Affinage

MAPKAPK5

MAP kinase-activated protein kinase 5 · UniProt Q8IW41

Length
473 aa
Mass
54.2 kDa
Annotated
2026-06-10
88 papers in source corpus 34 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MAPKAPK5 (PRAK/MK5) is a serine/threonine kinase that integrates signals from classical and atypical MAP kinase pathways to control cytoskeletal dynamics, cellular senescence, growth, and stress responses (PMID:9628874, PMID:17254968). It was originally defined as a p38α/β-activated kinase whose regulatory Thr182 is phosphorylated to drive activity toward HSP27, coupling MK5 to F-actin remodeling (PMID:9628874, PMID:19166925). Distinct from MK2, endogenous MK5 does not chaperone p38 or respond to canonical extracellular stresses (PMID:14560018); instead its activation and cytoplasmic anchoring are dominated by the atypical MAPKs ERK3 and ERK4, which bind MK5 through a FRIEDE motif in their C-terminal L16 extension, mutually stabilizing the partners and translocating MK5 out of the nucleus (PMID:15577943, PMID:15538386, PMID:19473979). MK5 subcellular distribution is further tuned by p38α versus p38β docking, which respectively retain it in the nucleus or cytoplasm, and by PKA, which phosphorylates Ser115 to drive nuclear export (PMID:12808055, PMID:18268017, PMID:20734105). Functionally, MK5 enforces oncogene-induced senescence by directly phosphorylating p53 downstream of a ras→p38→Tip60 acetylation cascade, with knockout mice showing enhanced carcinogenesis (PMID:17254968, PMID:23685072). It additionally phosphorylates Rheb-Ser130 to suppress mTORC1 during energy starvation, FoxO transcription factors to control Myc-suppressing miR-34b/c and Rag transcription, NRF2-Ser558 to maintain redox homeostasis, and GSK3β via a long splice isoform, linking MK5 to metabolic, immune, and Wnt signaling outputs (PMID:21336308, PMID:21329882, PMID:23878308, PMID:37126714, PMID:41954085). Loss-of-function variants in MAPKAPK5 cause a developmental disorder with neurological, cardiac, and digital anomalies, with patient fibroblasts showing reduced ERK3 levels and impaired F-actin recovery (PMID:33442026).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1998 High

    Established MK5/PRAK as a p38-activated kinase and identified its regulatory phosphorylation site and a first substrate, defining where it sits in stress signaling.

    Evidence In vitro and in-gel kinase assays with Thr182 mutagenesis and Co-IP, plus parallel recombinant kinase work showing ERK/p38 activation

    PMID:9480836 PMID:9628874

    Open questions at the time
    • Physiological upstream activator in vivo not resolved among p38/ERK
    • Substrate spectrum beyond HSP27/myosin light chain peptide unknown
  2. 2003 High

    Distinguished MK5 from MK2 and showed its localization is governed by p38 docking, redefining MK5 as a distinct enzyme rather than a p38 chaperone.

    Evidence MK5 knockout fibroblasts with kinase and Co-IP assays; imaging plus NES/NLS mutants and leptomycin B

    PMID:12808055 PMID:14560018

    Open questions at the time
    • Conflicts with founding HSP27 substrate claim left unreconciled
    • True physiological activator still unidentified at this stage
  3. 2004 High

    Identified ERK3 (and later ERK4) as the atypical MAPK partners that bind, activate, and cytoplasmically anchor MK5, resolving the missing upstream activator and revealing reciprocal protein stabilization.

    Evidence Reciprocal Co-IP, siRNA, ERK3/MK5 knockout fibroblasts and embryonic-lethal mice, kinase-dead mutants, immunofluorescence

    PMID:15538386 PMID:15577943 PMID:16973613

    Open questions at the time
    • Why ERK3 acts catalysis-independently while ERK4 requires its own activity
    • Physiological signals that engage the ERK3/4-MK5 module unknown
  4. 2007 High

    Linked MK5 to tumor suppression by showing it phosphorylates p53 to drive ras-induced senescence, and to PKA signaling controlling actin remodeling, expanding MK5 into cell-fate and cytoskeletal control.

    Evidence In vitro kinase assays, PRAK knockout mice with DMBA carcinogenesis, transformation assays; PKA Cα Co-IP, siRNA, F-actin readouts

    PMID:17254968 PMID:17728103 PMID:17947239

    Open questions at the time
    • Whether p38-MK5-p53 axis operates beyond ras-driven contexts
    • Relative contribution of nuclear vs cytoplasmic MK5 pools to each output
  5. 2009 High

    Defined the FRIEDE motif as the structural basis of ERK3/4-MK5 binding and confirmed HSP27-Ser78/82 as a cellular substrate, mechanizing both complex assembly and cytoskeletal output.

    Evidence Peptide overlay and FRIEDE mutagenesis with binding/activation/localization readouts; phospho-specific antibodies and Hsp27-3A rescue

    PMID:18248330 PMID:18268017 PMID:18720373 PMID:19166925 PMID:19473979

    Open questions at the time
    • Identity of the kinase phosphorylating ERK4 SEG motif
    • How activation-loop phosphorylation gates FRIEDE accessibility mechanistically
  6. 2011 High

    Connected MK5 to growth and transcriptional control by identifying Rheb-Ser130 (mTORC1 suppression) and FoxO3a/Foxo1 (miR-34b/c-Myc loop, Rag activation) as direct substrates.

    Evidence In vitro kinase assays with site mapping, kinome/mutant screens, reporter assays, epistasis, and primary B-cell rescue

    PMID:21329882 PMID:21336308 PMID:23878308

    Open questions at the time
    • How a single kinase selects between cytoskeletal, senescence, and transcriptional substrates
    • In vivo significance of MK5-Rheb axis across tissues
  7. 2013 High

    Resolved the activation logic of MK5 in senescence as a PTM cascade (p38-dependent Tip60 acetylation of PRAK-K364) and added Hsp40/DnaJB1 as a substrate, refining the activation and chaperone interface.

    Evidence In vitro acetyltransferase and kinase assays with Tip60-T158/PRAK-K364 mutagenesis, Co-IP, senescence and ATPase/reporter assays

    PMID:23685072 PMID:24309468

    Open questions at the time
    • Generality of acetylation-dependent activation beyond ras senescence
    • Functional consequence of Hsp40 phosphorylation in vivo
  8. 2014 Medium

    Extended MK5 into oxidative-stress and motility control through interactions with DJ-1, Septin 8, and Src/FAK, implicating it in apoptosis regulation and focal-adhesion dynamics.

    Evidence Yeast two-hybrid, Co-IP, FRET, in vitro phosphorylation, knockout-cell localization assays; Src/FAK overlay and motility assays

    PMID:22649572 PMID:25383140 PMID:26042227

    Open questions at the time
    • Src/FAK axis rests on a single low-tier study without independent confirmation
    • Physiological stimuli engaging DJ-1 and Septin 8 phosphorylation unclear
  9. 2019 Medium

    Implicated MK5 in Hippo and metastasis biology by showing it protects YAP from CK1-mediated degradation and is required for HIF-1α synthesis and lung metastasis.

    Evidence RNAi screen, Co-IP, ubiquitination assays, kinase-dead mutant, xenografts; PRAK knockout PyMT and IV-injection metastasis models

    PMID:31578200 PMID:33741957

    Open questions at the time
    • Direct YAP phosphorylation site not defined
    • Mechanistic link between MK5, mTORC1, and HIF-1α translation incomplete
  10. 2021 Medium

    Established MAPKAPK5 as a disease gene, with loss-of-function variants causing a multisystem developmental disorder and confirming the F-actin role in patient cells.

    Evidence Exome sequencing in two families, patient fibroblast F-actin recovery assays, Western blot for MK5 isoforms and ERK3

    PMID:33442026

    Open questions at the time
    • Which substrate pathways drive the cardiac and digital phenotypes
    • Genotype-phenotype correlation across variant types
  11. 2026 Medium

    Broadened the MK5 substrate repertoire across immunity, neuroinflammation, alternative upstream kinases, and cancer-specific splice isoforms, showing context-dependent rewiring of the kinase.

    Evidence In vitro kinase assays and site mapping (NRF2-Ser558, GSK3β), Prak/MK5 knockout and conditional knockout mice (Th17/EAE, MCAO stroke), TLK1 phosphorylation rescue, FXR1-driven exon-6 splicing with ASO intervention

    PMID:35064619 PMID:35141958 PMID:37126714 PMID:40237440 PMID:41954085

    Open questions at the time
    • How distinct upstream kinases (TLK1, Src, PKA, p38, ERK3/4) are selected in each context
    • Whether splice-isoform-specific substrate selectivity generalizes beyond HCC

Open questions

Synthesis pass · forward-looking unresolved questions
  • How MK5 achieves substrate selectivity among its many targets and which upstream activator dominates in a given physiological setting remains unresolved.
  • No unifying model linking activator identity to substrate output
  • Structural basis of isoform- and compartment-specific substrate choice unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 12 GO:0016740 transferase activity 4 GO:0098772 molecular function regulator activity 3
Localization
GO:0005829 cytosol 5 GO:0005634 nucleus 3 GO:0005856 cytoskeleton 3
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-1640170 Cell Cycle 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-168256 Immune System 2
Partners
DNAJB1MAPK14MAPK4MAPK6PARK7PRKACASEPT8YWHAE
Complex memberships
ERK3-MK5 complexERK4-MK5 complexp38-MK5 complex

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 PRAK (MAPKAPK5) is a serine/threonine kinase activated by p38α and p38β both in vitro and in vivo; Thr182 was identified as the regulatory phosphorylation site. Activated PRAK phosphorylates small heat shock protein 27 (HSP27) at physiologically relevant sites. In vitro kinase assay, in-gel kinase assay, mutagenesis of Thr182, co-immunoprecipitation The EMBO journal High 9628874
1998 MAPKAPK5 can be phosphorylated and activated by ERK and p38 kinase in vitro (but not by JNK); phosphorylation by ERK and p38 increased its activity 9- and 15-fold respectively. Recombinant MAPKAPK5 phosphorylates a peptide derived from the regulatory light chain of myosin II. In vitro kinase assay with recombinant proteins Biochemical and biophysical research communications Medium 9480836
2003 Unlike MK2, endogenous MK5 does not interact with or chaperone p38 MAPK, is not activated by extracellular stresses such as arsenite or sorbitol, and cannot phosphorylate Hsp27 in vitro and in vivo in fibroblasts derived from knockout mice. MK5 knockout mouse fibroblasts, in vitro kinase assay, co-immunoprecipitation Molecular and cellular biology High 14560018
2003 PRAK subcellular localization is controlled by p38α and p38β through docking interactions: ectopically expressed PRAK resides in the nucleus but is redistributed to cytoplasm by co-expression of p38α/β. p38-mediated phosphorylation of PRAK promotes its nuclear export, while nuclear import is p38-independent. PRAK contains functional NES and NLS motifs required for nucleocytoplasmic shuttling. Immunostaining, nuclear export/import assays, docking groove and docking-site mutants, leptomycin B treatment Molecular biology of the cell High 12808055
2004 ERK3 specifically interacts with MK5, causing nuclear exclusion of both proteins and ERK3-dependent phosphorylation and activation of MK5 in vitro and in vivo. Endogenous MK5 activity is reduced by siRNA knockdown of ERK3 and in ERK3-/- fibroblasts. MK5 acts as a chaperone for ERK3 (MK5 depletion dramatically reduces ERK3 protein levels). Co-immunoprecipitation, siRNA knockdown, ERK3 knockout fibroblasts, in vitro kinase assay, immunofluorescence The EMBO journal High 15577943
2004 ERK3 scaffolds MK5 activation independent of ERK3 enzymatic activity but dependent on MK5 catalytic activity and the C-terminal extension of ERK3. ERK3-MK5 interaction causes nuclear-to-cytoplasmic translocation of MK5. MK5 deletion causes strong reduction of ERK3 protein levels and embryonic lethality at ~E11 in mice. Co-immunoprecipitation, kinase-dead mutants, MK5 knockout mouse, immunofluorescence, embryo analysis The EMBO journal High 15538386
2006 ERK4 (MAPK4), a stable protein, binds endogenous MK5 and translocates MK5 to the cytoplasm. Unlike ERK3, ERK4 requires its own catalytic activity to activate MK5 (direct phosphorylation). ERK4 can dimerize/oligomerize with ERK3, enabling ERK4 to relay activation to MK5 in the context of kinase-dead ERK3. Co-immunoprecipitation, kinase-dead mutants, transfection in HEK293 cells, immunofluorescence The Journal of biological chemistry Medium 16973613
2007 PRAK activates p53 by direct phosphorylation, mediating oncogenic ras-induced senescence downstream of p38 MAPK. PRAK deficiency in mice enhances DMBA-induced skin carcinogenesis coinciding with impaired senescence induction. In vitro kinase assay, PRAK knockout mice, primary cell transformation assay, DMBA skin carcinogenesis model Cell High 17254968
2007 PKA catalytic subunit Cα interacts with MK5 (but not MK2) in vivo, increases MK5 kinase activity and phosphorylation, and induces transient nuclear export of MK5, which requires kinase activity of both Cα and MK5 and Cα nuclear entry. MK5 is required for PKA-induced F-actin rearrangement in PC12 cells. Co-immunoprecipitation, kinase assays, siRNA depletion, constitutively active MK5 expression, fluorescence microscopy The Journal of biological chemistry High 17947239
2007 14-3-3ε interacts with MK5 in vivo and in vitro, and this interaction inhibits MK5-mediated phosphorylation of HSP27, thereby disrupting F-actin polymerization and inhibiting MK5-induced cell migration. Co-immunoprecipitation, in vitro binding assay, transfection, cell migration assay Cellular signalling Medium 17728103
2008 Activation loop phosphorylation of ERK3 and ERK4 (at their SEG motif) is required for formation of stable active complexes with MK5 and for efficient cytoplasmic redistribution of ERK3/ERK4-MK5 complexes. This phosphorylation is constitutive in resting cells and can be modulated by MK5 interaction. Phospho-specific antibodies, mutagenesis of SEG motif, co-immunoprecipitation, subcellular fractionation Journal of cellular physiology Medium 18720373
2008 ERK4 Ser186 (in its SEG motif) is phosphorylated in vivo by an upstream kinase (not autophosphorylation); Ser186 phosphorylation is required for ERK4 to interact with, activate, and cytoplasmatically anchor MK5. MK5 binding facilitates Ser186 phosphorylation and stabilizes the ERK4-MK5 complex. Mutagenesis of Ser186, phospho-specific antibodies, co-immunoprecipitation, kinase assays The Biochemical journal Medium 18248330
2008 Distinct amino acid residues in p38α (Asp145, Leu156) versus p38β (Gly145, Val156) determine the differential subcellular localization of p38α-PRAK (nuclear) versus p38β-PRAK (cytosolic) complexes. Nuclear localization of PRAK is required for its function in inhibiting NIH3T3 cell proliferation. Chimeric and point mutants of p38α/β, immunofluorescence, nuclear import/export assays, cell proliferation assay The Journal of biological chemistry Medium 18268017
2009 ERK3 and ERK4 contain a novel MK5-interaction motif (FRIEDE) in their L16 C-terminal extension, distinct from the classical CD domain. A single I→K substitution in FRIEDE abolishes binding, activation, and translocation of MK5 by both ERK3 and ERK4. Activation loop phosphorylation of ERK3/4 gates accessibility of the FRIEDE motif. Peptide overlay assays, mutagenesis of FRIEDE motif, co-immunoprecipitation, kinase activation assays The Journal of biological chemistry High 19473979
2009 MK5 interacts with HSP27 in vivo and phosphorylates HSP27 at Ser78 and Ser82 in cells. Expression of constitutively active MK5 induces F-actin rearrangement in PC12 cells, and co-expression of non-phosphorylatable Hsp27-3A abrogates this effect. Co-immunoprecipitation, phospho-specific antibodies, constitutively active MK5 expression, siRNA depletion of Hsp27, fluorescence microscopy Cellular signalling Medium 19166925
2010 PKA phosphorylates MK5 at Ser115 in vitro; PKA-induced nuclear export of MK5 requires Ser115 phosphorylation (S115A blocks PKA-induced export; S115D phosphomimetic causes cytoplasmic localization in resting cells). Mutations in Ser115 affect MK5 biological properties. In vitro kinase assay, mutagenesis of Ser115, nuclear export assay, phosphomimetic mutant analysis Cellular and molecular life sciences Medium 20734105
2011 MK5 regulates translation of c-Myc by promoting expression of miR-34b and miR-34c through phosphorylation of FoxO3a, which promotes nuclear localization of FoxO3a enabling it to induce miR-34b/c expression. This establishes a MK5-FoxO3a-miR-34b/c negative feedback loop that suppresses Myc and is disrupted in colorectal cancer. siRNA kinome screen, reporter assays, FoxO3a phosphorylation assay, nuclear localization of FoxO3a by immunofluorescence, miRNA expression analysis Molecular cell High 21329882
2011 MK5 activates FoxO3a by phosphorylation in developing B cells; this MK5-mediated phosphorylation of Foxo1 at Ser215 is required for transcriptional activation of Rag genes. MK5 is necessary and sufficient to activate Rag transcription in pro-B cells. Foxo1 mutant panel screen, in vitro and in vivo phosphorylation, B cell transformation and primary pro-B cell assays The Journal of experimental medicine Medium 23878308
2011 The p38β-PRAK cascade mediates energy-starvation-induced suppression of mTORC1. PRAK directly phosphorylates Rheb at Ser130, impairing Rheb nucleotide-binding ability and inhibiting Rheb-mediated mTORC1 activation. This pathway operates independently of AMPK-TSC2 and AMPK-Raptor pathways. In vitro kinase assay, Rheb phosphorylation mapping, siRNA depletion, mTORC1 activity assays, cell-size measurement Nature cell biology High 21336308
2012 In IGF2BP1-expressing tumor cells, inhibition of MAPK4 mRNA translation by IGF2BP1 antagonizes MK5 activation and prevents MK5-mediated HSP27 phosphorylation, which would otherwise sequester actin monomers, reducing availability of G-actin for F-actin polymerization and cell migration. Translational inhibition assay, MK5 activity measurements, HSP27 phosphorylation, F-actin/G-actin assays, cell migration assay Genes & development Medium 22279049
2013 Tip60 acetylates PRAK at K364 in a manner that depends on prior phosphorylation of both Tip60 (Thr158 by p38) and PRAK by p38, inducing PRAK kinase activity. This defines a cascade: ras→p38→Tip60 acetylation→PRAK activation→oncogene-induced senescence. In vitro acetyltransferase assay, mutagenesis of Tip60-Thr158 and PRAK-K364, co-immunoprecipitation, senescence assays Molecular cell High 23685072
2013 MK5 physically interacts with Hsp40/DnaJB1 in cells via C-terminal regions of both proteins and phosphorylates Hsp40/DnaJB1 at Ser149 and/or Ser151 and Ser171 in vivo. MK5 modestly stimulates Hsp40/Hsp70 ATPase activity and enhances Hsp40/DnaJB1-mediated repression of HSF1-driven transcription. Co-immunoprecipitation, in vitro kinase assay, phospho-specific antibodies, ATPase activity assay, luciferase reporter assay The international journal of biochemistry & cell biology Medium 24309468
2014 PRAK interacts with DJ-1 (via yeast two-hybrid confirmed by Co-IP) and phosphorylates DJ-1 in vitro and in vivo upon H2O2 stimulation. In PRAK-/- cells, DJ-1 translocates from nucleus to cytoplasm after H2O2, losing its ability to sequester the pro-apoptotic protein Daxx in the nucleus, leading to cell death. Yeast two-hybrid, Co-immunoprecipitation, in vitro kinase assay, immunofluorescence in PRAK+/+ vs PRAK-/- cells, Daxx localization assay Oxidative medicine and cellular longevity Medium 25383140
2014 PRAK is phosphorylated by Src kinase, directing PRAK to focal adhesions. Overexpressed PRAK inhibits cell motility by phosphorylating FAK at Y861, thereby impairing FAK activation. PRAK and Src/FAK interact physically in focal adhesions. In situ kinase overlay assay, co-immunoprecipitation, phospho-specific antibodies for FAK Y861, motility assay, immunofluorescence Journal of cancer biology & research Low 26042227
2016 PRAK interacts with RAGE (receptor for advanced glycation end-products) and Aβ treatment increases PRAK phosphorylation and PRAK-RAGE interaction. PRAK knockdown rescues mTORC1 inactivation induced by Aβ and decreases Aβ-induced autophagosome formation, placing PRAK in the RAGE-mTORC1-autophagy pathway in Alzheimer's disease models. Co-immunoprecipitation, siRNA knockdown, mTORC1 activity assay, autophagosome quantification Molecular neurodegeneration Low 26758977
2019 MK5 physically interacts with YAP and counteracts CK1δ/ε-mediated YAP ubiquitination and degradation in a LATS1/2-independent manner. MK5 kinase activity is essential for protecting YAP from ubiquitin-mediated degradation and cytoplasmic retention. RNAi screen, co-immunoprecipitation, ubiquitination assay, kinase-dead MK5 mutant, xenograft model Cancer research Medium 31578200
2021 Loss-of-function variants in MAPKAPK5 cause a developmental disorder with neurological, cardiac, and digital anomalies. Patient-derived fibroblasts lack MAPKAPK5 protein isoforms, have reduced ERK3 levels, and show impaired F-actin recovery after latrunculin B treatment, supporting a role of MAPKAPK5 in F-actin polymerization. Exome sequencing, patient-derived fibroblast functional assays (F-actin recovery after latrunculin B treatment), Western blot Genetics in medicine Medium 33442026
2021 PRAK deficiency abrogates lung metastases in PyMT mice and after intravenous injection of tumor cells, with no effect on primary tumor growth. Loss of PRAK leads to pronounced inhibition of HIF-1α protein synthesis, possibly due to reduced mTORC1 activities. Prak knockout mouse models, PyMT mammary tumor model, intravenous tumor injection, Western blot for HIF-1α and mTORC1 components Nature communications Medium 33741957
2022 TLK1 phosphorylates MK5 at three residues (S160, S354, S386), resulting in MK5 activation. MK5-S354A or kinase-dead MK5 in MK5-/- MEF cells fails to restore motility compared to wild-type MK5. The TLK1-MK5 axis promotes prostate cancer cell motility and invasion. In vitro kinase assay, phospho-specific antibody for pMK5-S354, mutagenesis, MK5 knockout MEF rescue, motility assay Molecular oncology Medium 35064619
2022 ERK3-MK5 signaling promotes FoxO3 degradation by MK5-mediated direct phosphorylation of FoxO3, reducing FoxO3 association with MyoD and inhibiting myogenic differentiation. Loss of ERK3 or MK5 causes precocious myoblast differentiation; depletion of FoxO3 rescues this premature differentiation. In vitro kinase assay, genetic inactivation of ERK3 (Mapk6KD/KD mice) and MK5, C2C12 and primary myoblast differentiation assays, FoxO3 depletion rescue experiments Journal of cellular physiology High 35141958
2023 PRAK phosphorylates NRF2 at Ser558, enhancing NRF2 protein stability independent of ubiquitination. Loss of PRAK increases cellular ROS, disrupts glycolysis and PKM2-dependent STAT3 phosphorylation, and impairs Th17 cell differentiation. Prak KO mice show resistance to EAE but impaired antitumor immunity. In vitro kinase assay identifying NRF2 as MK5/PRAK substrate, Prak knockout mice, Th17 differentiation assays, ROS measurement, glycolysis assays PNAS Medium 37126714
2012 Septin 8 is an interaction partner and in vitro substrate of MK5; the interaction is confirmed by GST pulldown, Co-IP, and FRET. MK5 phosphorylates Ser242 and Ser271 on Septin 8 in vitro. MK5 and Septin 8 co-localize in the perinuclear area, cell protrusions, and with synaptophysin-positive vesicles. Yeast two-hybrid, GST pulldown, Co-immunoprecipitation, FRET, in vitro kinase assay, confocal microscopy World journal of biological chemistry Medium 22649572
2026 FXR1 drives retention of exon 6 in MK5 pre-mRNA, generating a long kinase-competent MK5-L isoform in HCC. MK5-L phosphorylates GSK3β, activating Wnt/β-catenin signaling and promoting HCC progression and metastasis. Alternative splicing analysis, in vitro kinase assay, GSK3β phosphorylation, Wnt/β-catenin reporter, FXR1 knockdown/overexpression, xenograft model, antisense oligonucleotide therapeutic intervention Cancer science Medium 41954085
2025 Microglial MK5 regulates the neuroinflammatory response to ischemic stroke by controlling phosphorylation of HSP27 and NF-κB. Microglia-specific MK5 knockout exacerbates neurological deficits, increases infarct volume, upregulates pro-inflammatory cytokines, and reduces HSP27 phosphorylation while increasing NF-κB phosphorylation. Microglia-specific conditional MK5 knockout, MCAO mouse model, OGD/R BV2 cell model, Western blot for pHSP27 and pNF-κB, cytokine qPCR, immunofluorescence CNS neuroscience & therapeutics Medium 40237440

Source papers

Stage 0 corpus · 88 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 PRAK, a novel protein kinase regulated by the p38 MAP kinase. The EMBO journal 272 9628874
2007 PRAK is essential for ras-induced senescence and tumor suppression. Cell 260 17254968
2012 IGF2BP1 promotes cell migration by regulating MK5 and PTEN signaling. Genes & development 127 22279049
2011 The MK5/PRAK kinase and Myc form a negative feedback loop that is disrupted during colorectal tumorigenesis. Molecular cell 123 21329882
2004 Activation of MK5/PRAK by the atypical MAP kinase ERK3 defines a novel signal transduction pathway. The EMBO journal 115 15577943
2011 Inactivation of Rheb by PRAK-mediated phosphorylation is essential for energy-depletion-induced suppression of mTORC1. Nature cell biology 114 21336308
2004 Scaffolding by ERK3 regulates MK5 in development. The EMBO journal 102 15538386
1998 MAPKAPK5, a novel mitogen-activated protein kinase (MAPK)-activated protein kinase, is a substrate of the extracellular-regulated kinase (ERK) and p38 kinase. Biochemical and biophysical research communications 96 9480836
2006 Characterization of the atypical MAPK ERK4 and its activation of the MAPK-activated protein kinase MK5. The Journal of biological chemistry 74 16973613
2003 Elimination of protein kinase MK5/PRAK activity by targeted homologous recombination. Molecular and cellular biology 73 14560018
2009 PKA-induced F-actin rearrangement requires phosphorylation of Hsp27 by the MAPKAP kinase MK5. Cellular signalling 68 19166925
2003 Regulation of PRAK subcellular location by p38 MAP kinases. Molecular biology of the cell 65 12808055
2008 Activation loop phosphorylation of the atypical MAP kinases ERK3 and ERK4 is required for binding, activation and cytoplasmic relocalization of MK5. Journal of cellular physiology 64 18720373
2021 Long non-coding RNA MAPKAPK5-AS1/PLAGL2/HIF-1α signaling loop promotes hepatocellular carcinoma progression. Journal of experimental & clinical cancer research : CR 63 33596983
2007 14-3-3epsilon inhibits MK5-mediated cell migration by disrupting F-actin polymerization. Cellular signalling 60 17728103
2007 Modulation of F-actin rearrangement by the cyclic AMP/cAMP-dependent protein kinase (PKA) pathway is mediated by MAPK-activated protein kinase 5 and requires PKA-induced nuclear export of MK5. The Journal of biological chemistry 60 17947239
2010 Mitogen-activated protein kinase p38 and MK2, MK3 and MK5: ménage à trois or ménage à quatre? Cellular signalling 58 20227494
2023 The PRAK-NRF2 axis promotes the differentiation of Th17 cells by mediating the redox homeostasis and glycolysis. Proceedings of the National Academy of Sciences of the United States of America 48 37126714
2022 LncRNA MAPKAPK5_AS1 facilitates cell proliferation in hepatitis B virus -related hepatocellular carcinoma. Laboratory investigation; a journal of technical methods and pathology 40 35264707
2020 Long noncoding RNA MAPKAPK5-AS1 promotes colorectal cancer progression by cis-regulating the nearby gene MK5 and acting as a let-7f-1-3p sponge. Journal of experimental & clinical cancer research : CR 37 32690100
2009 Docking of PRAK/MK5 to the atypical MAPKs ERK3 and ERK4 defines a novel MAPK interaction motif. The Journal of biological chemistry 37 19473979
2013 A posttranslational modification cascade involving p38, Tip60, and PRAK mediates oncogene-induced senescence. Molecular cell 36 23685072
2018 Long noncoding RNA MAPKAPK5-AS1 promotes colorectal cancer proliferation by partly silencing p21 expression. Cancer science 33 30343528
2019 MK5 Regulates YAP Stability and Is a Molecular Target in YAP-Driven Cancers. Cancer research 32 31578200
2012 Tumour promoting and suppressing roles of the atypical MAP kinase signalling pathway ERK3/4-MK5. Journal of molecular signaling 29 22800433
2008 Determinants that control the distinct subcellular localization of p38alpha-PRAK and p38beta-PRAK complexes. The Journal of biological chemistry 29 18268017
2013 MK5 activates Rag transcription via Foxo1 in developing B cells. The Journal of experimental medicine 28 23878308
2013 Structure and function of MK5/PRAK: the loner among the mitogen-activated protein kinase-activated protein kinases. Biological chemistry 26 23729623
2020 IncRNA MAPKAPK5-AS1 promotes proliferation and migration of thyroid cancer cell lines by targeting miR-519e-5p/YWHAH. European journal of histochemistry : EJH 25 33272009
2016 The novel RAGE interactor PRAK is associated with autophagy signaling in Alzheimer's disease pathogenesis. Molecular neurodegeneration 25 26758977
2022 Exosomes from miR-374a-5p-modified mesenchymal stem cells inhibit the progression of renal fibrosis by regulating MAPK6/MK5/YAP axis. Bioengineered 24 35137672
2008 The Ser(186) phospho-acceptor site within ERK4 is essential for its ability to interact with and activate PRAK/MK5. The Biochemical journal 24 18248330
2021 The essential role of PRAK in tumor metastasis and its therapeutic potential. Nature communications 22 33741957
2013 Phosphorylation of heat shock protein 40 (Hsp40/DnaJB1) by mitogen-activated protein kinase-activated protein kinase 5 (MK5/PRAK). The international journal of biochemistry & cell biology 21 24309468
2008 Does MK5 reconcile classical and atypical MAP kinases? Frontiers in bioscience : a journal and virtual library 21 18508533
2007 Transgenic mice expressing constitutive active MAPKAPK5 display gender-dependent differences in exploration and activity. Behavioral and brain functions : BBF 21 17997833
2012 Oral administration of GLPG0259, an inhibitor of MAPKAPK5, a new target for the treatment of rheumatoid arthritis: a phase II, randomised, double-blind, placebo-controlled, multicentre trial. Annals of the rheumatic diseases 20 23161899
2009 The transcriptional regulation and cell-specific expression of the MAPK-activated protein kinase MK5. Cellular & molecular biology letters 20 19484198
2012 Septin 8 is an interaction partner and in vitro substrate of MK5. World journal of biological chemistry 18 22649572
2014 Cross-Phosphorylation and Interaction between Src/FAK and MAPKAP5/PRAK in Early Focal Adhesions Controls Cell Motility. Journal of cancer biology & research 17 26042227
2012 PRAK suppresses oncogenic ras-induced hematopoietic cancer development by antagonizing the JNK pathway. Molecular cancer research : MCR 17 22665523
2011 Distinct roles of MK2 and MK5 in cAMP/PKA- and stress/p38MAPK-induced heat shock protein 27 phosphorylation. Journal of molecular signaling 17 21575178
2010 Characterization of the expression and regulation of MK5 in the murine ventricular myocardium. Cellular signalling 17 20214976
2024 m6A-mediated lncRNA MAPKAPK5-AS1 induces apoptosis and suppresses inflammation via regulating miR-146a-3p/SIRT1/NF-κB axis in rheumatoid arthritis. Cell cycle (Georgetown, Tex.) 15 38225924
2014 PRAK interacts with DJ-1 and prevents oxidative stress-induced cell death. Oxidative medicine and cellular longevity 15 25383140
2022 The TTYH3/MK5 Positive Feedback Loop regulates Tumor Progression via GSK3-β/β-catenin signaling in HCC. International journal of biological sciences 14 35844789
2017 MK5 haplodeficiency attenuates hypertrophy and preserves diastolic function during remodeling induced by chronic pressure overload in the mouse heart. American journal of physiology. Heart and circulatory physiology 14 28432058
2021 Long noncoding RNA MAPKAPK5-AS1 promoted lipopolysaccharide-induced inflammatory damage in the myocardium by sponging microRNA-124-3p/E2F3. Molecular medicine (Cambridge, Mass.) 13 34666672
2016 New insights into the activation, interaction partners and possible functions of MK5/PRAK. Frontiers in bioscience (Landmark edition) 13 26709779
2015 Comparative Analysis of Two Gene-Targeting Approaches Challenges the Tumor-Suppressive Role of the Protein Kinase MK5/PRAK. PloS one 13 26295581
2013 Homology modeling and ligand docking of Mitogen-activated protein kinase-activated protein kinase 5 (MK5). Theoretical biology & medical modelling 13 24034446
2022 TLK1-mediated MK5-S354 phosphorylation drives prostate cancer cell motility and may signify distinct pathologies. Molecular oncology 12 35064619
2022 MAPKAPK5-AS1 drives the progression of hepatocellular carcinoma via regulating miR-429/ZEB1 axis. BMC molecular and cell biology 12 35468721
2021 [Xinfeng Capsules promotes apoptosis of synovial fibroblasts and attenuates inflammation in rheumatoid arthritis by regulating lncRNA MAPKAPK5-AS1]. Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica 12 34994147
2010 Serine residue 115 of MAPK-activated protein kinase MK5 is crucial for its PKA-regulated nuclear export and biological function. Cellular and molecular life sciences : CMLS 12 20734105
2010 Cross-talk between protein kinase A and the MAPK-activated protein kinases RSK1 and MK5. Journal of receptor and signal transduction research 12 20849292
2021 PRAK-03202: A triple antigen virus-like particle vaccine candidate against SARS CoV-2. Heliyon 11 34632131
2019 Transcript levels for extracellular matrix proteins are altered in MK5-deficient cardiac ventricular fibroblasts. Journal of molecular and cellular cardiology 11 31103477
2012 Pharmacokinetics, safety, and tolerability of GLPG0259, a mitogen-activated protein kinase-activated protein kinase 5 (MAPKAPK5) inhibitor, given as single and multiple doses to healthy male subjects. Drugs in R&D 11 22950522
2012 MK5 is degraded in response to doxorubicin and negatively regulates doxorubicin-induced apoptosis in hepatocellular carcinoma cells. Biochemical and biophysical research communications 11 23022185
2022 ERK3-MK5 signaling regulates myogenic differentiation and muscle regeneration by promoting FoxO3 degradation. Journal of cellular physiology 10 35141958
2017 MK5: A novel regulator of cardiac fibroblast function? IUBMB life 10 28941148
2022 The TLK1-MK5 Axis Regulates Motility, Invasion, and Metastasis of Prostate Cancer Cells. Cancers 9 36497211
2019 MK5 haplodeficiency decreases collagen deposition and scar size during post-myocardial infarction wound repair. American journal of physiology. Heart and circulatory physiology 8 30901279
2012 Discovery of a series of imidazopyrazine small molecule inhibitors of the kinase MAPKAPK5, that show activity using in vitro and in vivo models of rheumatoid arthritis. Bioorganic & medicinal chemistry letters 8 22342143
2010 The diterpenoid alkaloid noroxoaconitine is a Mapkap kinase 5 (MK5/PRAK) inhibitor. Cellular and molecular life sciences : CMLS 8 20640477
2023 Upregulation of MAPKAPK5-AS1, PXN-AS1 and URB1-AS1 lncRNAs in non-functioning pituitary adenoma. Journal of cellular and molecular medicine 6 37154079
2021 Biallelic truncating variants in MAPKAPK5 cause a new developmental disorder involving neurological, cardiac, and facial anomalies combined with synpolydactyly. Genetics in medicine : official journal of the American College of Medical Genetics 6 33442026
2021 PRAK Promotes the Pathogen Clearance by Macrophage Through Regulating Autophagy and Inflammasome Activation. Frontiers in immunology 6 33936034
2018 Prostate Cancer-Specific of DD3-driven Oncolytic Virus-harboring mK5 Gene. Open medicine (Warsaw, Poland) 6 30613790
2023 MAPKAPK5-AS1/miR-515-5p/CAB39 Axis Contributes to Non-small Cell Lung Cancer Cell Proliferation and Migration. Molecular biotechnology 5 36867352
2023 Extracellular vesicles derived from monomeric α-synuclein-treated microglia ameliorate neuroinflammation by delivery of miRNAs targeting PRAK. Neuroscience letters 5 37984486
2022 Long noncoding RNA MAPKAPK5-AS1 promotes metastasis through regulation miR-376b-5p/ECT2 axis in hepatocellular carcinoma. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 5 36567178
2021 The Essential Role of PRAK in Preserving Cardiac Function and Insulin Resistance in High-Fat Diet-Induced Diabetes. International journal of molecular sciences 5 34360761
2021 Combined oncolytic adenovirus carrying MnSOD and mK5 genes both regulated by survivin promoter has a synergistic inhibitory effect on gastric cancer. Neoplasma 5 34881625
2012 Rottlerin-mediated inhibition of Chlamydia trachomatis growth and uptake of sphingolipids is independent of p38-regulated/activated protein kinase (PRAK). PloS one 5 22970301
2022 Targeting ERK3/MK5 complex for treatment of obesity and diabetes. Biochemical and biophysical research communications 4 35523049
2021 Deletion of PRAK Mitigates the Mitochondria Function and Suppresses Insulin Signaling in C2C12 Myoblasts Exposed to High Glucose. Frontiers in pharmacology 4 34671252
2011 More, more, more: downregulation of a MK5-FoxO3a-mir34b/c pathway further increases c-Myc levels in colorectal cancer. Molecular cell 4 21329875
2007 Intensity dependent confidence intervals on microarray measurements of differentially expressed genes: a case study of the effect of MK5, FKRP and TAF4 on the transcriptome. Gene regulation and systems biology 4 19936079
2024 CAF-EVs carry lncRNA MAPKAPK5-AS1 into hepatocellular carcinoma cells and promote malignant cell proliferation. Communications biology 3 39739005
2022 Expanding the novel MAPKAPK5-related developmental disorder's genotype-phenotype correlation: Patient report and 19 months of follow-up. Clinical genetics 2 35575217
2011 Production of L-arabinose from corn hull arabinoxylan by Arthrobacter aurescens MK5 α-L-arabinofuranosidase. Journal of food science 2 21535740
2022 Consolidating the association of biallelic MAPKAPK5 pathogenic variants with a distinct syndromic neurodevelopmental disorder. Journal of medical genetics 1 36581449
2026 Targeted degradation of MK2 is insufficient to block inflammatory cytokine production in human cells due to cooperativity with MK3 and MK5. Frontiers in immunology 0 41613108
2026 FXR1-Directed Alternative Splicing of MK5 Drives Hepatocellular Carcinoma Progression by Activating GSK3β Signaling. Cancer science 0 41954085
2025 Targeting the TLK1-MK5 Axis Suppresses Prostate Cancer Metastasis. Cancers 0 40227796
2025 MK5 Regulates Microglial Activation and Neuroinflammation in Experimental Stroke Models. CNS neuroscience & therapeutics 0 40237440

Missed literature

Know a paper Affinage missed for MAPKAPK5? Flag it for the maintainers and the community.

No submissions yet.