Affinage

MAPK15

Mitogen-activated protein kinase 15 · UniProt Q8TD08

Length
544 aa
Mass
59.8 kDa
Annotated
2026-04-28
52 papers in source corpus 37 papers cited in narrative 37 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MAPK15 (ERK7/ERK8) is an atypical MAP kinase that functions as a stress-responsive, constitutively autophosphorylating signaling hub integrating nutrient sensing, genome maintenance, autophagy, ciliogenesis, and antioxidant defense. Its kinase activity depends on intramolecular autophosphorylation of its TEY motif—independent of upstream MEKs—and is regulated by its unique C-terminal domain, which also controls nuclear localization, protein–protein interactions (including c-Src, Dishevelled, and LC3/GABARAP family proteins), and rapid SCF-mediated proteasomal turnover (PMID:9891064, PMID:11287416, PMID:15033983, PMID:22948227). MAPK15 promotes autophagy and mitophagy through direct engagement of the ULK1/AMPK axis and PRKN Ser108 phosphorylation, thereby preventing mitochondrial ROS accumulation, DNA damage, and cellular senescence; it also stabilizes chromatin-bound PCNA by blocking HDM2-mediated ubiquitination, activates NRF2-dependent antioxidant transcription, and suppresses JNK–JUN–IFNB1 inflammatory signaling (PMID:30131341, PMID:35642724, PMID:20733054, PMID:38555711, PMID:40507959). Beyond genome and organelle homeostasis, MAPK15 is essential for primary and motile cilia biogenesis across species—phosphorylating CapZIP to organize the apical actin network for basal body migration—regulates GalNAc-transferase Golgi-to-ER trafficking to control O-glycosylation and cell motility, and limits hepatic lipid uptake by suppressing CD36 membrane localization, with Mapk15 knockout mice developing steatohepatitis (PMID:25823377, PMID:29021280, PMID:24618899, PMID:41610145).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1999 High

    Identification of ERK7/MAPK15 as an atypical MAP kinase with constitutive activity and a regulatory C-terminal domain resolved the question of whether all MAPKs require extracellular mitogenic stimulation and established that the C-terminal tail governs both nuclear localization and growth inhibition.

    Evidence Cloning, kinase assays, deletion mutants, and fluorescence localization in COS cells

    PMID:9891064

    Open questions at the time
    • Identity of endogenous upstream activating signals unknown
    • C-terminal domain structure unresolved
    • Physiological substrates not identified
  2. 2001 High

    Demonstration that ERK7 autophosphorylates its TEY activation motif intramolecularly, without requiring an upstream MEK, established a fundamentally different activation mechanism from classical MAPKs.

    Evidence In vitro autophosphorylation assays with kinase-dead mutants and MEK inhibitor insensitivity

    PMID:11287416

    Open questions at the time
    • Crystal structure of the kinase domain not determined
    • Mechanism by which the C-terminal domain stimulates autophosphorylation unclear
  3. 2002 High

    Finding that c-Src activates ERK8/MAPK15 via SH3-domain binding to the C-terminal region identified the first upstream regulatory input, acting through a MEK-independent route.

    Evidence In vitro SH3-domain pulldown, reciprocal Co-IP, epistasis with Src and MEK inhibitors

    PMID:11875070

    Open questions at the time
    • Whether Src phosphorylates MAPK15 directly or acts allosterically not resolved
    • Physiological contexts of Src–MAPK15 axis undefined
  4. 2004 High

    Revealing that MAPK15 undergoes rapid SCF-complex-mediated proteasomal degradation directed by its N-terminal 20 amino acids explained how a constitutively active kinase is kept at low steady-state levels.

    Evidence Proteasome inhibitors, ERK2–ERK7 chimeric constructs, dominant-negative Cullin-1, pulse-chase

    PMID:15033983

    Open questions at the time
    • Specific F-box protein not identified
    • Signals that stabilize MAPK15 under stress not defined
  5. 2006 High

    Biochemical dissection of TEY autophosphorylation showed Thr-175 is the critical activating residue (PP2A dephosphorylation eliminates >95% activity), while identification of H₂O₂ and osmotic shock as activators established MAPK15 as a stress-responsive kinase with a substrate specificity distinct from ERK1/2.

    Evidence In vitro phosphatase treatment (PP2A, PTP1B), kinase-dead mutant analysis, mass spectrometry

    PMID:16336213

    Open questions at the time
    • Endogenous stress-sensing mechanism upstream of autophosphorylation unresolved
    • Full substrate consensus motif not defined
  6. 2006 High

    Discovery that MAPK15 sequesters Hic-5 via its C-terminal domain to repress glucocorticoid and androgen receptor co-activation, and separately acts as an ERRα corepressor via LXXLL motifs promoting CRM1-dependent nuclear export, revealed kinase-independent transcriptional regulatory functions.

    Evidence Yeast two-hybrid, Co-IP, transcriptional reporters, siRNA, CRM1 inhibitor (for ERRα work in 2010)

    PMID:16624805 PMID:21190936

    Open questions at the time
    • Physiological relevance of steroid receptor regulation in vivo not tested
    • Whether kinase-dependent and kinase-independent functions are coordinated is unknown
  7. 2009 Medium

    Showing that DNA single-strand-break-generating agents activate MAPK15 and that alkylation damage triggers its proteasomal degradation linked MAPK15 to the DNA damage response, prior to identification of specific genome-maintenance substrates.

    Evidence Kinase activity assays after H₂O₂, alkylating agents, PARP inhibitor treatment; proteasome inhibitor rescue

    PMID:19166846

    Open questions at the time
    • Downstream DNA repair effectors not identified
    • Whether MAPK15 degradation is a feedback termination signal or pathological consequence unclear
  8. 2010 High

    Identification of PCNA as a chromatin-bound MAPK15 partner, whose stability MAPK15 maintains by blocking HDM2-mediated ubiquitination, provided the first direct mechanistic link between MAPK15 and genome integrity maintenance.

    Evidence Chromatin-fraction Co-IP, PIP-box mutant, siRNA with ectopic PCNA rescue, γH2AX assay

    PMID:20733054

    Open questions at the time
    • Whether MAPK15 phosphorylates PCNA or acts purely as a scaffold not resolved
    • In vivo genome instability phenotype not examined
  9. 2011 High

    Drosophila ERK7 was shown to phosphorylate Sec16 to disassemble ER exit sites upon starvation, establishing the first direct substrate connection and placing MAPK15 as a nutrient-sensing regulator of secretory pathway organization.

    Evidence Drosophila RNAi screen, Sec16 phosphorylation assays, human cell validation, TORC1 epistasis

    PMID:21847093

    Open questions at the time
    • Sec16 phosphorylation site identity not mapped in mammalian cells
    • Relationship to autophagy induction unclear at this stage
  10. 2012 High

    Discovery that MAPK15 binds ATG8-family proteins (LC3B, GABARAP, GABARAPL1) via a LIR motif and stimulates autophagosome formation in a kinase-dependent manner upon starvation established MAPK15 as a direct autophagy regulator.

    Evidence Co-IP, LIR mutant analysis, LC3 lipidation assays, SQSTM1 degradation, siRNA in multiple cell types

    PMID:22948227

    Open questions at the time
    • Direct kinase target in the autophagy cascade not yet identified
    • Whether MAPK15 acts upstream or in parallel to mTOR-dependent autophagy signals unknown
  11. 2014 High

    An RNAi screen identified MAPK15 as a negative regulator of O-GalNAc glycosylation by controlling COPI-dependent Golgi retention of GalNAc-transferases, revealing an unexpected role in Golgi trafficking and cell motility.

    Evidence Genome-wide RNAi screen, GalNAc-T localization imaging, COPI epistasis, cell motility assays

    PMID:24618899

    Open questions at the time
    • Direct MAPK15 substrate in the COPI retention pathway not identified
    • Whether this function is linked to ciliogenesis or secretion regulation is unknown
  12. 2015 High

    Identification of CapZIP as a direct MAPK15 phosphorylation substrate in Xenopus multiciliated cells, acting in cooperation with Dishevelled, established the molecular mechanism by which MAPK15 organizes the apical actin network for basal body docking and ciliogenesis.

    Evidence In vitro kinase assay (ERK7→CapZIP), Co-IP of ternary complex (Dvl–ERK7–CapZIP), morpholino knockdown, confocal imaging

    PMID:25823377

    Open questions at the time
    • CapZIP phosphorylation sites not fully mapped
    • Whether mammalian MAPK15 uses the same substrate for primary ciliogenesis untested
  13. 2017 High

    Studies in C. elegans and human cells demonstrated that MAPK15 localizes to basal bodies and is essential for primary cilia formation, ciliary protein trafficking (including BBS7 and PKD-2), and also regulates dopamine transporter surface expression via Rho GTPases, broadening MAPK15's roles to neuronal signaling.

    Evidence C. elegans forward genetic screen, GFP localization, loss-of-function mutants, Rho GTPase activation assays, conservation in human cells

    PMID:28745435 PMID:28842414 PMID:29021280

    Open questions at the time
    • Direct Rho GTPase substrate relationship not biochemically defined
    • How basal body localization is achieved in mammalian cells unclear
  14. 2018 High

    Placing MAPK15 within the ULK1 complex and showing it stimulates AMPK-dependent ULK1 activity identified the kinase cascade through which MAPK15 drives autophagosome biogenesis upon starvation.

    Evidence Co-IP of MAPK15–ULK1 complex, in vitro kinase cascade assay, starvation-induced autophagy readouts

    PMID:30131341

    Open questions at the time
    • Whether MAPK15 directly phosphorylates ULK1 or acts via AMPK not resolved
    • Relative contribution versus other ULK1 activators not quantified
  15. 2020 High

    The crystal structure of the Toxoplasma ERK7–AC9 complex revealed that AC9 inhibits ERK7 by displacing nucleotide from the active site, providing the first structural understanding of MAPK15 regulation and linking it to apical complex biogenesis in apicomplexan parasites.

    Evidence X-ray crystallography, BioID, conditional KO, yeast two-hybrid

    PMID:32409604

    Open questions at the time
    • Mammalian structural equivalent of AC9-mediated regulation not identified
    • Whether a similar allosteric inhibition occurs in metazoan MAPK15 unknown
  16. 2022 High

    MAPK15 was shown to prevent oxidative stress-induced cellular senescence by driving ULK1-dependent PRKN Ser108 phosphorylation and mitophagy, directly connecting MAPK15-regulated mitochondrial quality control to prevention of nuclear DNA damage and senescence in primary human cells.

    Evidence MAPK15 KO/KD, PRKN Ser108 phosphorylation immunoblot, mitophagy flux, respiration/ROS/ATP assays, senescence markers in primary airway epithelia

    PMID:35642724

    Open questions at the time
    • Whether MAPK15 phosphorylates PRKN directly or through ULK1 not fully dissected
    • Tissue-specific relevance beyond airway epithelium not established
  17. 2024 Medium

    Demonstration that MAPK15 activates NRF2 by inducing its phosphorylation and nuclear translocation upon oxidative stress (cigarette smoke) identified an additional antioxidant effector arm complementing its mitophagy function.

    Evidence siRNA knockdown, NRF2 phosphorylation immunoblot, nuclear fractionation, target gene expression in lung epithelial cells

    PMID:38555711

    Open questions at the time
    • NRF2 phosphorylation site by MAPK15 not mapped
    • Whether this is direct phosphorylation or mediated through Keap1 regulation unclear
  18. 2025 Medium

    MAPK15 was found to suppress IFNB1 expression and interferon-stimulated gene programs by preventing ROS-dependent JNK–JUN pathway activation, adding an anti-inflammatory dimension to its antioxidant functions.

    Evidence siRNA knockdown, IFNB1 promoter reporter, JNK inhibitor and NACET antioxidant epistasis, ELISA

    PMID:40507959

    Open questions at the time
    • Whether MAPK15 directly inhibits JNK or acts solely through ROS suppression not resolved
    • In vivo inflammatory phenotype not tested
  19. 2025 High

    Mapk15 knockout mice develop liver steatosis driven by increased CD36 membrane localization and lipid uptake, validated in human MASLD cohorts, establishing the first in vivo mammalian disease phenotype for MAPK15 loss.

    Evidence Mapk15−/− mouse model, CD36 expression/localization, western diet challenge, hepatocellular gain-of-function rescue, human cohort transcriptomics

    PMID:41610145

    Open questions at the time
    • Mechanism by which MAPK15 controls CD36 trafficking not defined
    • Whether metabolic phenotype is connected to autophagy/mitophagy functions of MAPK15 not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include: the full structural basis of mammalian MAPK15 autophosphorylation and C-terminal domain regulation, the identity of the F-box protein mediating its SCF-dependent turnover, how its diverse functions (ciliogenesis, autophagy/mitophagy, genome maintenance, Golgi trafficking, metabolic regulation) are coordinated in space and time, and whether MAPK15 loss-of-function causes human Mendelian disease.
  • No mammalian MAPK15 crystal structure exists
  • F-box protein identity unknown
  • Integrated signaling model connecting cilia, autophagy, and metabolic functions lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0098772 molecular function regulator activity 4 GO:0140110 transcription regulator activity 3 GO:0140657 ATP-dependent activity 3
Localization
GO:0005634 nucleus 4 GO:0005929 cilium 3 GO:0031410 cytoplasmic vesicle 2 GO:0005694 chromosome 1 GO:0005794 Golgi apparatus 1 GO:0005815 microtubule organizing center 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-8953897 Cellular responses to stimuli 4 R-HSA-9612973 Autophagy 4 R-HSA-1852241 Organelle biogenesis and maintenance 3 R-HSA-73894 DNA Repair 3 R-HSA-1430728 Metabolism 2 R-HSA-392499 Metabolism of proteins 2 R-HSA-5357801 Programmed Cell Death 2
Partners
DVLGABARAPMAP1LC3BNRF2PCNAPRKNSRCULK1
Complex memberships
ERK7-AC9-AC10 (Toxoplasma apical cap complex)ULK1 complex

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 ERK7 (MAPK15) has constitutive kinase activity in serum-starved cells dependent on its C-terminal domain; the C-terminal tail (not the kinase domain) regulates its nuclear localization and growth inhibition; it is not activated by extracellular stimuli that activate ERK1/2, JNK, or p38. Cloning, expression in COS cells, kinase assays, deletion mutant analysis, fluorescence localization Molecular and cellular biology High 9891064
2001 ERK7 (MAPK15) is activated by intramolecular autophosphorylation of its TEY motif without requiring an upstream MEK; multiple regions of the C-terminal domain regulate its kinase activity; MEK inhibitors do not suppress ERK7 activity. In vitro kinase assays, MEK inhibitor treatment, autophosphorylation assays, C-terminal deletion mutants The Journal of biological chemistry High 11287416
2002 ERK8 (MAPK15) associates with the c-Src SH3 domain via two SH3-binding motifs in its C-terminal region, co-immunoprecipitates with c-Src in vivo, and is activated downstream of c-Src (v-Src or constitutively active c-Src); this activation is MEK-independent. In vitro pulldown (SH3 domain binding), co-immunoprecipitation, co-transfection with v-Src/active c-Src, MEK inhibitor U0126 treatment, Src inhibitor PP2 treatment The Journal of biological chemistry High 11875070
2004 ERK7 (MAPK15) protein expression is regulated by ubiquitination and rapid proteasomal turnover; the N-terminal 20 amino acids of the kinase domain are necessary and sufficient to direct ERK7 degradation; ERK7 is ubiquitinated by the SCF (Skp1-Cullin-F-box) complex. Proteasome inhibitor treatment, ERK2-ERK7 chimeric proteins, GFP fusion constructs, dominant-negative Cullin-1 mutant co-expression, pulse-chase degradation assays The Journal of biological chemistry High 15033983
2006 ERK8 (MAPK15) phosphorylation of its TEY motif is an autophosphorylation event; dephosphorylation of Thr-175 by PP2A reduces activity >95% while dephosphorylation of Tyr-177 by PTP1B reduces activity only 15–20%; H2O2, okadaic acid, and osmotic shock activate ERK8 in cells; catalytically inactive mutants (D154A, K42A) are not phosphorylated, confirming autophosphorylation; ERK8 has a substrate specificity distinct from ERK1/2. In vitro phosphatase treatment (PP2A, PTP1B), kinase-dead mutant analysis, phosphosite identification by mass spectrometry, in vitro kinase assay with myelin basic protein The Biochemical journal High 16336213
2006 ERK8 (MAPK15) interacts with Hic-5 (ARA55) via the LIM3 and LIM4 domains of Hic-5 and the kinase-independent C-terminal region of ERK8; through this interaction, ERK8 negatively regulates glucocorticoid receptor (GRα) and androgen receptor transcriptional co-activation by Hic-5 in a kinase-independent manner. Yeast two-hybrid screen, co-immunoprecipitation in mammalian cells, transcriptional reporter assays, siRNA knockdown of endogenous ERK8 The Journal of biological chemistry High 16624805
2006 ERK8 (MAPK15) is activated by RET/PTC3 (an activated RET proto-oncogene) through a mechanism requiring Tyr981 of RET/PTC3 and c-Abl kinase activity (not strictly Src); ERK8 participates in RET/PTC3-dependent stimulation of the c-jun promoter; the C-terminal domain of ERK8 is the region modulated by RET/PTC3 and Abl. Co-transfection with RET/PTC3 mutants, kinase assays, c-jun promoter reporter assay, Abl inhibitor treatment The Journal of biological chemistry Medium 16484222
2009 ERK8 (MAPK15) activity is induced by DNA single-strand break-generating agents (H2O2, DNA alkylating agents, cross-linking agents, PARP inhibitor KU-0058948); the DNA alkylating agent MMS induces proteasome-dependent degradation of endogenous ERK8, linking ERK8 to DNA damage response. ERK8 kinase activity assays in transfected cells after agonist treatment, proteasome inhibitor rescue experiments FEBS letters Medium 19166846
2010 ERK8 (MAPK15) is chromatin-bound and interacts with PCNA via a conserved PIP box motif; chromatin-bound ERK8 prevents HDM2-mediated ubiquitination and degradation of PCNA by blocking PCNA–HDM2 association; silencing ERK8 decreases PCNA levels and increases DNA damage, which is rescued by ectopic PCNA expression. Co-immunoprecipitation (chromatin fraction), PIP-box mutant analysis, siRNA knockdown, ectopic PCNA rescue, DNA damage assays The Journal of cell biology High 20733054
2010 ERK8 (MAPK15) interacts with ERRα via two LXXLL motifs in ERK8; this interaction induces CRM1-dependent translocation of ERRα to the cytoplasm and inhibits ERRα transcriptional activity; ERK8 counteracts EGF receptor-induced ERRα activation in mammary cells. Co-immunoprecipitation, LXXLL mutant analysis, nuclear export (CRM1) inhibitor treatment, transcriptional reporter assays The Journal of biological chemistry High 21190936
2011 ERK7 (Drosophila ortholog of MAPK15) negatively regulates protein secretion in response to serum/amino-acid starvation by phosphorylating Sec16 at its C-terminus, causing cytoplasmic dispersion of Sec16 and disassembly of ER exit sites; this response is TORC1-independent. Drosophila RNAi screen, epistasis experiments in S2 cells and human cells, Sec16 phosphorylation assays, proteasome inhibition to stabilize ERK7 The EMBO journal High 21847093
2012 MAPK15 (ERK8) interacts with ATG8-family proteins (MAP1LC3B, GABARAP, GABARAPL1) via a conserved LC3-interacting region (LIR) motif; through this interaction, MAPK15 localizes to autophagic compartments and stimulates ATG8 lipidation, autophagosome formation, and SQSTM1 degradation in a kinase-dependent manner; MAPK15 activity is induced by serum and amino-acid starvation and is required for starvation-induced autophagy. Co-immunoprecipitation, LIR mutant analysis, autophagosome formation assays (LC3 lipidation, SQSTM1 degradation), confocal microscopy localization, siRNA knockdown Autophagy High 22948227
2013 ERK8 (MAPK15) localizes to the spindle fibers and microtubule asters during mouse oocyte meiotic maturation; knockdown of ERK8 by antibody microinjection or siRNA causes abnormal spindles, failed chromosome congression, and decreased polar body extrusion. Immunofluorescence localization, taxol treatment, antibody microinjection, siRNA knockdown, spindle morphology analysis Microscopy and microanalysis Medium 23351492
2013 A homology model of the ERK8 kinase domain was validated experimentally; compounds identified by virtual screening were confirmed as ATP-competitive inhibitors of ERK8; a gatekeeper mutant corroborated the predicted binding mode. Homology modeling, pharmacophore screening, molecular docking, in vitro kinase inhibition assays, gatekeeper mutant PloS one Medium 23326322
2014 ERK8 (MAPK15) is a negative regulator of O-GalNAc glycosylation; ERK8 is partially localized at the Golgi and its inhibition/knockdown induces relocation of GalNAc-transferases from the Golgi to the ER via a COPI-dependent pathway distinct from KDEL receptor trafficking; ERK8 downregulation activates cell motility. RNAi screen of 948 signaling genes, imaging of GalNAc-T subcellular localization, COPI pathway epistasis, cell motility assays eLife High 24618899
2014 In Drosophila, ERK7 (MAPK15 ortholog) is upregulated in insulin-producing cells (IPCs) upon ribosome biogenesis impairment or starvation, acts epistatically downstream of p53, and is sufficient and essential to inhibit insulin-like peptide (dILP) secretion; this defines a p53→ERK7 axis in a cell-autonomous ribosome surveillance response. Genetic epistasis (double mutant analysis), IPC-specific RNAi, ERK7 overexpression in IPCs, body size measurements, developmental timing PLoS genetics High 25393288
2015 ERK7 (Xenopus MAPK15 ortholog) regulates ciliogenesis by phosphorylating CapZIP (an actin regulator) in cooperation with Dishevelled; Dishevelled facilitates ERK7 phosphorylation of CapZIP by binding both ERK7 and CapZIP; ERK7 knockdown abolishes the apical actin meshwork, inhibits basal body apical migration, and reduces cilium number and length in multiciliated cells. Xenopus embryo knockdown (morpholino), in vitro kinase assay showing direct phosphorylation of CapZIP by ERK7, co-immunoprecipitation (Dishevelled-ERK7-CapZIP), confocal imaging of cilia and actin Nature communications High 25823377
2015 MAPK15 physically recruits BCR-ABL1 to autophagic vesicles via its LIR domain interaction with LC3-family proteins; MAPK15 mediates BCR-ABL1-induced autophagy; depletion of endogenous MAPK15 inhibits BCR-ABL1-dependent cell proliferation in vitro and tumor formation in vivo. Co-immunoprecipitation, LIR mutant analysis, autophagy assays in HeLa and K562 cells, pharmacological MAPK15 inhibition, xenograft tumor formation assay Autophagy High 26291129
2015 MAPK15 in gastric cancer cells sustains c-Jun phosphorylation and increases c-Jun protein stability/half-life; MAPK15 knockdown reduces c-Jun phosphorylation and shortens c-Jun half-life; MAPK15 overexpression increases c-Jun phosphorylation. siRNA knockdown, transient overexpression, c-Jun phosphorylation immunoblot, c-Jun half-life pulse-chase analysis Oncotarget Medium 26035356
2016 ERK8 (MAPK15) phosphorylates HuR in response to H2O2; this phosphorylation prevents HuR from binding to the PDCD4 3'UTR, allowing miR-21-mediated degradation of PDCD4 mRNA, thereby downregulating the tumor suppressor PDCD4. Co-immunoprecipitation, in vitro kinase assay, RNA pulldown/RIP (HuR-PDCD4 3'UTR binding), miR-21 reporter assay, H2O2 treatment Oncotarget Medium 26595526
2016 MAPK15 protects germ cell tumor cells from DNA damage by sustaining autophagy; MAPK15-dependent autophagy is required for basal DNA damage management and for p53 suppression; depletion of MAPK15 triggers p53-dependent cell cycle arrest. siRNA knockdown, autophagy inhibition, DNA damage marker analysis (γH2AX), p53 activation assays, xenograft tumor formation Oncotarget Medium 26988910
2017 MAPK15 (SWIP-13 in C. elegans) acts presynaptically to regulate DAT (dopamine transporter) surface expression and DA clearance; SWIP-13/ERK8 activates Rho GTPases to control DAT surface availability, a mechanism conserved in human ERK8. Forward genetic screen in C. elegans, in vitro Rho GTPase activation assays, in vivo DAT surface expression measurements, epistasis with Rho pathway mutants The Journal of neuroscience High 28842414
2017 MAPK15 localizes to a basal body subdomain and regulates primary cilia formation in C. elegans sensory neurons and human cells; MAPK15 regulates localization of ciliary proteins involved in cilium structure, IFT transport, and signaling (including BBS7). Fluorescence localization (GFP fusions), C. elegans loss-of-function mutants, human cell knockdown, ciliary protein trafficking assays Genetics High 29021280
2017 MAPK-15 in C. elegans localizes to cilia and is required for PKD-2 (polycystin-2) localization in male ray neurons; a catalytic-site mutant causes ciliary defects (dye uptake, dendrite extension, male mating); MAPK15 expression is partially DAF-19/RFX-dependent. GFP transgenic localization, catalytic mutant analysis, dye-filling assay, male mating behavior assay, rescue experiments Cytoskeleton Medium 28745435
2018 MAPK15 is part of the ULK1 complex and stimulates AMPK-dependent ULK1 activity toward downstream substrates; MAPK15 directly interacts with the ULK1 complex and mediates ULK1 activation induced by nutrient starvation, establishing a MAPK15→ULK1→autophagosome biogenesis cascade. Co-immunoprecipitation (MAPK15-ULK1 complex), in vitro kinase assays (ULK1 substrate phosphorylation), starvation-induced autophagy assays, ULK2 redundancy analysis The Journal of biological chemistry High 30131341
2020 In Toxoplasma gondii, ERK7 is regulated by AC9 (apical cap protein 9): AC9 directly binds ERK7 through a conserved C-terminal motif, is required for ERK7 localization to the apical cap, and inhibits ERK7 activity by displacing nucleotide from the active site; ERK7 is required for apical complex (conoid) biogenesis and parasite invasion/egress. Proximity biotinylation (BioID), crystal structure of ERK7-AC9 complex, genetic depletion (conditional KO), yeast two-hybrid, co-immunoprecipitation Proceedings of the National Academy of Sciences of the United States of America High 32409604
2020 In Drosophila, ERK7 controls subcellular localization of the chromatin-binding protein PWP1 in the fat body; PWP1 maintains expression of sugarbabe (a lipogenic transcription factor); ERK7 acts as an anti-anabolic kinase inhibiting lipid storage and growth under nutrient deprivation. ERK7 loss-of-function and gain-of-function in Drosophila larvae, genetic epistasis (PWP1 and sugarbabe mutants), TAG measurement, growth rate analysis EMBO reports Medium 33369866
2021 In Toxoplasma, ERK7 depletion causes loss of the apical polar ring, disorganization of subpellicular microtubules, severe impairment of microneme secretion, and accumulation of microneme proteins; ERK7 depletion phenocopies AC9 and AC10 depletion, consistent with an ERK7-AC9-AC10 complex controlling apical complex integrity. Conditional knockdown (dTAG system), ultrastructure expansion microscopy (U-ExM), comparative proteomics, electron microscopy mBio High 34607461
2021 MAPK15 controls primary ciliogenesis and canonical Hedgehog (HH) signaling in NIH3T3 cells; in SHH-driven medulloblastoma cells, MAPK15 regulates cancer stem cell self-renewal (medullo-sphere formation) through a cilia-dependent mechanism; pharmacological inhibition of MAPK15 prevents proliferation of SHH-driven medulloblastoma cells. siRNA knockdown, pharmacological inhibition, HH pathway reporter assays, oncogenic SMO-M2/GLI2-DN epistasis, medullo-sphere assays Cancers Medium 34638386
2022 In Toxoplasma, AC9, AC10, and ERK7 form an essential trimeric complex with multivalent pairwise interactions; AC10 is a foundational scaffold; multiple independent interaction regions enable oligomerization that concentrates ERK7 at the apical cap cytoskeleton. Yeast two-hybrid, deletion analyses, conditional knockdown, proximity biotinylation, functional complementation mBio High 35130732
2022 MAPK15 prevents oxidative stress-induced cellular senescence by controlling mitophagy: MAPK15 stimulates ULK1-dependent PRKN (Parkin) Ser108 phosphorylation, promotes recruitment of damaged mitochondria to autophagosomes/lysosomes, and participates in mitochondrial network reorganization prior to disposal; loss of MAPK15 reduces mitochondrial respiration, increases mitochondrial ROS, and drives nuclear DNA damage-induced senescence in primary human airway epithelial cells. siRNA knockdown, MAPK15 KO/KD, mitophagy flux assays, PRKN phosphorylation immunoblot, mitochondrial function assays (respiration, ATP, ROS), senescence markers (SA-β-gal, γH2AX) Aging cell High 35642724
2023 In Toxoplasma, the ERK7 interactome includes a putative E3 ligase CSAR1 that is normally localized to the residual body and responsible for maternal cytoskeleton turnover during cytokinesis; CSAR1 genetic disruption fully suppresses loss of the apical complex upon ERK7 knockdown, establishing a protein homeostasis pathway where ERK7 protects the apical complex from CSAR1-mediated degradation. Proximity biotinylation (ERK7 interactome), conditional knockdown (dTAG), genetic suppressor screen (CSAR1 disruption), immunofluorescence microscopy The Journal of cell biology High 37027006
2023 MAPK15 interacts with NF-κB p50 subunit and enters the nucleus together; the MAPK15–NF-κB p50 complex binds the EP3 (prostaglandin E2 receptor) promoter and transcriptionally upregulates EP3 expression, promoting lung adenocarcinoma cell migration. Co-immunoprecipitation (MAPK15-p50), luciferase reporter assay (EP3 promoter), siRNA knockdown, nuclear fractionation, transwell migration assay, in vivo metastasis model Cancers Medium 36900191
2024 MAPK15 controls the transactivating potential of NRF2 by inducing NRF2 activating phosphorylation, increasing NRF2 expression and nuclear translocation upon oxidative stress; MAPK15 is necessary for NRF2-dependent antioxidant gene expression in response to cigarette smoke in lung epithelial cells. siRNA knockdown, NRF2 phosphorylation immunoblot, nuclear fractionation, NRF2 target gene expression analysis, cigarette smoke extract treatment Redox biology Medium 38555711
2025 CLIC3 (chloride intracellular channel 3) interacts with ERK7 (MAPK15) at the plasma membrane and represses ERK7 activity; CLIC3-ERK7 interaction promotes cellular senescence; knockdown of CLIC3 mitigates senescence by de-repressing ERK7. Co-immunoprecipitation (CLIC3-ERK7), membrane fractionation, siRNA knockdown, senescence assays (SA-β-gal, SASP markers), ERK7 kinase activity assays Communications biology Medium 39809890
2025 MAPK15 suppresses IFNB1 expression by preventing oxidative stress-dependent JNK-JUN pathway activation; MAPK15 downregulation increases ROS, activates JNK-JUN signaling, and upregulates IFNB1 and interferon-stimulated genes; the antioxidant NACET blocks MAPK15 loss-induced JUN activation and IFNB1 expression. MAPK15 siRNA knockdown, luciferase reporter assays (IFNB1 promoter), JNK pharmacological inhibitor, NACET antioxidant rescue, ELISA (IFNB1 secretion), gene expression analysis International journal of molecular sciences Medium 40507959
2026 MAPK15 knockout mice exhibit liver steatosis (MASLD-like phenotype) due to increased expression and membrane localization of the CD36 fatty acid translocase; MAPK15 overexpression opposes lipid accumulation in hepatocellular models; Mapk15-/- mice fed a western diet accelerate to steatohepatitis. Knockout mouse model (Mapk15-/-), CD36 expression and localization analysis, western diet feeding, hepatocellular in vitro models, transcriptomic analysis of human MASLD cohorts Hepatology communications High 41610145

Source papers

Stage 0 corpus · 52 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 Extracellular signal-regulated kinase 7 (ERK7), a novel ERK with a C-terminal domain that regulates its activity, its cellular localization, and cell growth. Molecular and cellular biology 126 9891064
2002 ERK8, a new member of the mitogen-activated protein kinase family. The Journal of biological chemistry 98 11875070
2012 MAPK15/ERK8 stimulates autophagy by interacting with LC3 and GABARAP proteins. Autophagy 93 22948227
2011 ERK7 is a negative regulator of protein secretion in response to amino-acid starvation by modulating Sec16 membrane association. The EMBO journal 89 21847093
2001 ERK7 is an autoactivated member of the MAPK family. The Journal of biological chemistry 68 11287416
2010 A chromatin-bound kinase, ERK8, protects genomic integrity by inhibiting HDM2-mediated degradation of the DNA clamp PCNA. The Journal of cell biology 55 20733054
2006 Characterization of the reversible phosphorylation and activation of ERK8. The Biochemical journal 53 16336213
2014 ERK8 is a negative regulator of O-GalNAc glycosylation and cell migration. eLife 52 24618899
2006 ERK8 down-regulates transactivation of the glucocorticoid receptor through Hic-5. The Journal of biological chemistry 44 16624805
2006 Activation of the Erk8 mitogen-activated protein (MAP) kinase by RET/PTC3, a constitutively active form of the RET proto-oncogene. The Journal of biological chemistry 43 16484222
2020 Ancient MAPK ERK7 is regulated by an unusual inhibitory scaffold required for Toxoplasma apical complex biogenesis. Proceedings of the National Academy of Sciences of the United States of America 42 32409604
2015 MAPK15 mediates BCR-ABL1-induced autophagy and regulates oncogene-dependent cell proliferation and tumor formation. Autophagy 42 26291129
2016 MAPK15 upregulation promotes cell proliferation and prevents DNA damage in male germ cell tumors. Oncotarget 39 26988910
2015 ERK7 regulates ciliogenesis by phosphorylating the actin regulator CapZIP in cooperation with Dishevelled. Nature communications 38 25823377
2010 Extracellular signal-regulated kinase 8 (ERK8) controls estrogen-related receptor α (ERRα) cellular localization and inhibits its transcriptional activity. The Journal of biological chemistry 38 21190936
2004 ERK7 expression and kinase activity is regulated by the ubiquitin-proteosome pathway. The Journal of biological chemistry 38 15033983
2022 MAPK15 protects from oxidative stress-dependent cellular senescence by inducing the mitophagic process. Aging cell 31 35642724
2009 Regulation of the activity and expression of ERK8 by DNA damage. FEBS letters 31 19166846
2015 Overexpression of MAPK15 in gastric cancer is associated with copy number gain and contributes to the stability of c-Jun. Oncotarget 29 26035356
2021 Revisiting the Role of Toxoplasma gondii ERK7 in the Maintenance and Stability of the Apical Complex. mBio 28 34607461
2018 Quantitative Proteomic Analysis Identifies MAPK15 as a Potential Regulator of Radioresistance in Nasopharyngeal Carcinoma Cells. Frontiers in oncology 26 30524968
2014 p53- and ERK7-dependent ribosome surveillance response regulates Drosophila insulin-like peptide secretion. PLoS genetics 24 25393288
2017 Primary Cilium Formation and Ciliary Protein Trafficking Is Regulated by the Atypical MAP Kinase MAPK15 in Caenorhabditis elegans and Human Cells. Genetics 23 29021280
2022 Multivalent Interactions Drive the Toxoplasma AC9:AC10:ERK7 Complex To Concentrate ERK7 in the Apical Cap. mBio 20 35130732
2021 MAPK15-ULK1 signaling regulates mitophagy of airway epithelial cell in chronic obstructive pulmonary disease. Free radical biology & medicine 20 34224814
2017 The Atypical MAP Kinase SWIP-13/ERK8 Regulates Dopamine Transporters through a Rho-Dependent Mechanism. The Journal of neuroscience : the official journal of the Society for Neuroscience 20 28842414
2016 ERK8 is a novel HuR kinase that regulates tumour suppressor PDCD4 through a miR-21 dependent mechanism. Oncotarget 20 26595526
2023 Toxoplasma ERK7 protects the apical complex from premature degradation. The Journal of cell biology 17 37027006
2018 MAPK15 is part of the ULK complex and controls its activity to regulate early phases of the autophagic process. The Journal of biological chemistry 16 30131341
2013 Structure prediction and validation of the ERK8 kinase domain. PloS one 13 23326322
2021 MAPK15 Controls Hedgehog Signaling in Medulloblastoma Cells by Regulating Primary Ciliogenesis. Cancers 11 34638386
2020 Coordinated control of adiposity and growth by anti-anabolic kinase ERK7. EMBO reports 10 33369866
2016 Discovery and antiparasitic activity of AZ960 as a Trypanosoma brucei ERK8 inhibitor. Bioorganic & medicinal chemistry 9 27519462
2023 The Atypical MAP Kinase MAPK15 Is Required for Lung Adenocarcinoma Metastasis via Its Interaction with NF-κB p50 Subunit and Transcriptional Regulation of Prostaglandin E2 Receptor EP3 Subtype. Cancers 8 36900191
2020 Metastasis-associated gene MAPK15 promotes the migration and invasion of osteosarcoma cells via the c-Jun/MMPs pathway. Oncology letters 8 32565938
2018 Identification and functional analysis of a stress-responsive MAPK15 in Entamoeba invadens. Molecular and biochemical parasitology 7 29730364
2017 MAPK-15 is a ciliary protein required for PKD-2 localization and male mating behavior in Caenorhabditis elegans. Cytoskeleton (Hoboken, N.J.) 7 28745435
2022 Genome-wide transcriptional profiling and functional analysis reveal miR-330-MAPK15 axis involving in cellular responses to deoxynivalenol exposure. Chemosphere 6 35278444
2022 Cellular and physiological roles of the conserved atypical MAP kinase ERK7. FEBS letters 6 36266944
2024 MAPK15 controls cellular responses to oxidative stress by regulating NRF2 activity and expression of its downstream target genes. Redox biology 5 38555711
2022 Transcriptional upregulation of MAPK15 by NF-κB signaling boosts the efficacy of combination therapy with cisplatin and TNF-α. iScience 5 36425765
2025 Chloride intracellular channel CLIC3 mediates fibroblast cellular senescence by interacting with ERK7. Communications biology 4 39809890
2013 The distribution and possible role of ERK8 in mouse oocyte meiotic maturation and early embryo cleavage. Microscopy and microanalysis : the official journal of Microscopy Society of America, Microbeam Analysis Society, Microscopical Society of Canada 4 23351492
2010 Ligand interaction scan (LIScan) in the study of ERK8. Biochemical and biophysical research communications 4 20638370
2020 IGF1R and MAPK15 Emerge as Potential Targets of Pentabromobenzylisothioureas in Lung Neuroendocrine Neoplasms. Pharmaceuticals (Basel, Switzerland) 3 33138224
2025 Estrogen-induced circFAM171A1 regulates sheep myoblast proliferation through the oar-miR-485-5p/MAPK15/MAPK pathway. Cellular and molecular life sciences : CMLS 2 40105989
2025 EGR1 inhibits clear cell renal cell carcinoma proliferation and metastasis via the MAPK15 pathway. Oncology research 1 39866235
2026 MAPK15 controls intracellular lipid uptake and protects mammalian liver from steatotic disease. Hepatology communications 0 41610145
2025 MAPK15 Prevents IFNB1 Expression by Suppressing Oxidative Stress-Dependent Activation of the JNK-JUN Pathway. International journal of molecular sciences 0 40507959
2025 PFOA exposure promotes prostate cancer progression by enhancing autophagy through m6A modification of MAPK15 mRNA. Ecotoxicology and environmental safety 0 40784096
2025 Molecular docking to homology models of human and Trypanosoma brucei ERK8 that identified ortholog-specific inhibitors. PLoS neglected tropical diseases 0 40938944
2022 MAPK15 controls mitochondrial fitness and contributes to prevent cellular senescence. Autophagy reports 0 40396004