Affinage

MARK4

MAP/microtubule affinity-regulating kinase 4 · UniProt Q96L34

Length
752 aa
Mass
82.5 kDa
Annotated
2026-04-28
73 papers in source corpus 28 papers cited in narrative 28 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MARK4 is a centrosome- and microtubule-associated serine/threonine kinase of the AMPK family that phosphorylates microtubule-associated proteins (tau, MAP2, MAP4) at KXGS motifs to regulate microtubule dynamics, and integrates cytoskeletal remodeling with diverse signaling pathways including mTORC1, Hippo, NLRP3 inflammasome activation, and stress-responsive mRNA translation (PMID:14594945, PMID:23184942, PMID:28183853, PMID:28656979, PMID:40540400). In cardiomyocytes, MARK4-mediated MAP4 phosphorylation enables VASH2 access to microtubules for α-tubulin detyrosination, directly controlling contractile function, and Mark4 knockout protects against post-infarction systolic dysfunction (PMID:34040253). MARK4 is required for early ciliogenesis by interacting with the mother centriolar protein ODF2 to promote removal of the CP110–Cep97 cap, and it drives NLRP3 transport to the MTOC to nucleate inflammasome assembly (PMID:23400999, PMID:28656979). A gain-of-function MARK4 missense variant (p.Phe202Leu) with enhanced kinase activity toward tau and ribosomal protein S6 is linked to a neurodevelopmental disorder, and MARK4 deletion in a P301S tauopathy mouse model reduces pathological tau accumulation and neurodegeneration (PMID:38041405, PMID:38712317).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2003 High

    Establishing MARK4 as a functional kinase that phosphorylates MAPs and associates with the centrosome/microtubule network answered the foundational question of what this MARK family member does and where it acts.

    Evidence In vitro kinase assay on tau/MAP2/MAP4, TAP-MS identifying tubulin in MARK4 complex, immunofluorescence showing centrosome/MT co-localization

    PMID:14594945

    Open questions at the time
    • Upstream activating kinases for MARK4 not identified
    • Physiological consequences of MAP phosphorylation not tested in vivo
    • Functional distinction from MARK1–3 not resolved
  2. 2012 High

    Two studies revealed MARK4's roles beyond cytoskeletal regulation — as a negative regulator of mTORC1 via Raptor phosphorylation selectively on the Rag GTPase arm, and as a systemic metabolic regulator whose loss protects from diet-induced obesity — establishing MARK4 as a signaling kinase linking cytoskeletal and metabolic control.

    Evidence In vitro kinase assay on Raptor, epistasis with Rag vs. Rheb in Drosophila/mammalian cells; Mark4 KO mice with metabolic phenotyping including AMPK/AKT pathway readouts

    PMID:22992738 PMID:23184942

    Open questions at the time
    • Specific Raptor phosphosites mediating mTORC1 inhibition not mapped
    • Whether metabolic phenotype is cell-autonomous or systemic not dissected
    • Direct connection between mTORC1 inhibition and metabolic protection not tested
  3. 2013 High

    Identifying MARK4 as essential for early ciliogenesis — acting through ODF2 at the mother centriole to enable CP110–Cep97 removal — placed MARK4 upstream of the ciliary program and revealed a kinase-activity-dependent function at the basal body.

    Evidence RNAi screen, kinase-dead mutant analysis, Co-IP of MARK4–ODF2, ultrastructural analysis showing arrest before CP110 removal

    PMID:23400999

    Open questions at the time
    • Whether MARK4 directly phosphorylates CP110, Cep97, or ODF2 not determined
    • Mechanism by which MARK4 kinase activity triggers cap removal unknown
    • Relationship to other ciliogenesis kinases not clarified
  4. 2017 High

    Two discoveries expanded MARK4's signaling repertoire: direct binding to NLRP3 to drive it to the MTOC for inflammasome assembly, and phosphorylation of MST1/2 and SAV1 to inhibit the Hippo kinase cassette and promote YAP/TAZ activity — establishing MARK4 as a node connecting cytoskeletal transport to innate immunity and growth control.

    Evidence Reciprocal Co-IP for MARK4–NLRP3 and MARK4–MST1/SAV1, CRISPR KO, kinase-dead rescue, live-cell imaging of inflammasome speck formation

    PMID:28183853 PMID:28656979

    Open questions at the time
    • Specific NLRP3 phosphosites by MARK4 not identified
    • Whether MARK4 kinase activity or scaffolding drives NLRP3 transport not fully resolved
    • How Hippo pathway inhibition and inflammasome activation are coordinated is unknown
  5. 2019 High

    Cdk5 was identified as an activating kinase for MARK4 via spacer-domain phosphorylation, distinct from LKB1's activation-loop phosphorylation, synergistically enhancing tau phosphorylation and establishing a two-kinase activation model with relevance to neurodegeneration.

    Evidence In vitro kinase assay with phosphosite mapping, Drosophila tauopathy epistasis (Cdk5–Par-1 axis)

    PMID:31174206

    Open questions at the time
    • Specific spacer-domain phosphosites mediating activation not fully characterized
    • Whether Cdk5 and LKB1 activation are cooperative or redundant in vivo unknown
    • Contribution of this axis in mammalian tauopathy models not tested
  6. 2021 High

    In vivo cardiac studies demonstrated that MARK4-mediated MAP4 phosphorylation licenses VASH2 access to microtubules for detyrosination, directly controlling cardiomyocyte contractility, with Mark4 KO mice showing preserved ejection fraction after myocardial infarction — translating the cytoskeletal mechanism to organ-level function.

    Evidence Mark4 KO mice, MI model with echocardiography, biochemical MAP4 phosphorylation and microtubule detyrosination assays

    PMID:34040253

    Open questions at the time
    • Whether therapeutic MARK4 inhibition post-MI recapitulates the KO benefit unknown
    • Interaction between MARK4 and VASH2 may be indirect — direct binding not shown
    • Long-term cardiac remodeling effects of MARK4 loss not characterized
  7. 2023 Medium

    A gain-of-function MARK4 variant (p.Phe202Leu) with enhanced kinase activity toward tau and S6 was linked to neurodevelopmental disease, and MARK4 was shown to regulate mitochondrial fusion through physical interaction with MFN2 — extending MARK4's substrates and organellar roles.

    Evidence In vitro kinase assay of purified F202L mutant on tau/S6; Co-IP of MARK4–MFN2, Drosophila genetic epistasis, Seahorse respirometry

    PMID:37550059 PMID:38041405

    Open questions at the time
    • Whether MFN2 is a direct MARK4 substrate not determined
    • F202L variant studied in only one family — broader genotype–phenotype spectrum unknown
    • Whether mTORC1 upregulation or tau hyperphosphorylation drives the neurodevelopmental phenotype not resolved
  8. 2024 Medium

    MARK4 deletion in P301S tauopathy mice reduced pathological tau, neurodegeneration, and mortality, providing the strongest in vivo mammalian evidence that MARK4 kinase activity on tau is causally linked to tauopathy progression.

    Evidence Mark4 KO × PS19 cross, behavioral testing, immunohistochemistry for phospho-tau species and neurodegeneration markers

    PMID:38712317

    Open questions at the time
    • Whether benefit is solely via reduced tau phosphorylation or also via mTORC1/inflammatory pathways unknown
    • Therapeutic window for post-symptomatic MARK4 inhibition not tested
    • Contribution of individual MARK4 tau phosphosites to pathology not dissected
  9. 2025 Medium

    MARK4 was found to phosphorylate FTO at T6 upon stress, activating m6A demethylation at microtubule-associated translation microdomains to enable compartmentalized stress-response mRNA translation — revealing a novel role linking MARK4 to epitranscriptomic regulation.

    Evidence In vitro kinase assay identifying FTO-T6 as substrate, multi-omic validation, m6A methylation assays, MARK4/FTO inhibition with apoptosis readout

    PMID:40540400

    Open questions at the time
    • Structural basis for MARK4–FTO interaction not resolved
    • Whether FTO-T6 phosphorylation occurs under physiological (non-stress) conditions unknown
    • Identity of specific HARP mRNAs whose translation depends on this axis largely uncharacterized

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions remain: the structural basis for MARK4's substrate selectivity among MAPs and non-MAP substrates, how its centrosomal/stress-granule/MATM localizations are dynamically regulated, and whether therapeutic MARK4 inhibition can treat tauopathy or heart failure without disrupting ciliogenesis or immune function.
  • No structural model of full-length MARK4 with substrates exists
  • Functional redundancy with MARK1–3 in specific tissues not systematically mapped
  • Therapeutic index of MARK4 inhibition across its diverse biological roles unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 7 GO:0008092 cytoskeletal protein binding 3
Localization
GO:0005815 microtubule organizing center 3 GO:0005856 cytoskeleton 3 GO:0005929 cilium 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 2 R-HSA-168256 Immune System 2 R-HSA-1852241 Organelle biogenesis and maintenance 1 R-HSA-8953854 Metabolism of RNA 1
Partners
FTOMFN2MST1NLRP3ODF2RPTORSAV1TIA1

Evidence

Reading pass · 28 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; co-localizes with centrosomes and microtubules; overexpression causes microtubule network thinning and reorganization into bundles; tandem affinity-purified MARK4 complex contains α-, β-, and γ-tubulin In vitro kinase assay, immunofluorescence, tandem affinity purification/mass spectrometry, overexpression in cultured cells The Journal of biological chemistry High 14594945
2017 MARK4 binds directly to NLRP3 and drives it to the microtubule-organizing centre (MTOC) via a microtubule-dependent mechanism, enabling formation of a single large inflammasome speck; MARK4 knockdown/knockout or disruption of MARK4-NLRP3 interaction impairs NLRP3 spatial arrangement and limits inflammasome activation Co-immunoprecipitation, MARK4 knockdown and knockout, live-cell imaging, microtubule disruption experiments, genetic rescue Nature communications High 28656979
2017 MARK4 acts as a negative regulator of the Hippo kinase cassette: MARK4 binds MST1/2 and SAV1, 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, siRNA knockdown, CRISPR/Cas9 knockout, kinase-dead mutant rescue, proliferation/migration assays EMBO reports High 28183853
2012 MARK4 is a negative regulator of mTORC1: MARK4 selectively inhibits mTORC1 activation by Rag GTPases (amino acid signaling arm) but not by Rheb; MARK4 phosphorylates Raptor, a key mTORC1 component, potentially interfering with Raptor-Rag interaction RNAi knockdown in Drosophila S2 and mammalian cells, overexpression, in vitro kinase assay for Raptor phosphorylation, epistasis with Rag vs. Rheb The Journal of biological chemistry High 23184942
2021 MARK4 promotes phosphorylation of MAP4 in cardiomyocytes, facilitating access of vasohibin-2 (VASH2) to microtubules for α-tubulin detyrosination; MARK4 deficiency substantially limits reduction in left ventricular ejection fraction after acute myocardial infarction without affecting infarct size Mark4 knockout mice, myocardial infarction model, echocardiography, biochemical phosphorylation assays, microtubule detyrosination assays Nature High 34040253
2013 MARK4 kinase activity is required for initiation of axoneme extension during early ciliogenesis; MARK4 associates with the basal body and ciliary axoneme; MARK4 interacts with the mother centriolar protein ODF2 and is required for ODF2 localization; MARK4 or ODF2 knockdown arrests the ciliary program before removal of the CP110-Cep97 inhibitory complex from the mother centriole RNAi functional screen, kinase-dead mutant analysis, Co-immunoprecipitation (MARK4-ODF2), ultrastructural analysis, immunofluorescence localization The Journal of cell biology High 23400999
2012 MARK4 deficiency in mice causes hyperphagia, hyperactivity, hypermetabolism, protection from diet-induced obesity, enhanced insulin-stimulated AKT phosphorylation, and up-regulation of AMPK activity in metabolic tissues; identifies MARK4 as a regulator of energy homeostasis Targeted mark4 gene knockout in mice, metabolic phenotyping, Western blot for AKT and AMPK phosphorylation The Journal of biological chemistry High 22992738
2016 miR-515-5p directly inhibits MARK4 via 3′ UTR interaction; MARK4 knockdown mimics miR-515-5p inhibition of cancer cell migration; MARK4 overexpression rescues miR-515-5p-mediated inhibition of migration, establishing MARK4 as a downstream effector of miR-515-5p in cancer cell migration and metastasis 3′ UTR luciferase reporter assay, siRNA knockdown, rescue overexpression, in vivo xenograft metastasis model EMBO reports High 26882547
2019 Cdk5 phosphorylates MARK4 in the spacer domain (not the activation loop), increasing MARK4 kinase activity and enhancing tau phosphorylation at MARK target sites (Ser262) and Cdk5 target sites; co-expression of Cdk5 and MARK4 increases total tau levels; Cdk5 promotes tau accumulation and neurodegeneration in Drosophila via the MARK ortholog Par-1 In vitro kinase assay, phosphosite mapping, co-expression in mammalian cells, Cdk5 inhibitor treatment, Drosophila tau toxicity model with genetic rescue Human molecular genetics High 31174206
2004 MARK4 (MARKL1/9b5) is a functional serine/threonine protein kinase that phosphorylates a cognate peptide substrate for the AMP-kinase family; overexpression of wild-type but not kinase-dead MARK4 decreases cell viability, indicating kinase activity is required for its pro-apoptotic effect In vitro kinase assay with peptide substrate, kinase-dead mutant overexpression, cell viability assay Journal of neurochemistry Medium 15009667
2016 MARK4 promotes oxidative stress and inflammation in adipocytes by activating the IKKα/NF-κB signaling pathway; PPARγ binds to the MARK4 promoter region and inhibits MARK4 expression, and PPARγ physically interacts with MARK4 protein to inhibit its stimulatory effect on oxidative stress and inflammation ChIP assay (PPARγ binding to MARK4 promoter), co-immunoprecipitation (PPARγ-MARK4 interaction), ROS measurement, NF-κB pathway inhibitor experiments Scientific reports Medium 26888669
2014 MARK4 promotes adipogenesis and triggers apoptosis in adipocytes by activating JNK1 and inhibiting p38MAPK pathways; JNK1 activation promotes both apoptosis and adipogenesis, while p38MAPK inhibition contributes to lipid accumulation MARK4 overexpression in 3T3-L1 cells, specific kinase inhibitors (for JNK1 and p38MAPK), TUNEL apoptosis assay, lipid droplet staining Biology of the cell Medium 24989893
2014 MARK4 is expressed throughout the cell cycle and preferentially activated during mitosis; MARK4S depletion reduces cells in S and G2/M phases, increases G1 cells, and alters centrosome duplication and positioning, indicating MARK4 regulates G1/S transition; MARK4 co-localizes with vimentin, suggesting a role in intermediate filament cytoskeleton regulation Flow cytometry, siRNA knockdown, centrosome imaging by immunofluorescence, overexpression studies European journal of cell biology Medium 25123532
2016 Methylene blue inhibits MARK4 through two mechanisms: down-regulation of MARK4 protein level via the ubiquitin-proteasome pathway and direct inhibition of MARK4 kinase activity in vitro; MB treatment decreases MARK4-mediated tau phosphorylation in 293T cells In vitro kinase assay, proteasome inhibitor rescue experiment, cell-based tau phosphorylation assay Scientific reports Medium 27708431
2012 MARK4 is a component of the ectoplasmic specialization (ES) in the rat testis, co-localizing with α-tubulin and the desmosomal adaptor plakophilin-2 at apical and basal ES; MARK4 expression is stage-specific and its diminished expression associates with apical ES disruption and detachment of elongating spermatids Immunofluorescence co-localization, co-immunoprecipitation, stage-specific expression analysis, fractionation Spermatogenesis Medium 22670221
2022 MARK4 knockdown in Sertoli cells impairs the tight junction permeability barrier at the blood-testis barrier and disrupts microtubule- and actin-based cytoskeletal organization; MARK4 regulates microtubules differently from MARK2 — MARK4 loss causes MTs to retract from cell edges, whereas MARK2 loss causes MT bundles to arrange around cell periphery siRNA knockdown, TJ-permeability barrier assay, immunofluorescence for MT and actin cytoskeleton Endocrinology Medium 35971301
2019 MARK4 knockdown increases mTORC1 activity specifically; MARK4-dependent regulation operates through the Rag GTPase arm of mTORC1 signaling in the context of atherosclerosis; MARK4 deficiency in bone marrow-derived macrophages prevents cholesterol crystal-induced NLRP3 inflammasome activation (reduced caspase-1 activity, IL-1β, and IL-18) Bone marrow transplantation (Mark4 KO → irradiated Ldlr-/- mice), primary macrophage caspase-1 activity assay, atherosclerosis plaque measurement Arteriosclerosis, thrombosis, and vascular biology Medium 31167564
2023 MARK4 physically interacts with MFN2/Marf (mitofusin 2); loss of MARK4/PAR-1 rescues mitochondrial hyperfusion caused by MFN2/Marf overexpression in Drosophila muscles and cultured mammalian cells, and rescues respiratory dysfunction of mitochondria; MARK4 regulates mitochondrial fusion and synaptic integrity through MFN2 interaction Co-immunoprecipitation (MFN2-MARK4), Drosophila genetic epistasis, mammalian cell knockdown, mitochondrial morphology analysis, Seahorse respirometry eNeuro Medium 37550059
2020 Mark4 promotes autophagy in adipocytes by activating the AMPK pathway and inhibiting AKT/mTOR signaling, increasing LC3A-to-LC3B-II conversion and Beclin1/ATG7 expression; Mark4-induced autophagy inhibits browning of white adipose tissue by decreasing thermogenesis gene expression MARK4 overexpression in adipocytes, serum starvation and rapamycin autophagy models, Western blot for AMPK, AKT/mTOR, LC3, Beclin1, ATG7, P62 International journal of molecular sciences Medium 32326642
2024 MARK4 regulates cardiomyocyte lipid metabolism through ACSL4; MARK4 deficiency reduces ACSL4 expression, promotes lipid oxidation metabolism, reduces oxidative stress and apoptosis, and facilitates mitochondrial fusion in a diabetic cardiomyopathy model AAV9-shMARK4 in vivo knockdown, STZ/HFD diabetic cardiomyopathy model, RNA-seq for differentially expressed genes, Western blot for ACSL4 and apoptosis markers Scientific reports Medium 38839927
2024 MARK4 contributes to tau-mediated neuropathology in a P301S tauopathy mouse model: Mark4 knockout in PS19 mice improved mortality, memory, and reduced neurodegeneration, astrogliosis, and pathological tau forms (phospho-Ser356, AT8-positive tau, thioflavin S-positive tau) Cross of Mark4 KO with P301S (PS19) tauopathy mice, behavioral testing, immunohistochemistry, biochemical tau analysis Brain communications Medium 38712317
2023 A gain-of-function MARK4 missense variant (p.Phe202Leu) in the catalytic domain increases MARK4's ability to phosphorylate tau isoforms and increases phosphorylation of ribosomal protein S6 (indicating mTORC1 upregulation), linking MARK4 kinase activity to a neurodevelopmental disorder Functional studies of purified mutant protein (in vitro kinase assay with tau and S6 substrates), patient-derived variant analysis HGG advances Medium 38041405
2023 A cell-penetrating peptide derived from SARS-CoV-2 Orf9b inhibits MARK4 activity allosterically (not at the ATP/catalytic site), selectively over MARK2; Orf9b and TAT-Orf9b10-18_78-95 suppress MARK4-mediated tau phosphorylation at microtubule-binding repeats in primary neurons and reduce tau-induced neurodegeneration in Drosophila tauopathy model In vitro kinase assay, allosteric mechanism determination, primary neuron treatment, Drosophila genetic model, co-expression rescue Neurobiology of disease Medium 37884211
2019 Ischemic axonal injury up-regulates MARK4 in Layer 5 cortical neurons, which is associated with selective remodeling of the apical dendrite and tau phosphorylation in vivo; MARK4 promotes aggregation of human tau in a cell-based tau biosensor assay in vitro Mouse subcortical stroke model with retrograde tracing and FACS-sorted neurons, RNA-seq, tau biosensor aggregation assay Acta neuropathologica communications Medium 31429800
2024 Sp1 transcription factor binds the MARK4 promoter and activates its transcription; SET domain-containing protein 8 (Setd8/SET8) interacts with Sp1 and participates in transcriptional regulation of MARK4; MARK4 promotes vascular smooth muscle cell apoptosis and calcification by modulating AKT phosphorylation ChIP assay (Sp1 binding to MARK4 promoter), co-immunoprecipitation (Setd8-Sp1), siRNA knockdown of MARK4/Setd8, Western blot for AKT phosphorylation, calcification assays Aging Medium 38301049
2025 MARK4 is a component of stress granules (SGs) and enhances SG formation; MARK4 co-localizes with TIA1 in SGs via its spacer domain; both MARK4 localization to SGs and its kinase activity are required for enhanced SG formation; MARK4 and TIA1 synergistically increase tau accumulation in cultured cells; knockdown of fly TIA1 homolog suppresses tau toxicity in Drosophila Immunofluorescence co-localization with SG markers, domain deletion mutants (spacer domain), kinase-dead mutants, tau accumulation assays, Drosophila genetic model bioRxivpreprint Medium bio_10.1101_2025.04.30.651577
2025 MARK4 activates FTO (an m6A RNA demethylase) by phosphorylating it at T6 upon cellular stress; activated FTO demethylates a translation-inhibiting m6A signature on HARP mRNAs at microtubule-associated translation microdomains (MATMs) on γ-tubulin, enabling compartmentalized stress-response protein translation while global translation remains suppressed Unbiased proteomics/transcriptomics, in vitro kinase assay (MARK4 phosphorylating FTO at T6), m6A methylation assays, MARK4/FTO inhibition with apoptosis readout Cell reports Medium 40540400
2016 The ubiquitin-associated (UBA) domain of MARK4 is required for structural stability and ATPase activity at physiological pH; kinase domain constructs lacking the UBA domain aggregate at physiological pH but are stable at extremes of pH Cloning/expression of MARK4 UBA+kinase domain construct, spectroscopic stability measurements, ATPase activity assay at physiological pH International journal of biological macromolecules Low 27677563

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 126 28656979
2020 Rosmarinic Acid Exhibits Anticancer Effects via MARK4 Inhibition. Scientific reports 117 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 115 29683402
2017 MARK4 inhibits Hippo signaling to promote proliferation and migration of breast cancer cells. EMBO reports 104 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 91 29079437
2014 MARK4 and MARK3 associate with early tau phosphorylation in Alzheimer's disease granulovacuolar degeneration bodies. Acta neuropathologica communications 89 24533944
2001 Isolation of a novel human gene, MARKL1, homologous to MARK3 and its involvement in hepatocellular carcinogenesis. Neoplasia (New York, N.Y.) 89 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 76 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 67 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
2012 Microtubule affinity-regulating kinase 4 (MARK4) is a component of the ectoplasmic specialization in the rat testis. Spermatogenesis 53 22670221
2019 PCC0208017, a novel small-molecule inhibitor of MARK3/MARK4, suppresses glioma progression in vitro and in vivo. Acta pharmaceutica Sinica. B 51 32082974
2016 Attenuation of synaptic toxicity and MARK4/PAR1-mediated Tau phosphorylation by methylene blue for Alzheimer's disease treatment. Scientific reports 47 27708431
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 Structure-based investigation of MARK4 inhibitory potential of Naringenin for therapeutic management of cancer and neurodegenerative diseases. Journal of cellular biochemistry 43 34121218
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
2021 Myricetin inhibits breast and lung cancer cells proliferation via inhibiting MARK4. Journal of cellular biochemistry 38 34751461
2020 Structural and biochemical investigation of MARK4 inhibitory potential of cholic acid: Towards therapeutic implications in neurodegenerative diseases. International journal of biological macromolecules 38 32535203
2019 Cdk5 increases MARK4 activity and augments pathological tau accumulation and toxicity through tau phosphorylation at Ser262. Human molecular genetics 38 31174206
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 33 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
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
2020 Mark4 Inhibited the Browning of White Adipose Tissue by Promoting Adipocytes Autophagy in Mice. International journal of molecular sciences 15 32326642
2022 MARK2 and MARK4 Regulate Sertoli Cell BTB Dynamics Through Microtubule and Actin Cytoskeletons. Endocrinology 12 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 9 38839927
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 Qingzhuan dark tea Theabrownin alleviates hippocampal injury in HFD-induced obese mice through the MARK4/NLRP3 pathway. Heliyon 7 38455533
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
2019 Differential Expression of MARK4 Protein and Related Perturbations in Females with Ovulatory PCOS. Endocrine, metabolic & immune disorders drug targets 6 31322078
2024 Interaction of Sp1 and Setd8 promotes vascular smooth muscle cells apoptosis by activating Mark4 in vascular calcification. Aging 5 38301049
2024 Vanillin-Isatin Hybrid-Induced MARK4 Inhibition As a Promising Therapeutic Strategy against Hepatocellular Carcinoma. ACS omega 5 38911744
2024 MARK4 promotes the malignant phenotype of gastric cancer through the MAPK/ERK signaling pathway. Pathology, research and practice 5 39079384
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 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 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 0 40482619
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