Affinage

MAPK12

Mitogen-activated protein kinase 12 · UniProt P53778

Length
367 aa
Mass
41.9 kDa
Annotated
2026-06-10
100 papers in source corpus 46 papers cited in narrative 46 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

MAPK12/p38γ is a stress-activated serine/threonine kinase of the p38 family that couples cellular stress and oncogenic signaling to substrate phosphorylation governing cell cycle, metabolism, cytoskeletal/synaptic organization, and immune output (PMID:9029150, PMID:30971822). It is activated by the upstream MAP2Ks MKK6 (and MKK3) through dual phosphorylation of its activation loop, but is insensitive to the p38α/β inhibitor SB203580, and its active form is structurally distinct in adopting a monomeric conformation (PMID:9029150, PMID:10508788). NMR and crystallographic dynamics show inactive p38γ fluctuates between an open ground state and a compact, activation-like excited state via a DFG-loop switch, and that its docking sites are allosterically coupled to the active-site state (PMID:27353957, PMID:31794659). A defining feature is its C-terminal PDZ-binding motif, which targets PDZ-domain proteins—SAP90/PSD-95, SAP97/hDlg, and α1-syntrophin—whose phosphorylation reorganizes cytoskeletal and synaptic junctional complexes, and which reciprocally recruits the PDZ-domain phosphatases PTPN3/PTPH1 and PTPN4 that dephosphorylate and inactivate p38γ (PMID:14741046, PMID:15729360, PMID:25314968, PMID:27246854). Functionally, p38γ acts as a CDK-like kinase phosphorylating Rb to drive G0→G1 entry and liver tumorigenesis, and broadly rewires metabolism by phosphorylating PFKFB3 (Ser-467) to promote KRAS-driven aerobic glycolysis, GYS1 to control cardiac glycogen metabolism, DEPTOR to activate mTOR, and Akt to oppose AMPK signaling (PMID:30971822, PMID:32580961, PMID:34758018, PMID:26795633, PMID:32783890). In the heart it promotes pathological hypertrophy and arrhythmia via DEPTOR/mTOR, calpastatin, GYS1, and RyR2/Kv4.3 (PMID:26795633, PMID:31638431, PMID:34758018, PMID:39196141), in neurons it phosphorylates tau at Thr205 to confer neuroprotection against amyloid-β and seizures (PMID:32725265, PMID:36459557), and in macrophages it (with p38δ) controls innate immunity by stabilizing TPL2 and phosphorylating MEF2D at Ser-444 (PMID:22733747, PMID:37458356). Across cancers, p38γ cooperates with c-Jun/AP-1 and PTPH1 to drive Ras transformation, invasion, and drug resistance (PMID:20332238, PMID:22730326, PMID:28739874).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1996 High

    Established p38γ as an active, tyrosine-phosphorylated kinase with a developmental role, answering whether the protein was a functional MAPK and where it acts.

    Evidence Transfection in 293 cells with MBP kinase assay; wild-type and dominant-negative Y185F in C2C12 myoblast differentiation

    PMID:8633070

    Open questions at the time
    • Physiological upstream activator not identified
    • Endogenous substrates in muscle differentiation unknown
  2. 1997 High

    Defined the upstream activator and pharmacological/substrate distinctions from p38α, answering how p38γ is switched on and how it differs functionally.

    Evidence In vitro kinase assays, MKK6 co-transfection, substrate phosphorylation mapping (ATF2, Elk-1, SAP1), SB203580 testing

    PMID:9029150

    Open questions at the time
    • In vitro substrate set may not reflect physiological targets
    • Selectivity of MKK6 vs MKK3 not resolved
  3. 1999 High

    Provided the first structural and kinetic mechanism of the active enzyme, answering how activation-loop phosphorylation produces a catalytically competent monomer.

    Evidence X-ray crystallography of doubly phosphorylated p38γ with ATP analog; ATPase kinetics, FSBA affinity labeling at Lys-56

    PMID:10508788 PMID:10567720

    Open questions at the time
    • Structure of inactive state not yet determined
    • No structure with a physiological protein substrate
  4. 2000 High

    Placed p38γ in DNA-damage checkpoint control, answering whether the isoform has a non-redundant cell-cycle function.

    Evidence Dominant-negative MKK6/p38γ with ATM/Chk2 epistasis and cell cycle profiling after γ-irradiation

    PMID:10848581

    Open questions at the time
    • Direct p38γ substrate in the checkpoint not identified
    • A later study found p38γ RNAi alone did not impair IR checkpoints (#44)
  5. 2003 High

    Identified the PDZ-binding motif as the determinant of substrate specificity toward synaptic scaffolds, answering how p38γ selects PDZ-domain substrates.

    Evidence In vitro kinase assays, phospho-site mapping, PDZ binding and Tat-peptide disruption, co-IP from brain, confocal localization (SAP90/PSD-95, SAP97/hDlg)

    PMID:14741046 PMID:15729360

    Open questions at the time
    • In vivo consequence of synaptic scaffold phosphorylation not established
    • Stoichiometry of phosphorylation in neurons unknown
  6. 2005 Medium

    Connected p38γ to Ras transformation through both kinase-independent ERK complex formation and oncogenic cooperation, answering how it contributes to cancer.

    Evidence shRNA depletion, p38γ-ERK co-IP, Ras transformation assays; p38α-dependent degradation via c-Jun/proteasome

    PMID:15851477 PMID:17724032

    Open questions at the time
    • Phosphorylation-independent mechanism inferred from co-IP only
    • Single-lab observations
  7. 2010 High

    Defined the PTPH1/PTPN3 phosphatase as a reciprocal partner and oncogenic cofactor, answering how p38γ activity is turned off and amplified in Ras signaling.

    Evidence Yeast two-hybrid, co-IP, PDZ-binding analysis, Ras transformation; later proteomic identification of PTPH1 Ser-459 as a p38γ site

    PMID:20332238 PMID:22730326

    Open questions at the time
    • In vivo relevance of the p38γ-PTPH1 feedback loop incompletely defined
  8. 2014 High

    Solved the structural basis of p38γ dephosphorylation by PDZ-domain phosphatases, answering how PDZ engagement relieves phosphatase autoinhibition.

    Evidence Hybrid structural methods (X-ray, SAXS, XL-MS) of PTPN3-p38γ; crystal structure of PTPN4 PDZ-p38γ C-terminus with phosphatase assays

    PMID:25314968 PMID:27246854

    Open questions at the time
    • Cellular dynamics of complex assembly not quantified
    • Competition between substrate-PDZ and phosphatase-PDZ binding not resolved
  9. 2012 High

    Established p38γ as a regulator of immune ERK signaling via TPL2 stability, answering how p38γ/δ shape innate immune output.

    Evidence p38γ/δ double knockout mice, LPS stimulation, TPL2/phospho-ERK immunoblotting, bone-marrow chimeras; later 3'UTR/ACO1 translational mechanism

    PMID:22733747 PMID:35994673

    Open questions at the time
    • Direct phosphorylation events controlling TPL2 stability not fully mapped
    • Relative weight of stability vs translational control unclear
  10. 2019 High

    Reframed p38γ as a CDK-like kinase and master metabolic regulator, answering how a stress kinase drives proliferation and glycolytic rewiring in cancer.

    Evidence Hepatocyte-specific KO with Rb phosphorylation and inhibitor-sensitivity comparison; KRAS-dependent PFKFB3 Ser-467 phosphorylation with pancreatic KO; analog-sensitive identification of calpastatin

    PMID:30971822 PMID:31638431 PMID:32580961

    Open questions at the time
    • Determinants of CDK-like vs MAPK-like substrate choice not defined
    • Crosstalk between metabolic and proliferative substrate programs unmapped
  11. 2020 High

    Defined p38γ's neuroprotective tau-T205 phosphorylation and its metabolic action on Akt, answering tissue-specific protective and pathological roles.

    Evidence AAV gene therapy with tauT205A mutagenesis in AD/epilepsy mouse models; in vitro Akt kinase assay with imidazole-propionate mouse model and siRNA

    PMID:32725265 PMID:32783890 PMID:36459557

    Open questions at the time
    • Mechanism linking T205 phosphorylation to amyloid-β protection incompletely defined
    • Localization signals directing p38γ to postsynaptic compartments unknown
  12. 2023 High

    Consolidated cardiac and immune substrate programs, answering how p38γ/δ drive hypertrophy, arrhythmia, and immune gene control through discrete substrates.

    Evidence Cardiac-specific KO/knock-in mice with DEPTOR, GYS1, RyR2/Kv4.3, and MEF2D-Ser444 phosphorylation; MKK6-deficiency epistasis placing MKK3-p38γ/δ upstream of mTOR

    PMID:26795633 PMID:34758018 PMID:35971771 PMID:37458356 PMID:39196141

    Open questions at the time
    • Tissue-specific selectivity among the many substrates not mechanistically explained
    • p38γ vs p38δ division of labor incompletely separated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How p38γ's PDZ-motif, CDK-like, and stress-kinase activities are integrated to select among its diverse substrates in a given tissue and stimulus remains unresolved.
  • No unified model of substrate selection across contexts
  • No direct human disease-causing mutation defined in this corpus
  • Determinants of subcellular targeting between synapse, nucleus, and cytoplasm unknown

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 5 GO:0060089 molecular transducer activity 2 GO:0140657 ATP-dependent activity 1
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-1640170 Cell Cycle 4 R-HSA-1643685 Disease 4 R-HSA-1430728 Metabolism 3 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-8953897 Cellular responses to stimuli 2
Partners
DLG1DLG4JUNMKK3MKK6PFKFB3PTPN3PTPN4
Complex memberships
TPL2/ABIN2/NF-κB1p105 complexp38γ-PTPN3(PTPH1) complexp38γ-PTPN4 complex

Evidence

Reading pass · 46 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 SAPK3/p38γ is activated by SAPKK3 (MKK6) in vitro and in cells in response to cellular stresses, IL-1, and TNF. SAPKK3 is the specific upstream activator induced under these conditions. Unlike SAPK2/p38α, SAPK3/p38γ is not inhibited by SB203580. SAPK3/p38γ phosphorylates ATF2 at Thr69, Thr71, and Ser90 (whereas SAPK2 only phosphorylates Thr69 and Thr71), and also phosphorylates Elk-1 and SAP1, but is far less effective than SAPK2 at activating MAPKAP kinase-2 and MAPKAP kinase-3. In vitro kinase assay, co-transfection with MKK6 in mammalian cells, substrate phosphorylation mapping, pharmacological inhibition with SB203580 The EMBO journal High 9029150
1996 ERK6/p38γ is activated by tyrosine phosphorylation in transfected 293 cells, producing 46- and 56-kDa forms that phosphorylate myelin basic protein. Overexpression of wild-type ERK6 enhances C2C12 myoblast differentiation to myotubes, while the kinase-inactive Y185F mutant inhibits differentiation, without effects on proliferation. Transfection in 293 cells, kinase assay with myelin basic protein, overexpression and dominant-negative in C2C12 differentiation assay Proceedings of the National Academy of Sciences of the United States of America High 8633070
1999 Crystal structure of doubly phosphorylated (active) p38γ in complex with an ATP analog was determined by X-ray crystallography. Phospho-Thr183 forms hydrogen bonds with five basic amino acids inducing an interdomain rotation. The activation-loop conformation of active p38γ is nearly identical to activated ERK2. Unlike ERK2, activated p38γ exists as a monomer in both crystal and solution. X-ray crystallography, solution studies Structure (London, England : 1993) High 10508788
1999 Active p38γ exhibits basal ATPase activity independent of a substrate; addition of phosphoacceptor substrate increases kcat/Km 20-fold. AMP-PCP is competitive with ATP and non-competitive with phosphoacceptor substrate. The affinity label FSBA binds stoichiometrically at Lys-56 in the ATP site of both phosphorylated and unphosphorylated p38γ, but AMP-PCP protects only activated p38γ from FSBA inactivation, indicating AMP-PCP does not bind unphosphorylated p38γ. In vitro ATPase assay, competitive inhibition kinetics, affinity labeling with FSBA, site identification FEBS letters High 10567720
2000 Activation of the MKK6-p38γ cascade (but not other p38 isoforms) is required for γ-irradiation-induced G2 cell cycle arrest. This pathway is dependent on ATM and leads to activation of Chk2 (Cds1). Dominant-negative alleles of MKK6 or p38γ allow cells to escape DNA damage-induced G2 delay. Dominant-negative overexpression, epistasis analysis with ATM and Chk2, cell cycle profiling after γ-irradiation Molecular and cellular biology High 10848581
2003 Xp38γ/SAPK3 (Xenopus ortholog) promotes meiotic G2/M transition in Xenopus oocytes. Constitutively active MKK6 activates p38γ as the predominant p38 isoform in oocytes; co-expression induces maturation without progesterone. Xp38γ phosphorylates and activates Cdc25C, with Ser205 identified as a major phosphorylation site. Xenopus oocyte overexpression, kinase assay on Cdc25C, phosphorylation site mapping, kinase-dead mutant epistasis The EMBO journal High 14592973
2004 SAPK3/p38γ binds through its C-terminal PDZ-binding motif to the third PDZ domain of SAP90/PSD-95 and phosphorylates it at Thr287 and Ser290 in vitro, and at Ser290 in cells under stress. Phosphorylation requires PDZ-domain binding; disrupting this interaction with a cell-permeant Tat fusion peptide abolishes phosphorylation. p38γ co-localizes and co-immunoprecipitates with SAP90 from brain synaptic junctional preparations. In vitro kinase assay, phosphorylation site mapping, PDZ domain binding assay, co-IP from brain fractions, Tat peptide disruption, confocal co-localization in neurons The Biochemical journal High 14741046
2005 SAPK3/p38γ-catalyzed phosphorylation of SAP97/hDlg triggers its dissociation from GKAP, releasing SAP97 from the cytoskeleton. This regulates the integrity of intercellular junctional complexes and cell shape/volume in response to osmotic stress. In vitro kinase assay, co-IP, osmotic stress treatment, phosphorylation-dependent protein complex analysis The EMBO journal High 15729360
2005 K-Ras activates p38γ by inducing its expression without increasing its phosphorylation. Unphosphorylated p38γ promotes Ras transformation through increased complex formation with ERK proteins. Depletion of p38γ suppresses K-Ras transformation in rat intestinal epithelial cells. shRNA depletion, co-immunoprecipitation of p38γ-ERK complex, Ras transformation assay, expression analysis The Journal of biological chemistry Medium 15851477
2007 p38α phosphorylation depletes p38γ protein via c-Jun-dependent ubiquitin-proteasome pathways, acting as a gatekeeper. Active p38α increases c-Jun phosphorylation and AP-1 activation, whereas active p38γ suppresses c-Jun phosphorylation and AP-1 and is itself degraded when p38α is activated. This cross-regulation controls Ras transformation and stress response. MKK6-p38 fusion (constitutively active) constructs, AP-1 reporter assay, proteasome inhibitor treatment, co-expression studies The Journal of biological chemistry Medium 17724032
2009 p38γ is essential for endurance exercise-induced mitochondrial biogenesis and angiogenesis in skeletal muscle, operating through a p38γ-PGC-1α regulatory axis. Muscle-specific deletion of p38γ (but not p38α or p38β) abolishes contractile activity-dependent Pgc-1α and Vegf transcription. Gene transfer of dominant-negative p38γ blocked motor-nerve-stimulation-induced Pgc-1α transcription. Muscle-specific gene deletion in mice, motor nerve stimulation, gene transfer with dominant-negative constructs, real-time PCR and microarray PloS one High 19936205
2009 p38γ (but not p38α) mediates oncogenic Ras-induced senescence by phosphorylating p53 at Ser33, thereby stimulating p53 transcriptional activity. shRNA silencing of p38γ abrogates Ras-induced senescence; constitutive activation of p38γ causes premature senescence. shRNA knockdown, constitutively active p38γ overexpression, p53 phosphorylation assay, senescence assay The Journal of biological chemistry Medium 19251701
2010 p38γ cooperates with c-Jun as both an activator and a cofactor: activated c-Jun recruits p38γ into the MMP9 promoter to induce its trans-activation and cell invasion. p38γ requires phosphorylation and its C-terminus to bind c-Jun; both are required for MMP9 trans-activation. ChIP, co-IP, promoter reporter assay, invasion assay, dominant-negative and overexpression studies The Journal of biological chemistry Medium 20231272
2010 PTPH1 is a specific phosphatase for p38γ through PDZ-mediated binding. PTPH1 dephosphorylates p38γ and cooperates with it in Ras oncogenesis. Ras increases both p38γ and PTPH1 expression, and there is co-overexpression of p38γ and PTPH1 in primary colon cancer. Yeast two-hybrid, co-IP in vitro and in vivo, PDZ-binding domain analysis, Ras transformation assay Cancer research Medium 20332238
2010 Loss of p38γ in HeLa cells causes multipolar spindle formation and chromosome misalignment, inducing M-phase arrest followed by cell death. p38γ is required for normal kinetochore localization of Polo-like kinase 1 (Plk1), and p38 MAPKs are activated at kinetochores and spindle poles throughout mitosis. siRNA knockdown, live-cell imaging, immunofluorescence of mitotic structures and kinetochore proteins Journal of cell science Medium 21172807
2010 In response to hyperosmotic stress, p38γ in the nucleus increases its association with nuclear hDlg, causing dissociation of hDlg-PSF complexes and hDlg-RNA dissociation, independently of p38γ kinase activity. This suggests a non-catalytic scaffolding role for p38γ in regulating mRNA processing/transcription. Co-IP, subcellular fractionation, osmotic stress treatment, kinase-dead mutant analysis Journal of cell science Medium 20605917
2011 p38γ promotes breast cancer cell motility and metastasis by controlling expression of RhoC GTPase through modulation of RhoC ubiquitination. siRNA knockdown, overexpression, ubiquitination assay, migration/invasion assay, in vivo metastasis model Cancer research Medium 21862636
2012 p38γ is specifically activated by topoisomerase II drugs (not paclitaxel) in breast cancer cells; activated p38γ phosphorylates and stabilizes Topo IIα protein, enhancing growth inhibition by Topo II drugs. p38γ activity is necessary and sufficient for Topo IIα expression. In vitro kinase assay, overexpression and knockdown, protein stability assay, cell viability assay The Journal of biological chemistry Medium 21878638
2012 p38γ is selectively activated by tamoxifen treatment; it phosphorylates ERα at Ser-118 and stimulates c-Jun transcription, switching ER signaling from classical (ERE) to nonclassical (AP-1) pathway. ERα phosphorylation at Ser-118 is required for ER to bind both p38γ and c-Jun, promoting ER relocation from ERE to AP-1 promoter sites. Kinase assay, co-IP, ChIP, ERE/AP-1 reporter assay, site-directed mutagenesis (Ser-118) The Journal of biological chemistry Medium 22399296
2012 p38γ phosphorylates its specific phosphatase PTPH1 at Ser-459 through PDZ-mediated complex formation in vitro and in vivo. Ser-459 phosphorylation is directly regulated by Ras signaling and is important for Ras, p38γ, and PTPH1 oncogenic activity. Unbiased proteomic analysis, in vitro kinase assay, phospho-site-specific mutagenesis (Ser-459), co-IP, genetic and pharmacological epistasis The Journal of biological chemistry High 22730326
2012 p38γ and p38δ maintain steady-state levels of TPL2 kinase in macrophages and dendritic cells, enabling ERK1/2 activation after TLR4 stimulation by LPS. Loss of p38γ/δ blocks ERK1/2 activation and alters cytokine production profile. p38γ/δ double knockout mice, LPS stimulation, immunoblotting for TPL2 and phospho-ERK1/2, cytokine ELISA, bone marrow transplant chimeras Proceedings of the National Academy of Sciences of the United States of America High 22733747
2014 The PTPN3 (PTPH1)-p38γ complex structure was determined by hybrid methods (X-ray crystallography, SAXS, chemical cross-linking/MS). The E-loop of PTPN3's phosphatase domain defines substrate specificity toward fully activated p38γ. The PDZ domain of PTPN3 stabilizes the active-state complex via interaction with the PDZ-binding motif of p38γ, alleviating PTPN3 autoinhibition and enabling efficient tyrosine dephosphorylation of p38γ. X-ray crystallography, SAXS, chemical cross-linking coupled to mass spectrometry, PDZ-binding assay Science signaling High 25314968
2016 Crystal structure of the PDZ domain of PTPN4 bound to the C-terminus of p38γ was determined. The p38γ C-terminus binds the PDZ domain with highest affinity among endogenous PTPN4 partners; this binding activates PTPN4 by abolishing its catalytic autoinhibition, enabling efficient dephosphorylation of the p38γ activation loop. X-ray crystallography, co-IP, PDZ binding affinity measurements, phosphatase activity assay The Journal of biological chemistry High 27246854
2016 p38γ and p38δ promote cardiac hypertrophy by phosphorylating DEPTOR, leading to its proteasomal degradation and consequent mTOR activation. Hearts from mice lacking one or both kinases have elevated DEPTOR, reduced mTOR activity, and reduced protein synthesis. Cardiac phenotype is rescued by mTOR overactivation, Deptor shRNA knockdown, or cardiomyocyte overexpression of active p38γ/δ. Cardiac-specific KO mice, rescue experiments with mTOR activation/Deptor shRNA/active kinase overexpression, in vitro phosphorylation assay, protein stability assay Nature communications High 26795633
2019 p38γ acts as a CDK-like kinase, phosphorylating retinoblastoma protein (Rb) at known CDK target residues to promote the G0-to-G1 cell cycle transition. p38γ shares substrate specificity and inhibitor sensitivity with CDK family members. Lack of p38γ or pirfenidone treatment protects against chemically induced liver tumour formation. Hepatocyte-specific knockout, partial hepatectomy model, Rb phosphorylation assay, sequence homology and inhibitor sensitivity comparison, pharmacological inhibition Nature High 30971822
2019 p38γ interacts with the glycolytic activator PFKFB3 in a KRAS-dependent manner. p38γ phosphorylates PFKFB3 at Ser-467, stabilizing PFKFB3 and promoting its interaction with GLUT2, thereby enhancing aerobic glycolysis. Pancreatic knockout of p38γ decreases p-PFKFB3/PFKFB3/GLUT2 levels, reduces aerobic glycolysis, and inhibits PDAC tumorigenesis. Co-IP, in vitro kinase assay with phospho-site mapping (Ser-467), pancreatic KO in KPC mice, glycolysis assays, protein stability assay Cancer research High 32580961
2019 p38γ calpastatin as a direct substrate was identified using an analog-sensitive p38γ mutant. Phosphorylation of calpastatin by p38γ impairs its ability to inhibit the protease calpain. p38γ KO mice develop less ventricular hypertrophy after aortic banding, consistent with calpain disinhibition contributing to pathological remodeling. Analog-sensitive kinase substrate labeling, affinity purification/mass spectrometry, in vitro phosphorylation-inhibition assay for calpastatin-calpain, cardiac KO with aortic banding FASEB journal High 31638431
2020 Imidazole propionate activates p38γ, which acts as a novel kinase for Akt, inducing inhibitory Akt phosphorylation. This leads to inhibitory AMPK phosphorylation, blocking metformin-induced glucose lowering. p38γ kinase activity mediates the inhibitory action of imidazole propionate on metformin. In vitro kinase assay showing p38γ phosphorylates Akt, mouse model pretreatment with imidazole propionate, siRNA knockdown of p38γ, AMPK phosphorylation assay Cell metabolism High 32783890
2020 p38γ phosphorylates tau at Thr205 (T205) at postsynaptic compartments, inhibiting toxic amyloid-β signals. This phosphorylation event is critical for downstream neuroprotective effects: reconstitution with phosphorylation-deficient tauT205A abolished protection in APP-transgenic mice. Gene therapeutic AAV delivery, phospho-site mutagenesis (T205A), memory testing in AD mouse models, genome editing of T205 codon Acta neuropathologica High 32725265
2021 p38γ and p38δ contribute to the postnatal cardiac metabolic switch from glycolysis to fatty acid oxidation through inhibitory phosphorylation of glycogen synthase 1 (GYS1), leading to glycogen metabolism inactivation. p38γ/δ KO mice, cardiomyocyte-specific overexpression, GYS1 phosphorylation assay, metabolic measurements PLoS biology High 34758018
2022 MKK6 deficiency causes compensatory hyperactivation of the MKK3-p38γ/δ pathway, leading to increased mTOR signaling and cardiac hypertrophy. Cardiac hypertrophy in MKK6-KO mice is reverted by knocking out p38γ or p38δ or by rapamycin treatment, placing MKK3-p38γ/δ upstream of mTOR in cardiac hypertrophy. MKK6 KO mice, double KO (MKK6/p38γ or MKK6/p38δ), rapamycin treatment, cardiac function measurements eLife High 35971771
2022 p38γ-mediated phosphorylation of tau at T205 is essential for seizure protection in epilepsy models. AAV-mediated p38γ activity enhancement reduces seizure susceptibility and ameliorates neuronal deficits; lack of the p38γ-tau-T205 interaction reinstates pathological features. AAV gene delivery of p38γ in mouse epilepsy models, phosphorylation-deficient tauT205A mutant, seizure threshold measurement Science advances High 36459557
2023 p38γ and p38δ phosphorylate the transcription factor MEF2D at Ser444, and this phosphorylation suppresses MEF2D transcriptional activity. Mutation of MEF2D Ser444 to Ala (non-phosphorylatable) increased transcriptional activity and expression of Nos2 and Il1b mRNA, demonstrating that p38γ/δ govern innate immune responses through MEF2D regulation. Phospho-proteomic analysis, in vitro kinase assay, site-directed mutagenesis (S444A), gene expression analysis in p38γ/δ kinase-inactive knock-in mouse macrophages eLife High 37458356
2023 p38γ and p38δ regulate TPL2 protein levels posttranscriptionally by two mechanisms: (1) interacting with the TPL2/ABIN2/NF-κB1p105 complex to increase TPL2 protein stability, and (2) regulating TPL2 mRNA translation through modulation of the repressor function of TPL2 3'UTR mediated by aconitase-1 (ACO1). p38δ binds ACO1 and its expression restores TPL2 protein levels. Co-IP, mRNA translation assay with 3'UTR reporter, ACO1 overexpression, p38δ rescue in KO cells Proceedings of the National Academy of Sciences of the United States of America Medium 35994673
2023 p38γ phosphorylates CARM1 at Ser-595 under oxidative stress, causing CARM1 translocation from nucleus to cytoplasm. Cytoplasmic CARM1 methylates DRP1 and accelerates mitochondrial fission, enhancing ROS production and driving cellular senescence. This creates a positive feedback loop between ROS, p38γ activation, and CARM1 cytoplasmic localization. In vitro kinase assay, co-IP, subcellular fractionation, phospho-site specific analysis (S595), mitochondrial dynamics imaging Redox biology Medium 39265499
2023 p38γ and p38δ phosphorylate ryanodine receptor 2 (RyR2) and disrupt Kv4.3 channel localization upon activation, promoting sarcoplasmic reticulum calcium leak, Ito current reduction, and action potential duration prolongation, increasing susceptibility to ventricular fibrillation. Phosphorylation assays, ion channel electrophysiology, calcium imaging, p38γ/δ KO and activation mouse models Nature cardiovascular research High 39196141
2002 SAPK3/p38γ localizes to punctate, non-nuclear structures in cardiac myocytes, distinct from the non-punctate cytosolic/nuclear distribution of p38α/β. Treatment with Leptomycin B (blocking nuclear export) increases nuclear p38α/β but does not alter SAPK3/p38γ localization, suggesting p38γ does not undergo nuclear export-dependent cycling. Monoclonal antibody generation, immunofluorescence, confocal microscopy, Leptomycin B treatment Journal of molecular and cellular cardiology Medium 11991731
2016 NMR chemical shift perturbation mapping of p38γ reveals intramolecular allosteric networks and information flux between regulatory sites (activation loop, DFG loop, ATP-binding site, docking sites). The network is differentially accessed in different functional states (apo, phosphorylated, ATP-bound), demonstrating that p38γ docking sites are allosterically regulated by active-site state. NMR spectroscopy, chemical shift perturbation analysis in multiple states Scientific reports Medium 27353957
2019 Inactive p38γ fluctuates on a millisecond timescale between an open ground state and a weakly populated compact excited state (similar to the activated enzyme conformation) involving a molecular switch associated with the DFG loop. This was identified by X-ray crystallography (two molecules in asymmetric unit) and NMR relaxation dispersion. X-ray crystallography (inactive apo p38γ), NMR relaxation dispersion measurements Biochemistry High 31794659
2015 p38γ stimulates Nanog transcription through c-Jun/AP-1 via multi-protein complex formation, driving cancer stem-like cell expansion in triple-negative breast cancer. ChIP, co-IP (multi-protein complex), reporter assay, siRNA knockdown, mammosphere formation assay Stem cells (Dayton, Ohio) Medium 26077647
2017 The K-Ras effector p38γ confers resistance to EGFR tyrosine kinase inhibitors by concurrently increasing EGFR transcription (via c-Jun promoter binding) and promoting EGFR dephosphorylation (via activation of PTPH1). Silencing the p38γ/c-Jun/PTPH1 network restores TKI sensitivity in K-Ras mutant cancer cells. ChIP, co-IP, siRNA knockdown, kinase inhibitor sensitivity assays, promoter reporter assay The Journal of biological chemistry Medium 28739874
2018 p38γ induces EMT in breast cancer cells and augments cancer stem cell populations by inhibiting GATA3 through ubiquitination-dependent proteasomal degradation, which suppresses miR-200b expression, leading to increased Suz12 and EMT. Overexpression and siRNA knockdown, ubiquitination assay, miR-200b mimic/inhibitor, proteasome inhibitor treatment Biochimica et biophysica acta. Molecular basis of disease Medium 30251680
2015 p38γ promotes β-catenin/Wnt signaling in colon cancer by phosphorylating β-catenin at Ser605, stimulating Wnt transcription. Intestinal epithelial-specific p38γ KO attenuates colitis and inhibits pro-inflammatory cytokine expression and tumorigenesis in a colitis-associated mouse model. Intestinal epithelial-specific KO, phosphorylation assay (Ser605), Wnt reporter assay, colitis-associated tumorigenesis model Oncogene Medium 25961922
2003 p38γ (ERK6) expression is developmentally regulated in skeletal muscle: mRNA and protein levels increase during differentiation of myoblast cell lines in vitro and during postnatal development in rat hindlimb muscle in vivo, in contrast to p42/p44 MAPK and p38, which do not change. Northern blot, immunoblotting during in vitro differentiation and in vivo postnatal development Biochemical and biophysical research communications Medium 12788083
2004 MRK (a MAP3K) is a specific upstream activator of p38γ but not p38α after ionizing radiation. MRK depletion reduces IR-induced p38γ activation. Inhibition of p38γ alone by RNAi did not impair IR-induced checkpoints, suggesting MRK controls checkpoint signaling through a p38γ-independent pathway (Chk2-Cdc25A) in parallel to p38γ activation. siRNA knockdown of MRK and p38γ, phospho-specific antibody to MRK, Chk2 phosphorylation assay, cell cycle checkpoint analysis The Journal of biological chemistry Medium 15342622
2020 In DLB/PD brains and α-synuclein transgenic mice, p38γ is redistributed from synaptic terminals to neuronal cell bodies and colocalizes with α-synuclein aggregates. α-synuclein co-immunoprecipitates with p38γ but not p38α in vitro. In healthy tissue, p38γ localizes to presynaptic terminals where it normally associates with α1-syntrophin. Immunohistochemistry, co-immunoprecipitation, immunoblotting, qPCR, subcellular fractionation in human and mouse brain Frontiers in neuroscience Medium 32296304

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 Activation of stress-activated protein kinase-3 (SAPK3) by cytokines and cellular stresses is mediated via SAPKK3 (MKK6); comparison of the specificities of SAPK3 and SAPK2 (RK/p38). The EMBO journal 327 9029150
1996 ERK6, a mitogen-activated protein kinase involved in C2C12 myoblast differentiation. Proceedings of the National Academy of Sciences of the United States of America 269 8633070
2000 Involvement of the MKK6-p38gamma cascade in gamma-radiation-induced cell cycle arrest. Molecular and cellular biology 228 10848581
2005 p38gamma regulates the localisation of SAP97 in the cytoskeleton by modulating its interaction with GKAP. The EMBO journal 206 15729360
1999 Selective activation of p38alpha and p38gamma by hypoxia. Role in regulation of cyclin D1 by hypoxia in PC12 cells. The Journal of biological chemistry 164 10438538
2002 Aldosterone stimulates proliferation of cardiac fibroblasts by activating Ki-RasA and MAPK1/2 signaling. American journal of physiology. Heart and circulatory physiology 156 12388314
1999 The structure of phosphorylated p38gamma is monomeric and reveals a conserved activation-loop conformation. Structure (London, England : 1993) 128 10508788
2009 p38gamma mitogen-activated protein kinase is a key regulator in skeletal muscle metabolic adaptation in mice. PloS one 124 19936205
2020 Microbial Imidazole Propionate Affects Responses to Metformin through p38γ-Dependent Inhibitory AMPK Phosphorylation. Cell metabolism 119 32783890
2012 p38γ and p38δ kinases regulate the Toll-like receptor 4 (TLR4)-induced cytokine production by controlling ERK1/2 protein kinase pathway activation. Proceedings of the National Academy of Sciences of the United States of America 108 22733747
2019 p38γ is essential for cell cycle progression and liver tumorigenesis. Nature 87 30971822
2017 p38γ and p38δ: From Spectators to Key Physiological Players. Trends in biochemical sciences 82 28473179
2003 p38gamma MAPK regulation of glucose transporter expression and glucose uptake in L6 myotubes and mouse skeletal muscle. American journal of physiology. Regulatory, integrative and comparative physiology 81 14592936
2010 p38gamma MAPK cooperates with c-Jun in trans-activating matrix metalloproteinase 9. The Journal of biological chemistry 80 20231272
2004 Stress- and mitogen-induced phosphorylation of the synapse-associated protein SAP90/PSD-95 by activation of SAPK3/p38gamma and ERK1/ERK2. The Biochemical journal 79 14741046
2014 Pro-oncogenic role of alternative p38 mitogen-activated protein kinases p38γ and p38δ, linking inflammation and cancer in colitis-associated colon cancer. Cancer research 73 25217523
2020 p38γ MAPK Is Essential for Aerobic Glycolysis and Pancreatic Tumorigenesis. Cancer research 70 32580961
2016 p38γ and δ promote heart hypertrophy by targeting the mTOR-inhibitory protein DEPTOR for degradation. Nature communications 66 26795633
2010 PTPH1 dephosphorylates and cooperates with p38gamma MAPK to increase ras oncogenesis through PDZ-mediated interaction. Cancer research 66 20332238
2011 New Insights into the p38γ and p38δ MAPK Pathways. Journal of signal transduction 64 22175015
2009 p38alpha and p38gamma mediate oncogenic ras-induced senescence through differential mechanisms. The Journal of biological chemistry 62 19251701
2016 p38γ and p38δ Mitogen Activated Protein Kinases (MAPKs), New Stars in the MAPK Galaxy. Frontiers in cell and developmental biology 61 27148533
2018 Role of p38γ MAPK in regulation of EMT and cancer stem cells. Biochimica et biophysica acta. Molecular basis of disease 56 30251680
2007 p38alpha antagonizes p38gamma activity through c-Jun-dependent ubiquitin-proteasome pathways in regulating Ras transformation and stress response. The Journal of biological chemistry 55 17724032
2005 Essential role of p38gamma in K-Ras transformation independent of phosphorylation. The Journal of biological chemistry 55 15851477
2016 ErbB2 and p38γ MAPK mediate alcohol-induced increase in breast cancer stem cells and metastasis. Molecular cancer 52 27416801
2011 p38γ promotes breast cancer cell motility and metastasis through regulation of RhoC GTPase, cytoskeletal architecture, and a novel leading edge behavior. Cancer research 52 21862636
2011 p38γ mitogen-activated protein kinase contributes to oncogenic properties maintenance and resistance to poly (ADP-ribose)-polymerase-1 inhibition in breast cancer. Neoplasia (New York, N.Y.) 47 21532888
2002 Cardiac expression and subcellular localization of the p38 mitogen-activated protein kinase member, stress-activated protein kinase-3 (SAPK3). Journal of molecular and cellular cardiology 46 11991731
2006 Hyperactive variants of p38alpha induce, whereas hyperactive variants of p38gamma suppress, activating protein 1-mediated transcription. The Journal of biological chemistry 45 17088247
2006 p38gamma mitogen-activated protein kinase integrates signaling crosstalk between Ras and estrogen receptor to increase breast cancer invasion. Cancer research 42 16885352
2004 Regulation of Na+ transport by aldosterone: signaling convergence and cross talk between the PI3-K and MAPK1/2 cascades. American journal of physiology. Renal physiology 42 15039143
2003 Xp38gamma/SAPK3 promotes meiotic G(2)/M transition in Xenopus oocytes and activates Cdc25C. The EMBO journal 42 14592973
2008 Efficient adult skeletal muscle regeneration in mice deficient in p38beta, p38gamma and p38delta MAP kinases. Cell cycle (Georgetown, Tex.) 39 18641461
2015 p38γ MAPK is required for inflammation-associated colon tumorigenesis. Oncogene 36 25961922
2016 Chronic ethanol exposure enhances the aggressiveness of breast cancer: the role of p38γ. Oncotarget 35 26655092
2015 p38γ MAPK Is a Therapeutic Target for Triple-Negative Breast Cancer by Stimulation of Cancer Stem-Like Cell Expansion. Stem cells (Dayton, Ohio) 34 26077647
2023 Inhibition of p38α MAPK restores neuronal p38γ MAPK and ameliorates synaptic degeneration in a mouse model of DLB/PD. Science translational medicine 31 37163617
2021 The Role of p38γ in Cancer: From review to outlook. International journal of biological sciences 31 34671218
2020 Reduction of advanced tau-mediated memory deficits by the MAP kinase p38γ. Acta neuropathologica 30 32725265
2013 p38γ overexpression in gliomas and its role in proliferation and apoptosis. Scientific reports 30 23807566
2010 Loss of p38gamma MAPK induces pleiotropic mitotic defects and massive cell death. Journal of cell science 30 21172807
2000 Cisplatin and UV radiation induce activation of the stress-activated protein kinase p38gamma in human melanoma cells. Biochemical and biophysical research communications 29 11095975
2002 Potent transforming activity of the small GTP-binding protein Rit in NIH 3T3 cells: evidence for a role of a p38gamma-dependent signaling pathway. FEBS letters 28 11821041
2022 MKK6 deficiency promotes cardiac dysfunction through MKK3-p38γ/δ-mTOR hyperactivation. eLife 27 35971771
2015 Combined deletion of p38γ and p38δ reduces skin inflammation and protects from carcinogenesis. Oncotarget 27 26079427
2011 Evidence of p38γ and p38δ involvement in cell transformation processes. Carcinogenesis 27 21558321
2004 The stress kinase MRK contributes to regulation of DNA damage checkpoints through a p38gamma-independent pathway. The Journal of biological chemistry 27 15342622
2018 Myeloid cell deficiency of p38γ/p38δ protects against candidiasis and regulates antifungal immunity. EMBO molecular medicine 26 29661910
2012 p38γ mitogen-activated protein kinase (MAPK) confers breast cancer hormone sensitivity by switching estrogen receptor (ER) signaling from classical to nonclassical pathway via stimulating ER phosphorylation and c-Jun transcription. The Journal of biological chemistry 26 22399296
2011 Phosphorylation and stabilization of topoisomerase IIα protein by p38γ mitogen-activated protein kinase sensitize breast cancer cells to its poisons. The Journal of biological chemistry 26 21878638
2010 p38gamma mitogen-activated protein kinase suppresses chondrocyte production of MMP-13 in response to catabolic stimulation. Osteoarthritis and cartilage 26 20633667
1999 Kinetic mechanism and ATP-binding site reactivity of p38gamma MAP kinase. FEBS letters 26 10567720
2012 p38γ Mitogen-activated protein kinase signals through phosphorylating its phosphatase PTPH1 in regulating ras protein oncogenesis and stress response. The Journal of biological chemistry 25 22730326
2022 The pro-tumorigenic activity of p38γ overexpression in nasopharyngeal carcinoma. Cell death & disease 24 35246508
2024 CARM1 phosphorylation at S595 by p38γ MAPK drives ROS-mediated cellular senescence. Redox biology 22 39265499
2016 Molecular Basis of the Interaction of the Human Protein Tyrosine Phosphatase Non-receptor Type 4 (PTPN4) with the Mitogen-activated Protein Kinase p38γ. The Journal of biological chemistry 22 27246854
2014 Loss-of-function RNAi screens in breast cancer cells identify AURKB, PLK1, PIK3R1, MAPK12, PRKD2, and PTK6 as sensitizing targets of rapamycin activity. Cancer letters 22 25193464
2010 Essential role for p38alpha MAPK but not p38gamma MAPK in Igf2 expression and myoblast differentiation. Endocrinology 22 20610565
2016 NMR Characterization of Information Flow and Allosteric Communities in the MAP Kinase p38γ. Scientific reports 21 27353957
2014 Reciprocal allosteric regulation of p38γ and PTPN3 involves a PDZ domain-modulated complex formation. Science signaling 21 25314968
2003 ERK6 is expressed in a developmentally regulated manner in rodent skeletal muscle. Biochemical and biophysical research communications 21 12788083
2024 Targeting the senescence-related genes MAPK12 and FOS to alleviate osteoarthritis. Journal of orthopaedic translation 20 39007035
2020 Role of Alterations in Protein Kinase p38γ in the Pathogenesis of the Synaptic Pathology in Dementia With Lewy Bodies and α-Synuclein Transgenic Models. Frontiers in neuroscience 20 32296304
2018 Diagnostic Significance of p38 Isoforms (p38α, p38β, p38γ, p38δ) in Head and Neck Squamous Cell Carcinoma: Comparative Serum Level Evaluation and Design of Novel Peptide Inhibitor Targeting the Same. Cancer research and treatment 20 29747487
2020 B Cell Development and T-Dependent Antibody Response Are Regulated by p38γ and p38δ. Frontiers in cell and developmental biology 19 32266269
2019 Targeting p38γ to inhibit human colorectal cancer cell progression. Biochemical and biophysical research communications 19 31349971
2018 Multi-Kinase Inhibitor with Anti-p38γ Activity in Cutaneous T-Cell Lymphoma. The Journal of investigative dermatology 19 29758280
2015 ErbB4 Activated p38γ MAPK Isoform Mediates Early Cardiogenesis Through NKx2.5 in Human Pluripotent Stem Cells. Stem cells (Dayton, Ohio) 18 26418945
2010 p38gamma regulates interaction of nuclear PSF and RNA with the tumour-suppressor hDlg in response to osmotic shock. Journal of cell science 18 20605917
2018 p38γ and p38δ Are Involved in T Lymphocyte Development. Frontiers in immunology 17 29434594
2017 miR-187 inhibits tumor growth and invasion by directly targeting MAPK12 in osteosarcoma. Experimental and therapeutic medicine 17 28810556
2012 p38γ activity is required for maintenance of slow skeletal muscle size. Muscle & nerve 17 22246884
2010 p38γ regulates UV-induced checkpoint signaling and repair of UV-induced DNA damage. Protein & cell 17 21170151
2023 P38γ modulates the lipid metabolism in non-alcoholic fatty liver disease by regulating the JAK-STAT signaling pathway. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 16 36527390
2023 p38γ MAPK Inflammatory and Metabolic Signaling in Physiology and Disease. Cells 15 37443708
2021 Deletion of p38γ attenuates ethanol consumption- and acetaminophen-induced liver injury in mice through promoting Dlg1. Acta pharmacologica Sinica 14 34789918
2023 Prolactin Regulates Ovine Ovarian Granulosa Cell Apoptosis by Affecting the Expression of MAPK12 Gene. International journal of molecular sciences 13 37373417
2021 p38γ and p38δ regulate postnatal cardiac metabolism through glycogen synthase 1. PLoS biology 13 34758018
2015 Clinicopathological significance of p38β, p38γ, and p38δ and its biological roles in esophageal squamous cell carcinoma. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 13 26666822
2019 p38γ MAPK contributes to left ventricular remodeling after pathologic stress and disinhibits calpain through phosphorylation of calpastatin. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 12 31638431
2016 Exenatide Regulates Substrate Preferences Through the p38γ MAPK Pathway After Ischaemia/Reperfusion Injury in a Rat Heart. Heart, lung & circulation 12 27574735
2011 p38γ activation triggers dynamical changes in allosteric docking sites. Biochemistry 12 21235211
2022 Treatment of epilepsy using a targeted p38γ kinase gene therapy. Science advances 11 36459557
2017 The K-Ras effector p38γ MAPK confers intrinsic resistance to tyrosine kinase inhibitors by stimulating EGFR transcription and EGFR dephosphorylation. The Journal of biological chemistry 11 28739874
2000 Novel regulation of p38gamma by dopamine D2 receptors during hypoxia. Cellular signalling 10 10989281
2024 p38γ MAPK delays myelination and remyelination and is abundant in multiple sclerosis lesions. Brain : a journal of neurology 9 38128553
2023 p38γ and p38δ modulate innate immune response by regulating MEF2D activation. eLife 9 37458356
2019 p38gamma overexpression promotes renal cell carcinoma cell growth, proliferation and migration. Biochemical and biophysical research communications 9 31229268
2011 Therapeutic hypothermia cardioprotection in murine hemorrhagic shock/resuscitation differentially affects p38α/p38γ, Akt, and HspB1. The Journal of trauma 9 22071928
2020 p38γ overexpression promotes osteosarcoma cell progression. Aging 8 32970611
2016 Comparative chemical array screening for p38γ/δ MAPK inhibitors using a single gatekeeper residue difference between p38α/β and p38γ/δ. Scientific reports 8 27431267
2022 TPL2 kinase expression is regulated by the p38γ/p38δ-dependent association of aconitase-1 with TPL2 mRNA. Proceedings of the National Academy of Sciences of the United States of America 7 35994673
2021 Targeting the non-ATP-binding pocket of the MAP kinase p38γ mediates a novel mechanism of cytotoxicity in cutaneous T-cell lymphoma (CTCL). FEBS letters 7 34455585
2020 p38γ Activation and BGP (Biliary Glycoprotein) Induction in Primates at Risk for Inflammatory Bowel Disease and Colorectal Cancer-A Comparative Study with Humans. Vaccines 7 33276422
2018 Impact of p38γ mitogen-activated protein kinase (MAPK) on MDA-MB-231 breast cancer cells using metabolomic approach. The international journal of biochemistry & cell biology 7 30447427
2019 A Dynamic Switch in Inactive p38γ Leads to an Excited State on the Pathway to an Active Kinase. Biochemistry 6 31794659
2025 p38γ modulates ferroptosis in brain injury caused by ethanol and cerebral ischemia/reperfusion by regulating the p53/SLC7A11 signaling pathway. Cellular signalling 5 40074192
2022 High Level Forebrain Expression of Active Tau Kinase p38γ Exacerbates Cognitive Dysfunction in Aged APP-transgenic Alzheimer's Mice. Neuroscience 5 35031398
2023 p38γ/δ activation alters cardiac electrical activity and predisposes to ventricular arrhythmia. Nature cardiovascular research 4 39196141

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