Affinage

MAPK6

Mitogen-activated protein kinase 6 · UniProt Q16659

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

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ERK3 (MAPK6) is an atypical MAP kinase that functions as a signaling hub integrating upstream activation by group I PAKs and multiple stability-regulating mechanisms to control diverse cellular processes including cell migration, lipolysis, myogenic differentiation, cytokinesis, and immune cell function. PAK1/2/3 phosphorylate ERK3 on its activation-loop residue Ser189, which is required for intrinsic catalytic activity and formation of stable cytoplasmic complexes with its primary substrate MK5/PRAK via a C-terminal FRIEDE docking motif; the ERK3–MK5 module signals through FOXO1/ATGL to drive adipocyte lipolysis, through FoxO3 to restrain myogenic differentiation, and through septin 7/Borg proteins to shape neuronal dendrites (PMID:21177870, PMID:15577943, PMID:19473979, PMID:32139423, PMID:35141958, PMID:22508986). Beyond MK5, ERK3 directly phosphorylates SRC-3 (promoting pro-invasive MMP expression), TDP2 (modulating DNA repair), AKT at Ser473 (bypassing mTORC2), supervillin (regulating cytokinesis), and ARP3 of the ARP2/3 complex, and additionally acts as a guanine nucleotide exchange factor for CDC42 to drive actin polymerization (PMID:22505454, PMID:26701725, PMID:34767444, PMID:36576983, PMID:37057894). ERK3 protein stability is tightly regulated: Cdk1-mediated C-terminal phosphorylation stabilizes ERK3 during mitosis, EGLN3-catalyzed hydroxylation protects it from chaperone-mediated autophagy, while FBXW7- and TRIM21-mediated ubiquitination and intracellular pH sensing promote its degradation (PMID:20236090, PMID:35124697, PMID:35022544, PMID:39763069, PMID:41123996).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1994 Medium

    Identification of ERK3 as a novel MAP kinase family member with kinase activity toward generic substrates established that this gene encodes a functional protein kinase responsive to mitogens.

    Evidence cDNA cloning and immune complex kinase assay in human fibroblasts

    PMID:7969157

    Open questions at the time
    • Physiological substrates unknown
    • Upstream activating kinase unidentified
    • Relationship to classical ERK pathway unclear
  2. 1996 High

    Demonstration that ERK3 is constitutively nuclear, autophosphorylates Ser189, and is phosphorylated at Ser189 by a novel cellular kinase distinct from MEKs resolved that ERK3 is not activated through the canonical MEK pathway and introduced the activation-loop phosphorylation site as the key regulatory modification.

    Evidence In vitro kinase assays with site-directed mutagenesis, immunofluorescence, biochemical purification of the Ser189 kinase

    PMID:8621539 PMID:8662649

    Open questions at the time
    • Identity of the upstream Ser189 kinase unknown
    • No physiological substrate identified
  3. 2003 High

    Discovery that ERK3 undergoes CRM1-dependent nuclear export and that compartmentalization modulates its ability to induce cell cycle arrest established that nucleocytoplasmic shuttling is a key regulatory feature of ERK3 biology.

    Evidence Leptomycin B treatment, CRM1 overexpression, GST pulldown for CRM1–ERK3 binding, cell cycle analysis

    PMID:12915405

    Open questions at the time
    • Signals controlling nuclear export timing unknown
    • Mechanism linking compartmentalization to cell cycle arrest undefined
  4. 2004 High

    Identification of MK5/PRAK as the first physiological substrate and stabilizing chaperone of ERK3, with reciprocal nuclear-cytoplasmic redistribution upon complex formation, defined the core ERK3–MK5 signaling module and explained why MK5 knockout leads to ERK3 destabilization and embryonic lethality.

    Evidence Reciprocal co-IP, in vitro kinase assay, ERK3−/− fibroblasts, MK5 knockout mice with embryonic lethality

    PMID:15538386 PMID:15577943

    Open questions at the time
    • Downstream targets of the ERK3–MK5 module unknown
    • Structural basis of ERK3–MK5 interaction unresolved
  5. 2009 High

    Mapping the FRIEDE docking motif in ERK3's L16 extension as the essential determinant for MK5 binding and activation, along with the requirement for activation-loop phosphorylation, defined the molecular rules governing ERK3–MK5 complex assembly.

    Evidence Peptide overlay assays, site-directed mutagenesis (I-to-K in FRIEDE), co-IP, MK5 translocation assay

    PMID:19473979

    Open questions at the time
    • No crystal structure of the ERK3–MK5 complex
    • Whether other kinases use the FRIEDE motif unknown
  6. 2009 High

    Targeted disruption of Mapk6 in mice revealed its essential role in fetal growth and lung maturation, establishing a non-redundant in vivo requirement for ERK3 in type II pneumocyte differentiation.

    Evidence Erk3 gene knockout mice with neonatal lethality, histology, glucocorticoid rescue, IGF-2 measurements

    PMID:19805361

    Open questions at the time
    • Direct phosphorylation target mediating lung phenotype unknown
    • Whether MK5 pathway mediates lung maturation untested
  7. 2010 High

    Identification of group I PAKs (PAK1/2/3) as the long-sought upstream kinases for ERK3 Ser189 phosphorylation, downstream of Rac1, completed the linear PAK→ERK3→MK5 signaling cascade.

    Evidence Biochemical purification, in vitro kinase assay, PAK1/2/3 RNAi, activated Rac1 expression, MK5 activity readout

    PMID:21177870 PMID:21317288

    Open questions at the time
    • Whether additional kinases contribute to Ser189 phosphorylation in specific tissues
    • Regulation of PAK→ERK3 pathway by extracellular signals incompletely mapped
  8. 2010 High

    Discovery that Cdk1 phosphorylates ERK3's C-terminal extension during mitosis to stabilize the protein, reversed by Cdc14A/B at mitotic exit, revealed cell-cycle-dependent regulation of ERK3 abundance.

    Evidence Mass spectrometry, in vitro kinase assay with cyclin B–Cdk1, alanine mutagenesis, pulse-chase stability

    PMID:18235225 PMID:20236090

    Open questions at the time
    • How mitotic stabilization of ERK3 feeds back to cell division machinery unclear
    • Whether Cdk1 phosphorylation affects ERK3 kinase activity directly untested
  9. 2012 High

    Identification of SRC-3 Ser857 phosphorylation by ERK3 as a driver of PEA3-dependent MMP expression and lung cancer invasion, and of the ERK3/MK5/septin 7 ternary complex in dendrite morphogenesis, expanded ERK3's functional repertoire beyond MK5 to direct substrate phosphorylation and neuronal development.

    Evidence In vitro kinase assay with S857 mutagenesis, xenograft model; ternary complex Co-IP, MK5 KO neuronal phenotype

    PMID:22505454 PMID:22508986

    Open questions at the time
    • Whether ERK3 and SRC-3 form a stable complex in non-cancer cells unknown
    • Borg/septin phosphorylation sites by ERK3/MK5 not fully mapped
  10. 2016 High

    Demonstration that ERK3 phosphorylates TDP2 at Ser60 to regulate its phosphodiesterase activity linked ERK3 to the DNA damage response and chemoresistance.

    Evidence In vitro kinase assay, S60 mutagenesis, TDP2 enzymatic activity measurement, siRNA, cell viability

    PMID:26701725

    Open questions at the time
    • Upstream signals activating ERK3-TDP2 axis during DNA damage not defined
    • Relevance in non-lung cancer contexts untested
  11. 2017 High

    Identification of DUSP2 as a direct phosphatase for ERK3/ERK4 activation-loop phosphorylation provided the first defined inactivation mechanism, completing the activation–inactivation cycle of ERK3.

    Evidence In vitro phosphatase assay, KIM/CD domain mapping, MK5 activity inhibition

    PMID:28252035

    Open questions at the time
    • Whether other DUSPs contribute to ERK3 inactivation in specific tissues
    • Regulation of DUSP2 expression in ERK3-active contexts not addressed
  12. 2020 High

    The ERK3–MK5–FOXO1–ATGL pathway was established as a central regulator of β-adrenergic-stimulated lipolysis in adipocytes, and crystal structures of the ERK3 kinase domain revealed its distinct ATP-binding pocket, together advancing both physiological understanding and pharmacological targeting.

    Evidence Adipocyte-specific ERK3 KO mice with lean phenotype, FOXO1/ATGL epistasis; X-ray crystallography of ERK3 kinase domain and inhibitor co-crystals

    PMID:32139423 PMID:32927028 PMID:33114754

    Open questions at the time
    • Whether ERK3 directly phosphorylates FOXO1 or acts only via MK5 not resolved
    • No structure of full-length ERK3 or ERK3–MK5 complex
  13. 2021 High

    Discovery that ERK3 directly phosphorylates AKT at Ser473 independently of mTORC2 revealed a previously unsuspected non-canonical AKT activation mechanism with implications for mTOR inhibitor resistance.

    Evidence In vitro kinase assay, domain mapping, mTOR inhibitor resistance phenotype

    PMID:34767444

    Open questions at the time
    • Physiological contexts where ERK3–AKT signaling predominates over mTORC2 not defined
    • Whether ERK3 also phosphorylates AKT at Thr308 untested
  14. 2022 High

    Multiple protein stability mechanisms were elucidated: EGLN3 hydroxylation protects ERK3 from CMA-lysosomal degradation, FBXW7-mediated ubiquitination targets ERK3 for proteasomal destruction via Thr417/Thr421, and ERK3/MK5 controls myogenic differentiation through FoxO3 and cytokinesis through supervillin Ser245 phosphorylation.

    Evidence EGLN3 hydroxylation assay and catalytic knock-in mice; FBXW7 ubiquitination assay with T417A/T421A mutagenesis; Mapk6-catalytic-dead knock-in mice with myoblast phenotype and FoxO3 rescue; phosphoproteomics identifying SVIL S245 with in vitro kinase assay and cytokinesis rescue

    PMID:35022544 PMID:35124697 PMID:35141958 PMID:36576983

    Open questions at the time
    • How multiple E3 ligases and stability mechanisms are coordinated in a single cell
    • Structural basis of EGLN3-ERK3 interaction unknown
    • Whether supervillin phosphorylation requires ERK3–MK5 or is MK5-independent
  15. 2023 High

    ERK3 was shown to possess guanine nucleotide exchange factor activity for CDC42 and to directly phosphorylate ARP3 at Ser418, establishing a kinase-independent (GEF) and kinase-dependent dual mechanism for actin cytoskeleton remodeling.

    Evidence In vitro GEF assay with purified proteins, in vitro actin polymerization assay with purified ARP2/3, filopodia quantification

    PMID:37057894

    Open questions at the time
    • Structural basis for ERK3 GEF activity toward CDC42 unknown
    • Whether GEF and kinase activities are coordinated or separable in vivo
  16. 2025 Medium

    Intracellular pH was identified as a novel regulator of ERK3 stability via C-terminal pH-sensing motifs, and TRIM21 was identified as an additional E3 ligase targeting ERK3 in endothelial cells under disturbed shear stress, expanding the repertoire of stability-controlling inputs.

    Evidence pH manipulation with pulse-chase and proteomics; TRIM21-MAPK6 Co-IP with endothelial conditional KO in ApoE−/− mice

    PMID:39763069 PMID:41123996

    Open questions at the time
    • pH-sensing residues not identified at single-amino-acid resolution
    • TRIM21-mediated regulation not confirmed outside endothelial context
    • Integration of pH sensing with FBXW7/CMA pathways untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include the structural basis of ERK3's dual GEF/kinase activities, how multiple stability-controlling mechanisms (FBXW7, TRIM21, EGLN3, CMA, Cdk1, pH) are integrated in different tissues, and whether ERK3's kinase-independent scaffolding functions (Snail stabilization, CDC42 GEF activity) operate through a common structural mechanism.
  • No full-length ERK3 structure or ERK3–MK5 complex structure available
  • Tissue-specific hierarchy of stability mechanisms unresolved
  • Structural basis of GEF activity for CDC42 unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 8 GO:0016740 transferase activity 5 GO:0098772 molecular function regulator activity 2
Localization
GO:0005829 cytosol 3 GO:0005634 nucleus 2 GO:0005856 cytoskeleton 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1640170 Cell Cycle 3 R-HSA-1266738 Developmental Biology 2 R-HSA-168256 Immune System 2 R-HSA-392499 Metabolism of proteins 2 R-HSA-1430728 Metabolism 1
Partners
DUSP2EGLN3FBXW7MAPKAPK5PAK1PAK2PAK3SRC-3
Complex memberships
ERK3–MK5 complexERK3–MK5–septin 7 ternary complex

Evidence

Reading pass · 43 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 ERK3 specifically interacts with MK5/PRAK, and this binding results in nuclear exclusion of both ERK3 and MK5, accompanied by ERK3-dependent phosphorylation and activation of MK5 in vitro and in vivo. MK5 is the first identified physiological substrate of ERK3, and MK5 acts as a chaperone stabilizing ERK3 protein levels. Co-immunoprecipitation, in vitro kinase assay, siRNA knockdown, ERK3-/- mouse fibroblasts, PC12 cell NGF differentiation The EMBO journal High 15577943
2004 ERK3 specifically interacts with MK5 in vitro and in vivo; ERK3 expression causes nuclear-cytoplasmic translocation and activation of MK5 independent of ERK3 enzymatic activity, but dependent on a region in ERK3's C-terminal extension. Deletion of MK5 leads to strong reduction of ERK3 protein levels and embryonic lethality ~E11. Co-immunoprecipitation, kinase-dead ERK3 mutants, MK5 knockout mice, embryonic expression analysis The EMBO journal High 15538386
1996 ERK3 is constitutively localized in the nucleus in exponentially growing, quiescent, and growth factor-stimulated cells; the C-terminal 180 amino acid extension is not required for nuclear localization. ERK3 autophosphorylates on Ser189 (corresponding to the activating Thr183 of ERK2), and mutation of the catalytic Asp171 eliminates autophosphorylation. ERK3 does not phosphorylate typical MAP kinase substrates. Immunoblotting, immunofluorescence, in vitro kinase assay with recombinant protein, site-directed mutagenesis The Journal of biological chemistry High 8621539
2003 ERK3 is exported from the nucleus via a CRM1-dependent mechanism; treatment with leptomycin B causes nuclear accumulation, CRM1 overexpression promotes cytoplasmic relocalization, CRM1 binds ERK3 in vitro, and enforced localization in either compartment attenuates ERK3's ability to induce cell cycle arrest in fibroblasts. Leptomycin B treatment, CRM1 overexpression, snurportin-1 overexpression, GST pulldown (CRM1-ERK3 in vitro binding), cell cycle analysis The Journal of biological chemistry High 12915405
2008 Activation loop phosphorylation on Ser189 (ERK3) is exerted in trans by an upstream cellular kinase and stimulates ERK3 intrinsic catalytic activity; this phosphorylation is required for formation of stable active complexes with MK5 and for efficient cytoplasmic redistribution of ERK3-MK5 complexes. Interaction with MK5 can modulate activation loop phosphorylation indirectly. Phospho-specific antibodies, in vitro kinase assay, co-immunoprecipitation, cytoplasmic redistribution assay, S189A/S186A mutants Journal of cellular physiology High 18720373
2010 Group I p21-activated kinases (PAK1/2/3) directly phosphorylate ERK3 on Ser189 both in vitro and in vivo, constituting an upstream activating kinase for ERK3. Activated Rac1 augments this response; silencing PAK1/2/3 abolishes Rac1-induced Ser189 phosphorylation of ERK3. PAK-mediated phosphorylation results in ERK3 enzymatic activation and downstream activation of MK5, defining a PAK-ERK3/ERK4-MK5 signaling pathway. Biochemical kinase activity purification, in vitro kinase assay, phospho-specific antibodies, RNAi knockdown of PAK1/2/3, activated Rac1 expression, MK5 activity assay The Journal of biological chemistry High 21177870
2011 PAK2 directly phosphorylates ERK3 on Ser189 within its activation loop in vitro; selective inhibition of class I PAK kinase activity in cells promotes nuclear accumulation of ERK3, reduces Ser189 phosphorylation, and inhibits ERK3-PRAK complex formation. Protein microarray screen, in vitro kinase assay with recombinant ERK3, phospho-specific antisera, PAK inhibitor treatment, co-immunoprecipitation The Journal of biological chemistry High 21317288
2009 ERK3 and ERK4 bind MK5 through a novel FRIEDE interaction motif within the L16 extension lying C-terminal to the CD domain; a single isoleucine-to-lysine substitution in FRIEDE abrogates binding, activation, and translocation of MK5. The CD domain is dispensable for ERK3/4-MK5 interaction, and activation loop phosphorylation (SEG motif) is required for MK5 binding. Peptide overlay assays, site-directed mutagenesis, co-immunoprecipitation, MK5 translocation assay The Journal of biological chemistry High 19473979
2012 ERK3/MK5/Sept7 form a ternary complex; ERK3/MK5 can phosphorylate Sept7 regulators (Borgs). Kalirin-7 (Kal7) is an MK5 interaction partner and substrate. The ERK3/MK5 signaling module regulates septin-dependent dendrite development and spine formation in hippocampal neurons. Large-scale interaction screens (MK5 KO mouse model), co-immunoprecipitation, in vitro phosphorylation, transfected primary neurons, MK5 knockout mice Molecular and cellular biology High 22508986
2012 ERK3 interacts with and phosphorylates SRC-3 at Ser857; this phosphorylation is essential for SRC-3 interaction with ETS transcription factor PEA3, which promotes MMP gene expression and proinvasive activity in lung cancer cells. Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis (S857), siRNA knockdown, xenograft mouse model The Journal of clinical investigation High 22505454
2009 Targeted disruption of Mapk6 (encoding Erk3) in mice leads to intrauterine growth restriction, pulmonary hypoplasia, defective type II pneumocyte differentiation, and neonatal lethality; IGF-2 levels are decreased in serum of Erk3-deficient mice. Erk3 gene knockout mice, histological analysis, type II pneumocyte differentiation assay, glucocorticoid rescue, IGF-2 serum measurements Proceedings of the National Academy of Sciences of the United States of America High 19805361
1996 A novel protein kinase (not MEK1/2) in nuclear and cytosolic extracts phosphorylates ERK3 specifically at Ser189; this kinase is inactivated by PP2A and does not phosphorylate ERK2 or ERK2 mutants, distinguishing it from MEKs. Biochemical purification, in vitro kinase assay, phospho-specific identification, PP2A treatment, ERK3/ERK2 chimeric mutants The Journal of biological chemistry High 8662649
2010 ERK3 is hyperphosphorylated during mitosis at Ser684, Ser688, Thr698, and Ser705 in its C-terminal extension by cyclin B-Cdk1; phosphatases Cdc14A and Cdc14B bind ERK3 and reverse C-terminal phosphorylation at mitotic exit. Alanine substitution of these four sites markedly decreases ERK3 half-life in mitosis, linking Cdk1-mediated phosphorylation to ERK3 stabilization. Mass spectrometry identification of phosphorylation sites, in vitro kinase assay with purified cyclin B-Cdk1, Cdc14A/B binding assay, alanine substitution mutagenesis, pulse-chase stability assay The Biochemical journal High 20236090
2007 Human Cdc14A phosphatase directly binds ERK3 via ERK3's unique C-terminal domain (confirmed by GST pulldown); Cdc14A can remove Cdk-mediated phosphorylation from ERK3 in vitro. Cdc14A upregulation leads to redistribution of the ERK3 substrate MK5 from nucleus to cytoplasm and stabilizes ERK3-cyclin D3 complex formation. Yeast two-hybrid screen, GST pulldown, in vitro phosphatase assay, co-immunoprecipitation in human cells, MK5 redistribution assay Cell cycle (Georgetown, Tex.) High 18235225
2017 The dual-specificity phosphatase DUSP2 binds both ERK3 and ERK4 via a KIM (kinase interaction motif) in DUSP2 and the CD domain in ERK3/4; this interaction is direct, results in dephosphorylation of ERK3/4 activation loop, stabilizes DUSP2, and inhibits ERK3/4-mediated activation of MK5. Co-immunoprecipitation, in vitro phosphatase assay, domain mapping, MK5 activity assay Scientific reports High 28252035
2016 ERK3 phosphorylates TDP2 (tyrosyl DNA phosphodiesterase 2) at Ser60 and regulates TDP2's phosphodiesterase activity, thereby protecting lung cancer cells against Topoisomerase 2 inhibitor-induced DNA damage and growth inhibition. In vitro kinase assay, site-directed mutagenesis (S60), TDP2 phosphodiesterase activity assay, siRNA knockdown, cell viability assay Oncotarget High 26701725
2020 β-adrenergic stimulation stabilizes ERK3 protein, leading to ERK3/MK5 complex formation, which drives lipolysis in adipocytes. Mechanistically, ERK3/MK5 activates transcription factor FOXO1, which promotes expression of the major lipolytic enzyme ATGL. Adipocyte-specific deletion of ERK3 inhibits lipolysis but elevates energy dissipation, promoting a lean phenotype and ameliorating diabetes. High-throughput kinase screen, co-immunoprecipitation, ERK3 adipocyte-specific knockout mice, FOXO1/ATGL pathway analysis, metabolic phenotyping Genes & development High 32139423
2020 ERK3 is necessary for AP-1 signaling through interaction with and regulation of c-Jun protein, controlling production of IL-8 and other secreted factors; the secretome of ERK3-deficient cells is defective in chemotaxis of neutrophils and monocytes both in vitro and in vivo. 3D organoids, ERK3 knockout/knockdown, secretome analysis, IL-8 ELISA, in vitro and in vivo chemotaxis assay, co-immunoprecipitation (ERK3-c-Jun) eLife High 32314963
2023 ERK3 directly acts as a guanine nucleotide exchange factor for CDC42 and phosphorylates ARP3 subunit of the ARP2/3 complex at Ser418 to promote filopodia formation and actin polymerization. ERK3 also bound directly to purified ARP2/3 complex and augmented actin polymerization in vitro; depletion of ERK3 prevented basal and EGF-dependent RAC1 and CDC42 activation. In vitro GEF assay, in vitro actin polymerization assay, in vitro binding to purified ARP2/3, phospho-specific identification, ERK3 depletion with RAC1/CDC42 activation assay, filopodia formation assay eLife High 37057894
2021 MAPK6 directly activates AKT by phosphorylating it at Ser473 independent of mTORC2; MAPK6 interacts with AKT through its C34 region and C-terminal tail. MAPK6 expression correlates with AKT S473 phosphorylation in human cancer tissues. Co-immunoprecipitation, in vitro kinase assay, domain mapping, mTOR kinase inhibitor resistance assay, cancer cell growth assay Science advances High 34767444
2022 ERK3 interacts with HSC70 and LAMP2A (core components of chaperone-mediated autophagy/CMA); ERK3 is degraded by the CMA-lysosome pathway. EGLN3-catalyzed hydroxylation of ERK3 antagonizes CMA-dependent destruction by blunting the interaction of ERK3 with LAMP2A, thereby blocking lysosomal decay. Co-immunoprecipitation (ERK3-HSC70, ERK3-LAMP2A), EGLN3 hydroxylation assay, lysosomal degradation assay, EGLN3 catalytic knock-in mice Oncogene High 35124697
2022 FBXW7 acts as an E3 ubiquitin ligase for ERK3; ERK3 binds to FBXW7 via its C34D domain at Thr417 and Thr421 and the WD40 domain of FBXW7. SCF-FBXW7 complex formation destabilizes ERK3 via ubiquitination-mediated proteasomal degradation; T417A/T421A double mutant abolishes FBXW7-mediated ubiquitination. ERK3 knockdown inhibits lung cancer cell proliferation by regulating G1/S transition. Mammalian two-hybrid assay, co-immunoprecipitation, ubiquitination assay, domain mapping mutagenesis, ERK3 knockdown cell cycle analysis Experimental & molecular medicine High 35022544
2022 ERK3 and MK5 form a linear signaling pathway that controls postnatal myogenic differentiation by phosphorylating FoxO3, promoting FoxO3 degradation and reducing its association with MyoD; loss of ERK3 kinase activity or MK5 induces precocious myoblast differentiation that is partially rescued by FoxO3 depletion. Mapk6KD/KD (catalytic-dead knock-in) mice, MK5 knockout mice, C2C12 myoblast differentiation assay, in vitro MK5 phosphorylation of FoxO3, co-immunoprecipitation (FoxO3-MyoD), rescue by FoxO3 shRNA Journal of cellular physiology High 35141958
2022 ERK3 phosphorylates supervillin (SVIL) on Ser245 to regulate myosin II activation and cytokinesis completion in dividing cells; depletion of SVIL or ERK3 leads to increased cytokinesis failure and multinucleation, rescued by wild type SVIL but not non-phosphorylatable S245A mutant. Quantitative phosphoproteomics, in vitro kinase assay, site-directed mutagenesis (S245A), siRNA knockdown, multinucleation/cytokinesis assay Journal of cellular physiology High 36576983
2020 Crystal structure of the ERK3 kinase domain reveals a distinct ATP binding pocket compared to classical MAPK ERK2, explaining differences in inhibitor binding properties; medium-scale screening identified several inhibitors with sub-100 nM potencies. X-ray crystallography (crystal structure of ERK3 kinase domain), small molecule screening, biochemical kinase inhibition assay International journal of molecular sciences High 33114754
2020 Crystal structures of ERK3 in complex with triazolo[4,5-d]pyrimidin-5-amine inhibitors revealed type-I ATP-pocket binding mode affecting A-loop, GC-loop and αC-helix conformations, suggesting a structural link toward MK5 interaction via the FHIEDE motif. X-ray crystallography (ERK3-inhibitor co-crystal structures), biochemical ERK3 kinase assay using MK5 as substrate, cellular NanoBRET assay Bioorganic & medicinal chemistry letters High 32927028
2001 The C-terminal halves of ERK2 and ERK3 catalytic domain are primarily responsible for their different subcellular localizations in resting cells; the N-terminal folding domain of ERK2 is required for its activation by MEK1 and accumulation in the nucleus, while ERK3's N-terminal domain functions in phosphoryl transfer with ERK2's C-terminal domain in chimera experiments. ERK2/ERK3 chimeric protein expression, subcellular fractionation/immunofluorescence, co-expression with MEK1, in vitro kinase assay The Journal of biological chemistry Medium 11741894
1994 Human p97MAPK (ERK3 homolog) has kinase activity toward myelin basic protein and histone H1 in immune complex assays; treatment with serum or phorbol esters activates this kinase activity in human fibroblasts. cDNA cloning, in vitro transcription-translation, immune complex kinase assay, Western blotting Molecular and cellular biology Medium 7969157
1996 Increased expression of PKCβ1 or PKCβ2 leads to >10-fold constitutive activation of ERK3 kinase activity without changing ERK3 protein levels; phorbol ester treatment down-regulates both PKC and ERK3 activities, establishing a causal link. ERK3 activity is found in nuclear and membrane fractions in PKCβ transfectants. Stable transfection, in-gel kinase assay, immune complex kinase assay, immunoprecipitation, phorbol ester treatment The Journal of biological chemistry Medium 8626698
2015 ERK3 overexpression reduces cell spread area and increases migration speed of MDA-MB-231 breast cancer cells; a kinase-inactive ERK3 mutant phenocopies wild-type overexpression, suggesting a kinase-independent function. Endogenous ERK3 localizes at the cell periphery during adhesion to collagen I. ERK3 overexpression/depletion, kinase-dead ERK3 mutant, live-cell imaging, morphology quantification, migration speed measurement, collagen adhesion assay Cell adhesion & migration Medium 26588708
2006 ERK3 associates with MAP2 (microtubule associated protein 2) in pancreatic beta cells; PMA-induced ERK3 phosphorylation is accompanied by increased ERK3/MAP2 association and MAP2 phosphorylation. Antisense knockdown of ERK3 abolishes glucose-stimulated insulin secretion in rat islets. Co-immunoprecipitation (ERK3-MAP2), antisense oligonucleotide knockdown, insulin secretion assay, immunohistochemistry Molecular and cellular endocrinology Medium 16597486
2014 ERK3 promotes endothelial cell migration, proliferation, and tube formation by upregulating SRC-3/SP1-mediated VEGFR2 expression; ERK3 stimulates formation of a transcriptional complex involving SRC-3, SP-1, and CBP. ERK3 gene expression is regulated by c-Jun binding to the ERK3 gene promoter. siRNA knockdown, endothelial cell functional assays (migration, proliferation, tube formation), co-immunoprecipitation (SRC-3/SP-1/CBP complex), ChIP assay (c-Jun at ERK3 promoter) Journal of cellular physiology Medium 24585635
2010 ERK3 localizes to spindles from pre-MI to MII stages in mouse oocytes, co-localizing with α-tubulin; ERK3 knockdown by morpholino results in MI arrest with impaired spindles, misaligned chromosomes, persistent BubR1 on kinetochores, disrupted kinetochore-microtubule attachments, and failure of homologous chromosome segregation. Immunofluorescence, ERK3 morpholino microinjection, spindle assembly checkpoint analysis (BubR1), low-temperature kinetochore-microtubule attachment assay, chromosome spreading PloS one Medium 20927325
2023 ERK3 interacts with diacylglycerol kinase ζ (DGKζ) through ERK3's C34 domain (ERK3 binding to N-terminal and C1 domains of DGKζ); co-overexpression of DGKζ completely blocks ERK3-promoted lung cancer cell migration, identifying DGKζ as a negative regulator of ERK3-mediated cell motility. Yeast two-hybrid, co-immunoprecipitation, in vitro binding assay, domain mapping, co-localization, cell migration assay Frontiers in cell and developmental biology Medium 37287450
2023 ERK3 interacts with Snail and enhances its protein stability by inhibiting the binding of FBXO11 (an E3 ubiquitin ligase) to Snail, thereby preventing Snail ubiquitination and degradation; ERK3 does not directly phosphorylate Snail. Co-immunoprecipitation, ubiquitination assay, ERK3 kinase assay (showing no direct phosphorylation of Snail), Snail stability assay Cancers Medium 38201533
2025 Intracellular pH regulates ERK3 stability: acidification increases ERK3 half-life and alkalinization accelerates its degradation via ubiquitin-mediated pathways; pH-sensing motifs are located in the C-terminus of ERK3. pH manipulation (acidification/alkalinization), pulse-chase stability assay, quantitative proteomics, C-terminal domain mapping Proceedings of the National Academy of Sciences of the United States of America Medium 41123996
2022 Rab31 interacts with MAPK6 and inhibits its degradation; Rab31 knockdown promotes MAPK6 degradation and reduces migration/invasion of cervical cancer cells, while MAPK6 overexpression restores the decreased migration caused by Rab31 knockdown. Co-immunoprecipitation (Rab31-MAPK6), protein degradation assay, siRNA knockdown, xenograft mouse model International journal of biological sciences Medium 34975321
1996 ERK3 specifically co-elutes with B-Raf (but not c-Raf1) in rat hippocampal lysates by ion exchange chromatography; ERK3 is released from B-Raf immunoprecipitate after ATP incubation, suggesting a specific ERK3-B-Raf association. QMA anion exchange chromatography fractionation, B-Raf and c-Raf immunoprecipitation, ATP-dependent release assay Biochemical and biophysical research communications Low 8954940
2018 ERK3 activation loop phosphorylation (Ser189) is important for kinase activity toward SRC-3; S189A mutation greatly decreases ERK3 kinase activity toward SRC-3 and reduces the ability to stimulate MMP expression and promote lung cancer cell migration and invasion. A catalytically inactive ERK3 mutant still partially promotes invasion, indicating both kinase-dependent and kinase-independent mechanisms. S189A mutagenesis, in vitro kinase assay (SRC-3 substrate), MMP expression (Western blot), migration/invasion assay The Journal of biological chemistry High 30166347
2020 The C-terminus tail of ERK3 is required for full kinase activity toward SRC-3 and for interaction with septin 7; depletion of septin 7 abolishes ERK3-promoted migration, establishing septin 7 as a downstream effector for ERK3-induced cancer cell migration. C-terminus deletion mutants, in vitro kinase assay (SRC-3 substrate), co-immunoprecipitation (ERK3-septin7), siRNA depletion of septin7, migration assay International journal of molecular sciences Medium 32516969
2025 TRIM21 ubiquitin ligase binds MAPK6 and promotes its proteasomal degradation in endothelial cells in response to disturbed shear stress (DSS); endothelial MAPK6 overexpression exerts antiatherosclerotic effects in ApoE-/- mice and regulates endothelial inflammation through the EGR1/CXCL12 axis. Co-immunoprecipitation (TRIM21-MAPK6), RNA-seq, proteomic analysis, AAV-MAPK6 delivery, ApoE-/-MAPK6flox/floxTEKCre conditional KO mice, CXCL12 neutralization Clinical and translational medicine Medium 39763069
2017 BMI1 upregulates ERK3 expression by suppressing the tumor suppressive microRNA let-7i, which directly targets ERK3 mRNA; ERK3 acts as an important downstream mediator of BMI1 in promoting head and neck cancer cell migration. BMI1 overexpression/knockdown, let-7i mimic/inhibitor, luciferase reporter assay (let-7i targeting ERK3 3'UTR), migration assay, ERK3 rescue experiment Molecular oncology Medium 28079973
2014 ERK3-deficient T cells have decreased proliferation and impaired cytokine secretion following TCR stimulation; ERK3 expression in T cells is induced by TCR-activated ERK1/2 signaling, and ERK3 protein associates with MK5 in activated primary T cells. ERK3-deficient mouse T cells, in vitro TCR stimulation, proliferation assay, cytokine measurement, co-immunoprecipitation (ERK3-MK5), ERK1/2 inhibitor PloS one Medium 24475167

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Activation of MK5/PRAK by the atypical MAP kinase ERK3 defines a novel signal transduction pathway. The EMBO journal 115 15577943
2012 ERK3 signals through SRC-3 coactivator to promote human lung cancer cell invasion. The Journal of clinical investigation 106 22505454
2004 Scaffolding by ERK3 regulates MK5 in development. The EMBO journal 102 15538386
1996 ERK3 is a constitutively nuclear protein kinase. The Journal of biological chemistry 86 8621539
2019 MicroRNA-374a protects against myocardial ischemia-reperfusion injury in mice by targeting the MAPK6 pathway. Life sciences 73 31265855
2018 NEAT1/hsa-mir-98-5p/MAPK6 axis is involved in non-small-cell lung cancer development. Journal of cellular biochemistry 69 29095526
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2017 Metformin potentiates the effect of arsenic trioxide suppressing intrahepatic cholangiocarcinoma: roles of p38 MAPK, ERK3, and mTORC1. Journal of hematology & oncology 59 28241849
2009 Loss of Erk3 function in mice leads to intrauterine growth restriction, pulmonary immaturity, and neonatal lethality. Proceedings of the National Academy of Sciences of the United States of America 59 19805361
2010 Activation loop phosphorylation of ERK3/ERK4 by group I p21-activated kinases (PAKs) defines a novel PAK-ERK3/4-MAPK-activated protein kinase 5 signaling pathway. The Journal of biological chemistry 58 21177870
2018 Long non-coding RNA SNHG6 enhances cell proliferation, migration and invasion by regulating miR-26a-5p/MAPK6 in breast cancer. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 57 30522015
2018 Effects of miR-26a-5p on neuropathic pain development by targeting MAPK6 in in CCI rat models. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 55 30118880
2012 The extracellular signal-regulated kinase 3 (mitogen-activated protein kinase 6 [MAPK6])-MAPK-activated protein kinase 5 signaling complex regulates septin function and dendrite morphology. Molecular and cellular biology 55 22508986
2011 Identification of the atypical MAPK Erk3 as a novel substrate for p21-activated kinase (Pak) activity. The Journal of biological chemistry 54 21317288
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2019 MiR-144-3p: a novel tumor suppressor targeting MAPK6 in cervical cancer. Journal of physiology and biochemistry 41 31016619
2017 Propofol protects against hepatic ischemia/reperfusion injury via miR-133a-5p regulating the expression of MAPK6. Cell biology international 39 28198596
2017 MicroRNA-26a targets MAPK6 to inhibit smooth muscle cell proliferation and vein graft neointimal hyperplasia. Scientific reports 39 28429763
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2007 A functional link between the human cell cycle-regulatory phosphatase Cdc14A and the atypical mitogen-activated kinase Erk3. Cell cycle (Georgetown, Tex.) 36 18235225
2020 ERK3/MAPK6 controls IL-8 production and chemotaxis. eLife 35 32314963
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2014 ERK3 promotes endothelial cell functions by upregulating SRC-3/SP1-mediated VEGFR2 expression. Journal of cellular physiology 32 24585635
2016 ERK3 regulates TDP2-mediated DNA damage response and chemoresistance in lung cancer cells. Oncotarget 31 26701725
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2022 Inactivation of EGLN3 hydroxylase facilitates Erk3 degradation via autophagy and impedes lung cancer growth. Oncogene 30 35124697
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2022 Rab31 promotes the invasion and metastasis of cervical cancer cells by inhibiting MAPK6 degradation. International journal of biological sciences 25 34975321
2021 MAPK6-AKT signaling promotes tumor growth and resistance to mTOR kinase blockade. Science advances 25 34767444
2017 A regulatory BMI1/let-7i/ERK3 pathway controls the motility of head and neck cancer cells. Molecular oncology 25 28079973
2023 ERK3/MAPK6 dictates CDC42/RAC1 activity and ARP2/3-dependent actin polymerization. eLife 24 37057894
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2023 CircDNAJC11 interacts with TAF15 to promote breast cancer progression via enhancing MAPK6 expression and activating the MAPK signaling pathway. Journal of translational medicine 23 36895010
2022 Exosomes from miR-374a-5p-modified mesenchymal stem cells inhibit the progression of renal fibrosis by regulating MAPK6/MK5/YAP axis. Bioengineered 23 35137672
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2010 Targeted inactivation of Mapk4 in mice reveals specific nonredundant functions of Erk3/Erk4 subfamily mitogen-activated protein kinases. Molecular and cellular biology 23 20956558
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2022 FBXW7-mediated ERK3 degradation regulates the proliferation of lung cancer cells. Experimental & molecular medicine 21 35022544
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2020 Involvement of active MKK9-MAPK3/MAPK6 in increasing respiration in salt-treated Arabidopsis callus. Protoplasma 17 32008084
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2020 The C-Terminus Tail Regulates ERK3 Kinase Activity and Its Ability in Promoting Cancer Cell Migration and Invasion. International journal of molecular sciences 15 32516969
2019 TNF-α promotes tumor lymph angiogenesis in head and neck squamous cell carcinoma through regulation of ERK3. Translational cancer research 15 35116996
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2014 Administration of antenatal glucocorticoids and postnatal surfactant ameliorates respiratory distress syndrome-associated neonatal lethality in Erk3(-/-) mouse pups. Pediatric research 14 24732107
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2021 ERK3 is transcriptionally upregulated by ∆Np63α and mediates the role of ∆Np63α in suppressing cell migration in non-melanoma skin cancers. BMC cancer 12 33579235
2018 LncMAPK6 drives MAPK6 expression and liver TIC self-renewal. Journal of experimental & clinical cancer research : CR 12 29764463
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2022 miR-128-3p inhibits the inflammation by targeting MAPK6 in penicillin-induced astrocytes. Neuroreport 11 36250437
2020 Biochemical, cellular and structural characterization of novel and selective ERK3 inhibitors. Bioorganic & medicinal chemistry letters 11 32927028
2020 ERK3/MAPK6 is required for KRAS-mediated NSCLC tumorigenesis. Cancer gene therapy 11 33070159
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2022 ERK3-MK5 signaling regulates myogenic differentiation and muscle regeneration by promoting FoxO3 degradation. Journal of cellular physiology 10 35141958
2023 ERK3 Increases Snail Protein Stability by Inhibiting FBXO11-Mediated Snail Ubiquitination. Cancers 9 38201533
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2020 CircRNA_100395 protects breast carcinoma deterioration by targeting MAPK6. European review for medical and pharmacological sciences 9 33336740
2024 Long non-coding RNA DANCR increases spinal cord neuron apoptosis and inflammation of spinal cord injury by mediating the microRNA-146a-5p/MAPK6 axis. European spine journal : official publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society 8 38551688
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2011 Expression analysis of MAP2K9 and MAPK6 during pathogenesis of Alternaria blight in Arabidopsis thaliana ecotype Columbia. Molecular biology reports 8 21947882
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2023 HNF4G increases cisplatin resistance in lung adenocarcinoma via the MAPK6/Akt pathway. PeerJ 7 36923501
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2020 let7f‑5p attenuates inflammatory injury in in vitro pneumonia models by targeting MAPK6. Molecular medicine reports 7 33300070
2018 MicroRNA-138 inhibits proliferation and induces apoptosis of laryngeal carcinoma via targeting MAPK6. European review for medical and pharmacological sciences 7 30229830
2025 Disturbed shear stress promotes atherosclerosis through TRIM21-regulated MAPK6 degradation and consequent endothelial inflammation. Clinical and translational medicine 6 39763069
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2023 ERK3 and DGKζ interact to modulate cell motility in lung cancer cells. Frontiers in cell and developmental biology 6 37287450
2016 Structural and transcriptomic response to antenatal corticosteroids in an Erk3-null mouse model of respiratory distress. American journal of obstetrics and gynecology 6 27143398
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2023 CircGAB1 Facilitates Podocyte Injury Through Sponging miR-346 and Activating MAPK6 in Diabetic Nephropathy. Applied biochemistry and biotechnology 5 37440116
2022 Phosphoproteomic analysis identifies supervillin as an ERK3 substrate regulating cytokinesis and cell ploidy. Journal of cellular physiology 5 36576983
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2024 The circ_0003928/miR-31-5p/MAPK6 cascade affects high glucose-induced inflammatory response, fibrosis and oxidative stress in HK-2 cells. Transplant immunology 4 38964515
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2025 Anticancer Effects of MAPK6 siRNA-Loaded PLGA Nanoparticles in the Treatment of Breast Cancer. Journal of cellular and molecular medicine 2 39823246
2020 Knockdown of long non-coding RNA TTTY15 protects cardiomyocytes from hypoxia-induced injury by regulating let-7b/MAPK6 axis. International journal of clinical and experimental pathology 2 32922590
2018 The atypical mitogen-activated protein kinase ERK3 is essential for establishment of epithelial architecture. The Journal of biological chemistry 2 29674317
2025 SERPINA1 methylation as a novel diagnostic marker for early-stage papillary thyroid carcinoma via MAPK6-AKT/mTOR pathway. Clinical epigenetics 1 40442821
2025 Intracellular pH regulates ubiquitin-mediated degradation of the MAP kinase ERK3. Proceedings of the National Academy of Sciences of the United States of America 1 41123996
2023 Triazolo[4,5-d]pyrimidin-5-amines based ERK3 inhibitors fail to demonstrate selective effects on adipocyte function. Archives of biochemistry and biophysics 1 37992885