics. Molecular diversity 4 39841316
2024 Tauopathy in AD: Therapeutic Potential of MARK-4. Current Alzheimer research 3 39931856
2023 Mechanistic insights into MARK4 inhibition by galantamine toward therapeutic targeting of Alzheimer's disease. Frontiers in pharmacology 3 37795023
2023 A cell-penetrating peptide derived from SARS-CoV-2 protein Orf9b allosterically inhibits MARK4 activity and mitigates tau toxicity. Neurobiology of disease 3 37884211
2023 Gain-of-function MARK4 variant associates with pediatric neurodevelopmental disorder and dysmorphism. HGG advances 3 38041405
2019 MARK4 protein can explore the active-like conformations in its non-phosphorylated state. Scientific reports 3 31506531
2024 Mark4 ablation attenuates pathological phenotypes in a mouse model of tauopathy. Brain communications 2 38712317
2025 4,6-Disubstituted pyrimidine-based microtubule affinity-regulating kinase 4 (MARK4) inhibitors: synthesis, characterization, in-vitro activity and in-silico studies. Frontiers in pharmacology 1 39902071
2025 Rhein Mitigates Lung Injury in Severe Acute Pancreatitis Through the Inhibition of MARK4-Mediated Microtubule Destabilization. Journal of inflammation research 1 39906137
2025 Discovery of a novel MARK4 antagonist from safflower to improve ischemic stroke by inhibiting microglial NLRP3 inflammasome activation. Phytomedicine : international journal of phytotherapy and phytopharmacology 1 40482619
2025 Hyperacute response proteins synthesized on γ-tubulin-FTO-MARK4 translation microdomains regulate cancer's acute stress response. Cell reports 1 40540400
2024 Design, synthesis, molecular docking and anti-proliferative activity of novel phenothiazine containing imidazo[1,2-a]pyridine derivatives against MARK4 protein. RSC medicinal chemistry 1 38911173
2026 Structure-based virtual screening and experimental validation of a MARK4 inhibitor for targeted cancer therapy. Journal of biomolecular structure & dynamics 0 41591785
2025 Experimental and theoretical studies on structural changes in the microtubule affinity-regulating kinase 4 (MARK4) protein induced by N-hetarenes: a new class of therapeutic candidates for Alzheimer's disease. Frontiers in medicine 0 40177269
2025 Increased Myocardial MARK4 Expression in Patients with Heart Failure and Sleep-Disordered Breathing. International journal of molecular sciences 0 40332117
2025 Phytochemicals from Bacopa monnieri as small molecule modulators of MARK4: A multi-modal strategy for preventing Alzheimer's disease-causing tau aggregation. Journal of molecular graphics & modelling 0 40773904
2025 Inhibition of MARK4 Promotes Mitochondrial Biogenesis by Inducing the Phosphorylation of AMPKα to Reduce Myocardial Damage in Rats With Myocardial Infarction. Cardiology research and practice 0 41122721
2025 Sophoridine alleviates sepsis-associated encephalopathy by inhibiting MARK4 and NLRP3 signaling. Free radical biology & medicine 0 41167535
2025 MARK4 as a novel biomarker of acute myocardial ischemia-induced sudden cardiac death. Legal medicine (Tokyo, Japan) 0 41421298
2024 Role of MARK4 in methamphetamine-induced acute kidney injury. Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences 0 39311784

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