Affinage

Showing MAPKAPK2 — MK2 is a alias.

MAPKAPK2

MAP kinase-activated protein kinase 2 · UniProt P49137

Length
400 aa
Mass
45.6 kDa
Annotated
2026-06-10
100 papers in source corpus 37 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MAPKAPK2 (MK2) is a stress-activated serine/threonine kinase that operates as the principal downstream effector of p38 MAPK, integrating inflammatory, genotoxic, and mechanical stress signals into control of mRNA stability, cytoskeletal dynamics, cell death, and autophagy (PMID:12052889, PMID:23028373). p38 MAPKα/β bind a basic docking motif in the MK2 C-terminus and phosphorylate its regulatory sites, triggering nuclear export of MK2 together with active p38; MK2 also stabilizes p38 protein levels through a C-terminal interaction that is independent of its catalytic activity, while p38α reciprocally is required for MK2 protein expression (PMID:12052889, PMID:16198317). A central MK2 output is post-transcriptional control of inflammatory gene expression: MK2 phosphorylates the ARE-binding proteins tristetraprolin (TTP/ZFP36) at S52/S178 and ZFP36L1, lowering their affinity for AU-rich elements, releasing ARE-containing transcripts such as TNF, ICAM-1, IL-8, and SASP factors from repression and degradation, and permitting HuR-mediated translation (PMID:23028373, PMID:20599781, PMID:31527197, PMID:26280535, PMID:22268119). Through phosphorylation of the small heat-shock protein Hsp27/Hsp25 at S86, MK2 remodels the actin cytoskeleton and modulates stress resistance, driving cell migration downstream of BMP-2 and TGFβ and promoting invasion and chemoresistance in cancer (PMID:16840785, PMID:21297993, PMID:16407830, PMID:34851698). MK2 directly phosphorylates a broad substrate spectrum that diversifies its biology: RIPK1 at S321 to suppress TNF-induced apoptosis and necroptosis (PMID:28506461, PMID:28920954, PMID:28920952), Beclin 1 at S90 to promote starvation-induced autophagy (PMID:25693418), CEP131 at S47/S78 and NELFE at S115 to create 14-3-3 docking sites controlling centriolar satellite remodelling and RNA Pol II elongation after UV stress (PMID:26616734, PMID:29523821), PDE4A5 at S147 to amplify cAMP signalling (PMID:21323643), and epithelial keratins K18-S52 and K20-S13 to regulate mucin secretion (PMID:20724476). Distinct structural regions and modifications partition these functions — the catalytic activity drives cytokine production while a proline-rich N-terminal region is required for migration, and SUMOylation at K339 dampens kinase output (PMID:12052889, PMID:21131586). In vivo, MK2 governs zebrafish epiboly via F-actin at the yolk margin, hematopoietic stem cell self-renewal through a polycomb interaction, hippocampal mGluR-LTD, and tumor-promoting macrophage polarization and stromal signalling (PMID:19282986, PMID:19369945, PMID:25134715, PMID:29666270, PMID:29844172).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2002 High

    Established how MK2 is activated and how its modular architecture partitions distinct outputs, defining MK2 as a p38-controlled effector with separable functions for cytokine production versus migration.

    Evidence MK2 knockout macrophages and MEFs with reconstitution of MK2 isoforms/mutants, p38 protein measurement, TNF and migration assays

    PMID:12052889

    Open questions at the time
    • Did not enumerate the full substrate set downstream of activation
    • Structural basis of the C-terminal docking and p38 stabilization not resolved here
  2. 2005 Medium

    Showed the MK2–p38 relationship is mutually stabilizing at the protein level, with p38α required for MK2 expression, framing the pair as an interdependent module.

    Evidence p38α-null fibroblasts and embryonic extracts with p38α re-introduction rescue, MK2 immunoblotting

    PMID:16198317

    Open questions at the time
    • Mechanism of reciprocal stabilization at molecular level not defined
    • Single lab
  3. 2007 High

    Resolved the MK2 kinase domain and its ATP/inhibitor-binding site, providing a structural basis for selective inhibition and linking inhibition to suppression of TNF-α.

    Evidence X-ray crystallography of MK2-inhibitor complexes in two crystal forms, in vitro kinase and cellular TNF-α assays

    PMID:17449059 PMID:17480064

    Open questions at the time
    • No structure of MK2 bound to a physiological substrate
    • Conformational states during activation not captured
  4. 2006 High

    Demonstrated that MK2 phosphorylation of Hsp25/Hsp27 controls oligomer disaggregation, 14-3-3 binding, and stress resistance, establishing the central cytoskeletal/chaperone branch of MK2 signalling.

    Evidence MK2 knockout fibroblasts, in vitro phosphorylation, 14-3-3 binding, GFP-Hsp25 imaging and solubility fractionation under multiple stresses

    PMID:16840785

    Open questions at the time
    • Downstream actin-remodeling effectors not fully mapped
    • Relationship between Hsp25 phosphorylation and cell-fate decisions partly correlative
  5. 2012 High

    Defined the molecular logic of MK2-driven mRNA stabilization by showing MK2 phosphorylation of TTP triggers a TTP-to-HuR exchange that switches transcripts from unstable/untranslated to stable/translated.

    Evidence ARE reporter assays, TTP/HuR binding and phospho-site mutagenesis in MK2 knockout macrophages

    PMID:23028373

    Open questions at the time
    • In vivo physiological scope of the exchange beyond TNF not fully delineated here
  6. 2010 High

    Genetic knockout/knock-in models identified MK2 and MK3 as the kinases phosphorylating TTP at S52/S178 in vivo, anchoring MK2's role in post-transcriptional control of inflammation.

    Evidence MK2 KO, MK3 KO, MK2/3 double-KO macrophages and TTP phospho-site knock-in mice with cytokine and mRNA stability readouts

    PMID:20599781 PMID:31527197

    Open questions at the time
    • Relative contribution of MK2 versus MK3 across cell types not fully resolved
  7. 2015 High

    Expanded the substrate spectrum into autophagy and stress-response chromatin/organelle control, showing MK2 phosphorylates Beclin 1 (S90), CEP131 (S47/S78), and ZFP36L1 to govern autophagy, centriolar satellites, and SASP.

    Evidence In vitro kinase assays, phospho-site mutagenesis, 14-3-3 binding, autophagy flux, live-cell imaging, and senescence/SASP assays

    PMID:25693418 PMID:26280535 PMID:26616734

    Open questions at the time
    • Coordination among these parallel substrate branches in a single cell unclear
    • Upstream stimulus selectivity for each substrate not defined
  8. 2017 High

    Established MK2 as a direct brake on cell death by phosphorylating RIPK1 at S321 to block its kinase activation and FADD/caspase-8 engagement, suppressing apoptosis and necroptosis.

    Evidence In vitro kinase assay, S321D phospho-mimetic mutagenesis, Co-IP, and cell death assays, replicated across three labs

    PMID:28506461 PMID:28920952 PMID:28920954

    Open questions at the time
    • Integration with the cytokine-producing arm of MK2 in the same TNF response not fully reconciled
  9. 2018 High

    Showed MK2 couples DNA-damage stress to transcription by phosphorylating NELFE (S115) to evict the NELF complex and license RNA Pol II elongation via 14-3-3 recruitment.

    Evidence Quantitative phosphoproteomics, in vitro phosphorylation, 14-3-3 binding, chromatin fractionation, and Pol II elongation assays

    PMID:29523821

    Open questions at the time
    • Genome-wide set of MK2-dependent elongation targets not defined
    • Single comprehensive study
  10. 2021 High

    Demonstrated therapeutic relevance of the MK2–Hsp27 axis, showing chemotherapy-induced TNFα drives TAK1→MK2→Hsp27 signalling and protective autophagy to confer chemoresistance in pancreatic cancer.

    Evidence Reverse-phase protein array, siRNA, MK2 inhibitor ATI-450, in vitro kinase and Beclin1 phosphorylation assays in an autochthonous PDAC mouse model

    PMID:34851698

    Open questions at the time
    • Relative contribution of Hsp27 versus Beclin1 branches to resistance not separated
    • Durability of MK2 inhibition not addressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How MK2 selects among its many substrates in a given stress context, and how isoform, SUMOylation, and subcellular partitioning route signal flow, remains unresolved.
  • No unified model of substrate prioritization under combined stresses
  • Regulatory role of the long CUG-initiated MK2 isoform incompletely mapped
  • Structural basis of substrate docking not determined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 7 GO:0016740 transferase activity 6 GO:0140657 ATP-dependent activity 2
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 2
Pathway
R-HSA-168256 Immune System 4 R-HSA-8953854 Metabolism of RNA 4 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-5357801 Programmed Cell Death 2 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-9612973 Autophagy 2
Partners
BECN1CEP131HSPB1MAPK14NELFEPDE4A5RIPK1ZFP36

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 mTOR controls SASP by differentially regulating translation of MAPKAPK2 (MK2) through 4EBP1; activated MK2 then phosphorylates the RNA-binding protein ZFP36L1 during senescence, inhibiting its ability to degrade transcripts of SASP components. Drug screen, genetic rescue, mTOR inhibitor rapamycin treatment, overexpression of constitutively active ZFP36L1, phosphorylation assays Nature cell biology High 26280535
2017 MK2 directly phosphorylates RIPK1 at serine 321 in the TNF signaling pathway, inhibiting RIPK1 kinase activation, blocking its ability to bind FADD/caspase-8, and suppressing RIPK1-dependent apoptosis and necroptosis; a phospho-mimetic S321D RIPK1 mutation limits TNF-induced death. In vitro kinase assay, phospho-mimetic mutagenesis (S321D), Co-IP, cell death assays Molecular cell High 28506461 28920952 28920954
2002 MK2 is activated by p38 MAPKα and -β, which bind to a basic docking motif in the C terminus of MK2 and phosphorylate its regulatory sites; upon activation, MK2 is exported from nucleus to cytoplasm and cotransports active p38 MAPK. MK2 stabilizes p38 MAPK protein levels through its C terminus (independent of catalytic activity). TNF biosynthesis requires MK2 catalytic activity. Cell migration requires both MK2 catalytic activity and its proline-rich N-terminal region. MK2 knockout macrophages and MEFs, MK2 isoform/mutant reconstitution, p38 MAPK protein level measurement, TNF production assay, cell migration assay on fibronectin Molecular and cellular biology High 12052889
2012 MK2 phosphorylates tristetraprolin (TTP) at S52/S178, decreasing TTP's affinity to AU-rich elements (AREs), inhibiting TTP's ability to replace HuR on target mRNAs, and permitting HuR-mediated initiation of translation of TNF mRNA; this exchange between TTP and HuR provides a reversible switch between unstable/non-translatable and stable/efficiently translated mRNAs. ARE reporter assays, TTP/HuR binding experiments, phosphorylation-site mutagenesis, MK2 knockout macrophages PLoS genetics High 23028373
2015 MAPKAPK2 (MK2) and MAPKAPK3 (MK3) phosphorylate Beclin 1 at serine 90 to positively regulate starvation-induced autophagy; BCL2 blocks MK2/MK3-dependent Beclin 1 S90 phosphorylation and thereby inhibits autophagy. In vitro kinase assay, phospho-site mutagenesis, autophagy flux assays in vitro and in vivo, BCL2 co-expression experiments eLife High 25693418
2015 MK2 activity is required for the p38-driven induction of miR-34c following DNA damage; miR-34c in turn represses c-Myc translation to prevent inappropriate DNA replication. In p53-deficient cells, the p38 MAPK/MK2 pathway drives miR-34c induction. MK2 inhibition/knockdown, miR-34c induction measurement, S-phase arrest assays, c-Myc depletion epistasis Proceedings of the National Academy of Sciences of the United States of America Medium 20212154
2007 Crystal structure of the MK2 kinase domain in complex with a high-affinity inhibitor (IC50 8.5 nM) was determined in two crystal forms, revealing conformational flexibility in the binding site and a potential intermediate state during substrate phosphorylation. X-ray crystallography (soaking and co-crystallization), two crystal forms Journal of molecular biology High 17449059
2007 Crystal structure of MK2 kinase domain with pyrrolopyridine inhibitor class defined the ATP binding site and provided structural basis for selective inhibition; inhibitors suppress TNF-α production and show efficacy in acute inflammation models. X-ray crystallography of MK2/inhibitor complex, in vitro kinase assays, cellular TNF-α suppression assays Journal of medicinal chemistry High 17480064
2011 MK2 phosphorylates PDE4A5 at Ser147 within the UCR1 domain; this phosphorylation does not alter PDE4A5 basal activity but markedly attenuates PDE4A5 activation by protein kinase A, amplifying intracellular cAMP accumulation. MK2 phosphorylation also triggers a conformational change in PDE4A5 that disrupts its interaction with DISC1 and AIP. In vitro kinase assay, phosphorylation site mutagenesis, MK2/3-null macrophage reconstitution, cAMP accumulation assays, co-IP for protein interactions The Biochemical journal High 21323643
2015 MK2 phosphorylates CEP131 at S47 and S78 following UV-induced stress; phosphorylation creates direct binding sites for 14-3-3 proteins, which sequester CEP131 in the cytoplasm, blocking formation of new centriolar satellites and causing rapid depletion of these structures. Phosphoproteomics, in vitro kinase assay, phospho-site mutagenesis of CEP131, 14-3-3 binding assays, live-cell imaging of centriolar satellite remodeling Nature communications High 26616734
2018 MK2 phosphorylates the RNA-binding subunit of the NELF complex, NELFE, at Serine 115 following UV-induced DNA damage; NELFE phosphorylation promotes recruitment of 14-3-3 proteins and rapid dissociation of the NELF complex from chromatin, accompanied by RNA polymerase II elongation. Quantitative phosphoproteomics, kinase inhibition, in vitro phosphorylation, 14-3-3 binding assays, chromatin fractionation, RNA Pol II elongation assays Nature communications High 29523821
2010 MK2 directly phosphorylates keratins K18 at Ser52 and K20 at Ser13 in vitro and in vivo; p38 directly phosphorylates K8-Ser73; MK2 and p38 cooperate to phosphorylate epithelial keratins in intestinal epithelia, and MK2-dependent K20-Ser13 phosphorylation regulates mucin secretion. Phosphoproteomics, in vitro kinase assays, MK2/3 knockout mouse cells, small molecule inhibitors, MK2 knockdown in HT29 cells, mucin secretion assay The Journal of biological chemistry High 20724476
2009 MAPKAPK2 functions in the yolk cell downstream of p38 MAPK to regulate epiboly during zebrafish development by modulating F-actin network activity at the yolk cell margin; loss-of-function (betty boop mutant) causes premature constriction of an F-actin network and blastoderm margin constriction at 50% epiboly. Positional cloning, whole-blastoderm transplants, mRNA microinjection rescue, p38 inhibitor epistasis, calcium imaging, F-actin visualization PLoS genetics High 19282986
2006 MK2-dependent phosphorylation of Hsp25 (Ser86) is required for stress-induced disaggregation and insolubilization of Hsp25 oligomers; in MK2-deficient fibroblasts, Hsp25 insolubilization is delayed, 14-3-3 binding is absent, and cells show increased resistance to arsenite, H2O2, and sublethal heat shock. MK2 phosphorylation of Hsp25 correlates with stress-induced cell damage under sublethal conditions. MK2 knockout fibroblasts, in vitro phosphorylation, 14-3-3 binding assays, GFP-Hsp25 imaging, apoptosis assays, solubility fractionation The Journal of biological chemistry High 16840785
2010 MK2 phosphorylates LSP1 at Ser243 (murine)/Ser252 (human), the major phosphorylation site in its C-terminal F-actin binding region; phosphorylated LSP1 localizes to F-actin-enriched lamellipodia and stabilizes F-actin polarization during neutrophil chemotaxis toward fMLP. MK2-/- neutrophils show only transient rather than persistent F-actin polarization. Phospho-site mutagenesis, phospho-specific antibody generation, immunostaining, F-actin polarization assays in WT and MK2-/- neutrophils, p38 inhibitor SB203580 Biochemical and biophysical research communications Medium 17481585
2010 MK2 SUMOylation at lysine K339 (by TNF-α stimulus) inhibits MK2 kinase activity and limits HSP27 phosphorylation; loss of the SUMOylation site (MK2-K339R) increases kinase activity, prolongs HSP27 phosphorylation, enhances actin filament remodeling, and alters endothelial cell migration. SUMOylation site mutagenesis (K339R), kinase activity assays, HSP27 phosphorylation, actin filament imaging, EC migration assays, dominant-negative MK2 Blood Medium 21131586
2012 MK2 regulates mGluR-LTD in the hippocampus; MK2/3 double-knockout mice show impaired mGluR-LTD and deficient endocytosis of GluA1 AMPA receptor subunits, with corresponding deficits in hippocampal-dependent spatial reversal learning. MK2/3 double-knockout mice, electrophysiological LTD recordings, GluA1 endocytosis assays, spatial reversal learning behavioral tests Nature communications Medium 25134715
2009 MK2 is required for the self-renewal capacity of haematopoietic stem cells (HSCs); MK2-deficient mice have reduced HSC numbers and impaired competitive repopulation. This function requires MK2 interaction with the polycomb group (PcG) complex, as an Edr2-non-binding MK2 mutant fails to rescue the repopulation defect. MK2 knockout mice, competitive repopulation assays, MK2 mutant (Edr2-non-binding) rescue experiments, cell cycle analysis The EMBO journal Medium 19369945
2019 A long isoform of MK2 is constitutively translated from an alternative CUG translation initiation site in the 5' UTR of its mRNA, dependent on the RNA helicase eIF4A1. The short (canonical) isoform phosphorylates Hsp27 in vivo, supports cell migration, and stress-induced immediate early gene expression; the long isoform has distinct interaction partners and does not perform these functions. Alternative translation initiation mapping, eIF4A1 inhibition, isoform-specific expression, in vivo Hsp27 phosphorylation assays, migration assays, interaction profiling (MS) Cell reports Medium 31167133
2010 MK2 and MK3 are the kinases responsible for phosphorylation of TTP at S52/S178 in LPS-stimulated macrophages; these phosphorylations stabilize TTP protein but release ARE-containing mRNAs from translational repression and inhibit their nucleolytic degradation. MK2/3 also contribute to de novo synthesis of TTP. MK2 KO, MK3 KO, MK2/3 double KO macrophages, TTP phospho-site knock-in (TTPaa) mice, cytokine measurement, mRNA stability assays Biochemical pharmacology High 20599781 31527197
2011 BMP-2-induced cell migration requires activation of the p38/MK2/Hsp25 pathway downstream of BMP receptors; genetic ablation of either p38α or MK2 blocks downstream effector activation and BMP-2-induced cell migration. Phosphorylated Hsp25 colocalizes with BMP receptor complexes in lamellipodia; a phosphorylation-null Hsp25 mutant abolishes BMP-2-induced migration. p38α and MK2 genetic ablation (MEFs), kinase activity assays, immunofluorescence of phospho-Hsp25 localization, overexpression of phospho-null Hsp25, cell migration assays PloS one Medium 21297993
2007 MAPKAPK2 and HSP27 are downstream effectors of p38 MAP kinase required for TGFβ-mediated MMP-2 activation and cell invasion in prostate cancer; dominant-negative MAPKAPK2 blocks HSP27 phosphorylation, and either dominant-negative MAPKAPK2 or non-phosphorylatable HSP27 blocks TGFβ-mediated MMP-2 activity and invasion. Transient transfection of wild-type, constitutively active, and dominant-negative MAPKAPK2; non-phosphorylatable HSP27 mutant; siRNA knockdown; MMP-2 activity assays; invasion assays Oncogene Medium 16407830
2002 The p38 MAPK/MAPKAPK2 signaling pathway regulates urokinase plasminogen activator (uPA) mRNA stability through AU-rich elements in its 3'-UTR in invasive breast cancer cells; the pathway is activated via Rac1-MKK3-p38-MAPKAPK2. Dominant-negative Rac1, constitutively active MKK3/MKK6 mutants, dominant-negative MKK3, beta-globin reporter with uPA 3'-UTR/ARE-deleted 3'-UTR, mRNA stability assays The Journal of biological chemistry Medium 12377770
2012 MK2 regulates TNF-α-induced ICAM-1 and IL-8 expression via phosphorylation of tristetraprolin (TTP) in human pulmonary microvascular endothelial cells; MK2 silencing reduces ICAM-1 and IL-8 mRNA half-lives and decreases TTP phosphorylation, while TTP silencing stabilizes these mRNAs. MK2 siRNA knockdown, TTP siRNA knockdown, mRNA stability assays (half-life measurement), TTP phosphorylation immunoblotting American journal of physiology. Lung cellular and molecular physiology Medium 22268119
2020 MK2 promotes SRC-3 (steroid receptor coactivator-3) phosphorylation at Ser857 via the p38MAPK-MK2 axis; this phosphorylation drives nuclear translocation of SRC-3 and enhances NF-κB-mediated IL-6 transcription. p38MAPK-MK2 pathway inhibition, phospho-site analysis, nuclear translocation assays, NF-κB reporter assays, IL-6 transcription measurement Scientific reports Medium 32647362
2018 MK2 phosphorylates p47phox at Ser329, enhancing NADPH oxidase activation and superoxide production in neutrophils; MK2-deficient neutrophils show reduced p47phox phosphorylation and lower superoxide generation in response to C5a. MK2-/- mice, myeloid-specific MK2 KO (MK2Lyz2-KO), Ser329 phosphorylation site identification, superoxide production assays, NADPH oxidase activity measurement Frontiers in immunology Medium 30483268
2021 FIRINOX chemotherapy triggers autocrine TNFα signaling that activates TAK1→MK2→Hsp27 axis in PDAC; MK2 directly phosphorylates Hsp27 to confer chemoresistance. MK2 inhibition blocks Hsp27 activation, sensitizes PDAC to apoptosis, and suppresses protective autophagy in part by blocking Beclin1 phosphorylation. Reverse-phase protein array, siRNA knockdown, MK2 inhibitor (ATI-450), in vitro kinase assays, autochthonous PDAC mouse model, Beclin1 phosphorylation assays Science translational medicine High 34851698
2022 The p38/MK2 complex phosphorylates MFF1 (mitochondrial fission factor 1) at S155, leading to VDAC1 oligomerization and mitochondrial membrane pore formation through which HSP60 is released; cytosolic HSP60 then activates the IKK complex to induce NF-κB-dependent survival gene expression. MFF1 phosphorylation site mutagenesis, VDAC1 oligomerization assays, HSP60 release measurement, IKK complex co-IP, NF-κB reporter assays, mouse xenograft model Redox biology Medium 35316673
2012 The p38-MK2 axis directly phosphorylates E2F1 at Ser-364 in vitro and mediates epirubicin-induced E2F1 induction, which in turn drives FOXM1 expression. MK2 also limits JNK induction by epirubicin, and JNK represses FOXM1 expression. In vitro phosphorylation assay (MK2 phosphorylates E2F1 at Ser-364), siRNA knockdown, MK2-/- MEFs, pharmacological inhibitors, transfection with E2F1 Ser-364 mutants Molecular cancer research : MCR Medium 22802261
2007 MK2 is required for TGFβ-induced myofibroblast differentiation (smooth muscle alpha-actin upregulation); in MK2-/- MEFs, TGFβ causes downregulation rather than upregulation of smooth muscle alpha-actin, associated with reduced smalpha mRNA stability rather than altered promoter activity. MK2 knockout MEFs, TGFβ stimulation, smalpha expression analysis, mRNA stability assays, serum-responsive promoter reporter assays Journal of cellular biochemistry Medium 17163490
2014 MK2 promotes M2 macrophage polarization and tumor angiogenesis; whole-animal and myeloid-specific MK2 KO demonstrates that MK2 activity in the myeloid compartment supports tumor neoangiogenesis and drives polarization of tumor-associated macrophages into protumorigenic, proangiogenic M2-like macrophages. Whole-animal and tissue-specific (myeloid) MK2 KO mice, tumor growth assays, macrophage polarization assays, angiogenesis assays, MK2 chemical inhibition in human cell lines Proceedings of the National Academy of Sciences of the United States of America Medium 29666270
2018 Mesenchymal MK2 drives intestinal carcinogenesis through phosphorylation of Hsp27, which affects downstream tumorigenic effector molecules controlling epithelial proliferation, apoptosis, and angiogenesis; deletion of MK2 in intestinal mesenchymal cells reduces tumor multiplicity and growth in the Apcmin/+ model. Conditional (mesenchymal, epithelial, endothelial) MK2 KO mice, Apcmin/+ model, colitis-associated carcinogenesis model, Hsp27 phosphorylation analysis, tumor growth/invasion assays Proceedings of the National Academy of Sciences of the United States of America High 29844172
2005 p38α is required for MAPKAPK2 (MK2) protein expression; in p38α-null fibroblasts and embryonic extracts, MK2 expression is greatly reduced and is restored by re-introduction of p38α. p38α knockout cell lines, embryonic extracts from p38α-null mice, p38α re-introduction rescue, immunoblotting for MK2 Biochemical and biophysical research communications Medium 16198317
2014 In HPV-positive cells, p38 and MK2 are phosphorylated and relocalize to the cytoplasm; pharmacological inhibition of MK2 or p38 blocks HPV genome amplification, identifying the p38/MK2 pathway as a key regulator of the HPV differentiation-dependent life cycle. MK2 and p38 inhibitor treatment, HPV genome amplification assays, subcellular localization analysis Journal of virology Low 25410865

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype. Nature cell biology 615 26280535
2009 Kinases that control the cell cycle in response to DNA damage: Chk1, Chk2, and MK2. Current opinion in cell biology 405 19230643
2017 MK2 Phosphorylates RIPK1 to Prevent TNF-Induced Cell Death. Molecular cell 266 28506461
2002 Distinct cellular functions of MK2. Molecular and cellular biology 205 12052889
2017 p38MAPK/MK2-dependent phosphorylation controls cytotoxic RIPK1 signalling in inflammation and infection. Nature cell biology 198 28920954
2010 p38 mitogen-activated protein kinase-driven MAPKAPK2 regulates invasion of bladder cancer by modulation of MMP-2 and MMP-9 activity. Cancer research 190 20068172
2012 The p38/MK2-driven exchange between tristetraprolin and HuR regulates AU-rich element-dependent translation. PLoS genetics 188 23028373
2017 MK2 phosphorylation of RIPK1 regulates TNF-mediated cell death. Nature cell biology 176 28920952
2006 MAPKAPK2 and HSP27 are downstream effectors of p38 MAP kinase-mediated matrix metalloproteinase type 2 activation and cell invasion in human prostate cancer. Oncogene 171 16407830
2015 The stress-responsive kinases MAPKAPK2/MAPKAPK3 activate starvation-induced autophagy through Beclin 1 phosphorylation. eLife 157 25693418
2010 p38 MAPK/MK2-mediated induction of miR-34c following DNA damage prevents Myc-dependent DNA replication. Proceedings of the National Academy of Sciences of the United States of America 148 20212154
2000 Ischemic preconditioning activates MAPKAPK2 in the isolated rabbit heart: evidence for involvement of p38 MAPK. Circulation research 145 10666409
2007 Pyrrolopyridine inhibitors of mitogen-activated protein kinase-activated protein kinase 2 (MK-2). Journal of medicinal chemistry 140 17480064
2018 Ubiquitin-Mediated Regulation of RIPK1 Kinase Activity Independent of IKK and MK2. Molecular cell 121 29452637
2015 A Synergistic Interaction between Chk1- and MK2 Inhibitors in KRAS-Mutant Cancer. Cell 106 26140595
2014 A p38MAPK/MK2 signaling pathway leading to redox stress, cell death and ischemia/reperfusion injury. Cell communication and signaling : CCS 104 24423080
2019 MAPKAPK2: the master regulator of RNA-binding proteins modulates transcript stability and tumor progression. Journal of experimental & clinical cancer research : CR 95 30850014
2018 MK2 contributes to tumor progression by promoting M2 macrophage polarization and tumor angiogenesis. Proceedings of the National Academy of Sciences of the United States of America 87 29666270
2010 MAPKAP kinases MK2 and MK3 in inflammation: complex regulation of TNF biosynthesis via expression and phosphorylation of tristetraprolin. Biochemical pharmacology 87 20599781
2018 Selective inhibition of the p38α MAPK-MK2 axis inhibits inflammatory cues including inflammasome priming signals. The Journal of experimental medicine 82 29549113
2012 Survival of cancer stem cells under hypoxia and serum depletion via decrease in PP2A activity and activation of p38-MAPKAPK2-Hsp27. PloS one 80 23185379
2007 Smooth muscle alpha-actin expression and myofibroblast differentiation by TGFbeta are dependent upon MK2. Journal of cellular biochemistry 80 17163490
2016 Targeting p38 or MK2 Enhances the Anti-Leukemic Activity of Smac-Mimetics. Cancer cell 79 26859455
2002 Rac1-MKK3-p38-MAPKAPK2 pathway promotes urokinase plasminogen activator mRNA stability in invasive breast cancer cells. The Journal of biological chemistry 74 12377770
2016 SB203580 Modulates p38 MAPK Signaling and Dengue Virus-Induced Liver Injury by Reducing MAPKAPK2, HSP27, and ATF2 Phosphorylation. PloS one 72 26901653
2017 Inhibition of MK2 suppresses IL-1β, IL-6, and TNF-α-dependent colorectal cancer growth. International journal of cancer 69 29197088
2018 p38-MK2 signaling axis regulates RNA metabolism after UV-light-induced DNA damage. Nature communications 68 29523821
2008 MK2: a novel molecular target for anti-inflammatory therapy. Expert opinion on therapeutic targets 67 18620516
2008 MK2 and MK3--a pair of isoenzymes? Frontiers in bioscience : a journal and virtual library 63 18508601
2015 Targeting Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MAPKAPK2, MK2): Medicinal Chemistry Efforts To Lead Small Molecule Inhibitors to Clinical Trials. Journal of medicinal chemistry 62 26502061
2014 The p38-MK2-HuR pathway potentiates EGFRvIII-IL-1β-driven IL-6 secretion in glioblastoma cells. Oncogene 62 25088200
2014 The MK2/3 cascade regulates AMPAR trafficking and cognitive flexibility. Nature communications 59 25134715
2010 Mitogen-activated protein kinase p38 and MK2, MK3 and MK5: ménage à trois or ménage à quatre? Cellular signalling 58 20227494
2018 Inhibition of the Stromal p38MAPK/MK2 Pathway Limits Breast Cancer Metastases and Chemotherapy-Induced Bone Loss. Cancer research 54 30093561
2017 Aryl hydrocarbon receptor inhibits inflammation in DSS‑induced colitis via the MK2/p‑MK2/TTP pathway. International journal of molecular medicine 53 29207040
2012 The p38 MAPK-MK2 axis regulates E2F1 and FOXM1 expression after epirubicin treatment. Molecular cancer research : MCR 51 22802261
2021 The p38MAPK-MK2 Signaling Axis as a Critical Link Between Inflammation and Synaptic Transmission. Frontiers in cell and developmental biology 50 33585492
2016 MK2/3 Are Pivotal for IL-33-Induced and Mast Cell-Dependent Leukocyte Recruitment and the Resulting Skin Inflammation. Journal of immunology (Baltimore, Md. : 1950) 50 27694493
2011 Phosphorylation of cAMP-specific PDE4A5 (phosphodiesterase-4A5) by MK2 (MAPKAPK2) attenuates its activation through protein kinase A phosphorylation. The Biochemical journal 50 21323643
2010 Mitogen-activated protein kinase-activated protein kinase 2 (MK2) contributes to secondary damage after spinal cord injury. The Journal of neuroscience : the official journal of the Society for Neuroscience 49 20943915
2013 MAPKAP kinase 2 (MK2)-dependent and -independent models of blister formation in pemphigus vulgaris. The Journal of investigative dermatology 48 23657501
2009 A novel role for MAPKAPK2 in morphogenesis during zebrafish development. PLoS genetics 48 19282986
2010 MAPKAPK-2 signaling is critical for cutaneous wound healing. The Journal of investigative dermatology 47 19609314
2015 p38- and MK2-dependent signalling promotes stress-induced centriolar satellite remodelling via 14-3-3-dependent sequestration of CEP131/AZI1. Nature communications 46 26616734
2018 IL-33 regulates cytokine production and neutrophil recruitment via the p38 MAPK-activated kinases MK2/3. Immunology and cell biology 44 30171775
2009 SAGE analysis highlights the importance of p53csv, ddx5, mapkapk2 and ranbp2 to multiple myeloma tumorigenesis. Cancer letters 44 19171422
2017 Biological functions and role of mitogen-activated protein kinase activated protein kinase 2 (MK2) in inflammatory diseases. Pharmacological reports : PR 43 28582691
2015 MK2 inhibitory peptide delivered in nanopolyplexes prevents vascular graft intimal hyperplasia. Science translational medicine 43 26062847
2021 Rutin prevents inflammation-associated colon damage via inhibiting the p38/MAPKAPK2 and PI3K/Akt/GSK3β/NF-κB signalling axes and enhancing splenic Tregs in DSS-induced murine chronic colitis. Food & function 42 34302158
2010 MK2 SUMOylation regulates actin filament remodeling and subsequent migration in endothelial cells by inhibiting MK2 kinase and HSP27 phosphorylation. Blood 42 21131586
2008 DNA damage-induced S phase arrest in human breast cancer depends on Chk1, but G2 arrest can occur independently of Chk1, Chk2 or MAPKAPK2. Cell cycle (Georgetown, Tex.) 42 18469532
2019 Resveratrol inhibits IL-33-mediated mast cell activation by targeting the MK2/3-PI3K/Akt axis. Scientific reports 41 31804564
2017 MK2-TNF-Signaling Comes Full Circle. Trends in biochemical sciences 41 29275999
2004 MK2-/- gene knockout mouse hearts carry anti-apoptotic signal and are resistant to ischemia reperfusion injury. Journal of molecular and cellular cardiology 41 15623425
2020 MK2 Is Required for Neutrophil-Derived ROS Production and Inflammatory Bowel Disease. Frontiers in medicine 39 32596245
2008 Mitogen-activated protein kinase-activated protein kinase 2 (MK2) modulates key biological pathways associated with OA disease pathology. Osteoarthritis and cartilage 39 18562219
2006 Gene deletion of MK2 inhibits TNF-alpha and IL-6 and protects against cerulein-induced pancreatitis. American journal of physiology. Gastrointestinal and liver physiology 39 16423921
2015 Blockade of MK2 is protective in inflammation-associated colorectal cancer development. International journal of cancer 37 26238259
2018 Mesenchymal MAPKAPK2/HSP27 drives intestinal carcinogenesis. Proceedings of the National Academy of Sciences of the United States of America 36 29844172
2011 The p38/MK2/Hsp25 pathway is required for BMP-2-induced cell migration. PloS one 36 21297993
2006 Analysis of properties of small heat shock protein Hsp25 in MAPK-activated protein kinase 2 (MK2)-deficient cells: MK2-dependent insolubilization of Hsp25 oligomers correlates with susceptibility to stress. The Journal of biological chemistry 36 16840785
2019 Sophoridine Inhibits Human Colorectal Cancer Progression via Targeting MAPKAPK2. Molecular cancer research : MCR 35 31575657
2018 A Role for MK2 in Enhancing Neutrophil-Derived ROS Production and Aggravating Liver Ischemia/Reperfusion Injury. Frontiers in immunology 35 30483268
2019 The Role of TTP Phosphorylation in the Regulation of Inflammatory Cytokine Production by MK2/3. Journal of immunology (Baltimore, Md. : 1950) 33 31527197
2005 p38 mitogen-activated protein kinase plays a key role in regulating MAPKAPK2 expression. Biochemical and biophysical research communications 33 16198317
2018 MK2 Regulates Macrophage Chemokine Activity and Recruitment to Promote Colon Tumor Growth. Frontiers in immunology 32 30298062
2009 MK2 regulates the early stages of skin tumor promotion. Carcinogenesis 31 19808857
2007 Structural basis for a high affinity inhibitor bound to protein kinase MK2. Journal of molecular biology 31 17449059
2016 Treatment with MAPKAP2 (MK2) inhibitor and DNA methylation inhibitor, 5-aza dC, synergistically triggers apoptosis in hepatocellular carcinoma (HCC) via tristetraprolin (TTP). Cellular signalling 30 27619201
2021 Mitogen-activated protein kinase-activated protein kinase-2 (MK2) and its role in cell survival, inflammatory signaling, and migration in promoting cancer. Molecular carcinogenesis 29 34559922
2018 MK2 mediates macrophage activation and acute lung injury by regulating let-7e miRNA. American journal of physiology. Lung cellular and molecular physiology 29 29770701
2010 p38 MAP kinase and MAPKAP kinases MK2/3 cooperatively phosphorylate epithelial keratins. The Journal of biological chemistry 29 20724476
2009 Low-molecular-weight MK2 inhibitors: a tough nut to crack! Future medicinal chemistry 29 21426101
2016 MK2 inhibitor reduces alkali burn-induced inflammation in rat cornea. Scientific reports 28 27329698
2015 Treatment of Obese Insulin-Resistant Mice With an Allosteric MAPKAPK2/3 Inhibitor Lowers Blood Glucose and Improves Insulin Sensitivity. Diabetes 28 26068544
2022 Discovery of CC-99677, a selective targeted covalent MAPKAPK2 (MK2) inhibitor for autoimmune disorders. Translational research : the journal of laboratory and clinical medicine 27 35691544
2015 MK2 Deletion in Mice Prevents Diabetes-Induced Perturbations in Lipid Metabolism and Cardiac Dysfunction. Diabetes 27 26558681
2007 MAPKAPK2-mediated LSP1 phosphorylation and FMLP-induced neutrophil polarization. Biochemical and biophysical research communications 27 17481585
2019 The MK2 cascade regulates mGluR-dependent synaptic plasticity and reversal learning. Neuropharmacology 26 31129151
2019 Alternative Translation Initiation Generates a Functionally Distinct Isoform of the Stress-Activated Protein Kinase MK2. Cell reports 26 31167133
2019 MAPKAPK2 (MK2) inhibition mediates radiation-induced inflammatory cytokine production and tumor growth in head and neck squamous cell carcinoma. Oncogene 26 31417185
2022 CC-99677, a novel, oral, selective covalent MK2 inhibitor, sustainably reduces pro-inflammatory cytokine production. Arthritis research & therapy 25 35982464
2021 The MK2/Hsp27 axis is a major survival mechanism for pancreatic ductal adenocarcinoma under genotoxic stress. Science translational medicine 25 34851698
2019 Proinflammatory Effect of Endothelial Microparticles Is Mitochondria Mediated and Modulated Through MAPKAPK2 (MAPK-Activated Protein Kinase 2) Leading to Attenuation of Cardiac Hypertrophy. Arteriosclerosis, thrombosis, and vascular biology 25 31070456
2017 Induction of oxidative metabolism by the p38α/MK2 pathway. Scientific reports 25 28900160
2021 Therapeutic MK2 inhibition blocks pathological vascular smooth muscle cell phenotype switch. JCI insight 24 34622803
2012 MK2 posttranscriptionally regulates TNF-α-induced expression of ICAM-1 and IL-8 via tristetraprolin in human pulmonary microvascular endothelial cells. American journal of physiology. Lung cellular and molecular physiology 24 22268119
2009 MAPKAP kinase MK2 maintains self-renewal capacity of haematopoietic stem cells. The EMBO journal 24 19369945
2021 MicroRNA-24-3p Inhibits Microglia Inflammation by Regulating MK2 Following Spinal Cord Injury. Neurochemical research 22 33439430
2019 MAPKAPK2 plays a crucial role in the progression of head and neck squamous cell carcinoma by regulating transcript stability. Journal of experimental & clinical cancer research : CR 22 31023373
2022 Heat shock protein 60 couples an oxidative stress-responsive p38/MK2 signaling and NF-κB survival machinery in cancer cells. Redox biology 21 35316673
2019 Substrate-based kinase activity inference identifies MK2 as driver of colitis. Integrative biology : quantitative biosciences from nano to macro 21 31617572
2020 The MK2 pathway is linked to G-CSF, cytokine production and metastasis in gastric cancer: a novel intercorrelation analysis approach. Journal of translational medicine 20 32216812
2018 Sec6 enhances cell migration and suppresses apoptosis by elevating the phosphorylation of p38 MAPK, MK2, and HSP27. Cellular signalling 20 29729335
2020 Phosphorylation of steroid receptor coactivator-3 (SRC-3) at serine 857 is regulated by the p38MAPK-MK2 axis and affects NF-κB-mediated transcription. Scientific reports 19 32647362
2014 p38MAPK and MK2 pathways are important for the differentiation-dependent human papillomavirus life cycle. Journal of virology 19 25410865
2011 Discovery and Hit-to-Lead Optimization of Non-ATP Competitive MK2 (MAPKAPK2) Inhibitors. ACS medicinal chemistry letters 19 24900358
2021 Inhibition of Mitogen-Activated Protein Kinase (MAPK)-Activated Protein Kinase 2 (MK2) is Protective in Pulmonary Hypertension. Hypertension (Dallas, Tex. : 1979) 18 33641361
2019 Novel Therapeutic Potential of Mitogen-Activated Protein Kinase Activated Protein Kinase 2 (MK2) in Chronic Airway Inflammatory Disorders. Current drug targets 18 30112991
2013 Crucial roles of the protein kinases MK2 and MK3 in a mouse model of glomerulonephritis. PloS one 18 23372691

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