Affinage

MAPK1

Mitogen-activated protein kinase 1 · UniProt P28482

Round 2 corrected
Length
360 aa
Mass
41.4 kDa
Annotated
2026-04-28
130 papers in source corpus 53 papers cited in narrative 53 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MAPK1/ERK2 is a central serine/threonine kinase in the Ras–Raf–MEK–ERK signaling cascade that transduces mitogenic, stress, and mechanical stimuli into phosphorylation of a broad substrate repertoire controlling proliferation, differentiation, survival, metabolism, cytoskeletal dynamics, and autophagy. Dual phosphorylation at Thr185/Tyr187 by MEK1/2 increases catalytic efficiency approximately 600,000-fold by inducing global conformational exchange dynamics that enable active-site domain closure, and promotes ERK2 homodimerization required for extranuclear signaling and nuclear translocation (PMID:11016942, PMID:24550275, PMID:9604935, PMID:26267534). In the nucleus, ERK2 phosphorylates transcription factors including Elk-1, Sp1, C/EBPβ, ETV3, NANOG, and Beta2/PDX-1, and can also bind gene promoters directly as a transcription factor; in the cytoplasm, it phosphorylates cPLA2, Smad1/2/3, TSC2, PKM2, RhoA, ULK1, PAK1, Bcl3, and dynein, linking ERK2 to arachidonate release, TGF-β/BMP antagonism, mTOR activation, the Warburg effect, protein turnover, mitophagy, and lipid droplet biogenesis (PMID:8381049, PMID:15851026, PMID:23178880, PMID:33213267, PMID:37817112). ERK2 activity is spatially controlled by cytoplasmic retention through MEK1 binding (residues 312–320) and inhibitory partners PEA-15 and Naf1α, and temporally controlled by dual-specificity phosphatases MKP-1, MKP3/DUSP6, and HePTP, while scaffold proteins β-arrestin/arrestin-2 and IQGAP1 direct pathway-specific signaling outputs (PMID:10521408, PMID:8221888, PMID:14690430, PMID:14970219, PMID:14769794).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1991 High

    Cloning of ERK2 established the founding paradigm of a protein-serine/threonine kinase activated by tyrosine phosphorylation, answering how growth factor and insulin receptor tyrosine kinase signals are converted into serine/threonine phosphorylation cascades.

    Evidence Molecular cloning and biochemical kinase assays in insulin/NGF-stimulated cells

    PMID:2032290

    Open questions at the time
    • Upstream activating kinase not yet identified
    • No substrates known at this stage
  2. 1992 High

    Positioning ERK2 downstream of oncogenic Ras resolved a critical gap in the Ras signaling pathway and explained how Ras transduces signals through cytoplasmic kinase cascades.

    Evidence Scrape-loading of p21ras into cells with ERK2 activity measurement; constitutive activation in Ras-transformed lines

    PMID:1371463

    Open questions at the time
    • Direct intermediary kinases between Ras and ERK2 not defined
    • Mechanism of ERK2 activation (dual phosphorylation requirement) not yet established
  3. 1993 High

    Identification of cPLA2 and Elk-1 as direct ERK substrates answered what ERK2 phosphorylates, connecting the kinase to both lipid signaling (arachidonate release) and transcriptional activation (serum response element), and establishing the MAPK proline-directed phosphorylation motif.

    Evidence In vitro kinase assays with site-directed mutagenesis (cPLA2 Ser505; Elk-1 C-terminal domain) and functional readouts

    PMID:8381049 PMID:8386592

    Open questions at the time
    • How ERK2 selects among multiple substrates unknown
    • Nuclear versus cytoplasmic substrate targeting mechanisms unresolved
  4. 1993 High

    Discovery that MKP-1 dephosphorylates both pThr and pTyr on ERK2 established the first negative-feedback mechanism for pathway termination, resolving how ERK2 is inactivated.

    Evidence In vitro phosphatase assay with catalytically inactive MKP-1 trapping phospho-ERK2 complex

    PMID:8221888

    Open questions at the time
    • Relative contributions of different phosphatases in different cell contexts unknown
    • Spatial control of dephosphorylation not addressed
  5. 1997 High

    Identification of Smad1 and Mnk1/2 as ERK2 substrates expanded the functional scope, showing ERK2 antagonizes BMP signaling by blocking Smad nuclear entry and controls translation initiation through Mnk-eIF4E phosphorylation.

    Evidence In vitro phosphorylation with site mapping and nuclear localization assays (Smad1); co-IP and kinase assays (Mnk1/2)

    PMID:9155017 PMID:9335504

    Open questions at the time
    • Whether ERK2 regulates all TGF-β superfamily Smads unknown
    • In vivo significance of Mnk pathway for translation control not tested
  6. 1998 High

    Crystal structure of phosphorylated ERK2 revealed the structural basis for dimerization and linked dimerization to nuclear accumulation, answering how activation-state controls subcellular distribution.

    Evidence X-ray crystallography combined with mutagenesis disrupting the dimer interface and microinjection nuclear translocation assays

    PMID:9604935

    Open questions at the time
    • Whether dimerization is required for all nuclear functions unknown
    • Mechanism of nuclear import (importin involvement) not defined
  7. 1999 High

    Mapping of ERK2 residues 312–320 as a MEK1-dependent cytoplasmic retention signal and residues 321–327 as a nuclear translocation element resolved the molecular mechanism of ERK2 shuttling between nucleus and cytoplasm.

    Evidence GFP-fusion alanine-scanning mutagenesis with subcellular localization imaging

    PMID:10521408

    Open questions at the time
    • Identity of nuclear import receptors interacting with residues 321–327 not determined
    • How phosphorylation releases the MEK1 anchor quantitatively not defined
  8. 1999 High

    Discovery that ERK2 phosphorylates Smad2/3 linker regions causing their cytoplasmic retention explained how oncogenic Ras signaling overrides TGF-β growth inhibition, a mechanism directly relevant to cancer biology.

    Evidence In vitro phosphorylation, mutagenesis, nuclear translocation and transcriptional reporter assays; Ras-resistant Smad3 mutant rescue

    PMID:10197981

    Open questions at the time
    • Whether this mechanism operates in all Ras-driven cancers not established
    • Phosphatase that reverses ERK-mediated Smad phosphorylation unknown
  9. 2001 High

    Quantitative kinetic analysis showed dual phosphorylation increases ERK2 catalytic efficiency ~600,000-fold, primarily through enhancement of the phosphoryl transfer step, answering why dual (not single) phosphorylation is required for full activation.

    Evidence Steady-state kinetics and solvent viscosimetry with purified mono- and dually-phosphorylated ERK2

    PMID:11016942

    Open questions at the time
    • Structural basis for the rate enhancement at the phosphoryl transfer step not resolved at atomic level
    • Contribution of each phosphosite individually not fully dissected
  10. 2003 High

    Mechanistic dissection of MKP3/DUSP6 revealed an intramolecular dephosphorylation mechanism within a 1:1 MKP3:pERK2 complex achieving >4000-fold rate enhancement, explaining the exquisite specificity and efficiency of ERK2 inactivation.

    Evidence In vitro phosphatase assay with chemical cross-linking, binding analyses, and engineered mutants

    PMID:14690430

    Open questions at the time
    • Whether this intramolecular mechanism applies to all DUSPs unknown
    • Structural basis of catalytic activation within the complex not resolved
  11. 2004 High

    In vivo genetic studies established ERK2 as the predominant isoform for cardioprotection against ischemia-reperfusion injury and for T cell development/positive selection, answering whether ERK1 and ERK2 are functionally redundant.

    Evidence ERK2 heterozygous knockout mice with cardiac ischemia model; conditional ERK2 knockout with T cell developmental analysis

    PMID:15096454 PMID:16226508

    Open questions at the time
    • Molecular basis for isoform-specific functions not resolved
    • Whether dose-dependence (ERK2 higher expression) explains non-redundancy not excluded
  12. 2005 High

    Identification of TSC2 as an ERK substrate whose phosphorylation disrupts the TSC1–TSC2 complex and activates mTOR signaling placed ERK2 as a direct link between Ras-MAPK and PI3K-mTOR pathways, resolving cross-talk relevant to cell growth and tumorigenesis.

    Evidence In vitro phosphorylation, co-IP, mutagenesis, and in vivo xenograft rescue with non-phosphorylatable TSC2

    PMID:15851026

    Open questions at the time
    • Quantitative contribution of ERK vs. Akt-mediated TSC2 phosphorylation in different contexts unknown
    • Whether ERK2 and ERK1 have differential activity toward TSC2 not tested
  13. 2005 High

    Characterization of PEA-15 binding through a reverse DEJL motif blocking ERK2 substrate access, and scaffold functions of IQGAP1, established that ERK2 signaling output is determined not only by phosphorylation state but by competitive binding partners that sequester or localize the kinase.

    Evidence Fluorescence anisotropy binding assay and peptide displacement (PEA-15); pull-down with purified proteins, siRNA knockdown and kinase assay (IQGAP1)

    PMID:14970219 PMID:16324895

    Open questions at the time
    • Full inventory of ERK2-sequestering proteins not available
    • Structural basis of PEA-15–ERK2 complex not determined at atomic resolution at this time
  14. 2012 High

    Discovery that ERK2 phosphorylates PKM2 at Ser37 to promote its nuclear translocation where PKM2 acts as β-catenin coactivator inducing c-Myc and the Warburg effect connected ERK2 directly to cancer metabolic reprogramming.

    Evidence In vitro kinase assay with docking site mutagenesis (Ile429/Leu431), nuclear fractionation, xenograft tumor model

    PMID:23178880

    Open questions at the time
    • Whether this mechanism operates in all cancer types with activated ERK unknown
    • Other kinases that might redundantly phosphorylate PKM2 Ser37 not excluded
  15. 2014 High

    NMR relaxation dispersion experiments revealed that dual phosphorylation triggers global two-state conformational exchange (kex ~300 s⁻¹) throughout the kinase core, providing the biophysical mechanism underlying the massive catalytic rate enhancement and explaining how a distal phosphorylation event remodels the active site.

    Evidence ¹³C side-chain methyl NMR relaxation dispersion on phosphorylated and unphosphorylated ERK2

    PMID:24550275

    Open questions at the time
    • How substrate binding shifts the conformational equilibrium not determined
    • Whether conformational dynamics differ for different substrate classes unknown
  16. 2015 High

    A dimerization-disrupting small molecule showed that ERK2 dimerization specifically governs extranuclear (cytoplasmic) signaling and RAS-driven tumorigenesis without affecting nuclear ERK functions, resolving the long-standing question of what dimer-dependent signaling actually controls.

    Evidence Small molecule ERK dimerization inhibitor with dimerization assays, cancer cell transformation assays, and mouse tumor models

    PMID:26267534

    Open questions at the time
    • Identity of dimer-specific extranuclear substrates not fully catalogued
    • Whether monomer-selective inhibition spares normal tissue functions unknown
  17. 2017 High

    An unbiased CRISPR screen in BRAF-inhibitor-resistant melanoma identified ERK2 as the kinase driving a phenotype switch (EMT-like, MITF shutdown) through JUNB/FRA1 upon drug withdrawal, establishing ERK2's role in therapy-induced adaptive plasticity.

    Evidence Genome-wide CRISPR-Cas9 knockout screen, transcriptomics, mouse tumor models, patient sample validation

    PMID:28976960

    Open questions at the time
    • Whether ERK1 can substitute for ERK2 in drug-addiction phenotype not fully resolved
    • Direct ERK2 substrates mediating the MITF shutdown not identified
  18. 2020 High

    ERK2-mediated phosphorylation of ULK1 leading to its BTRC-dependent ubiquitination and proteasomal degradation linked ERK2 to suppression of mitophagy, accumulation of ROS-generating mitochondria, NLRP3 inflammasome activation, and breast cancer bone metastasis.

    Evidence In vitro kinase assay, ubiquitination assay, MEK inhibitor trametinib, xenograft bone metastasis model

    PMID:33213267

    Open questions at the time
    • Whether this mechanism is specific to breast cancer or generalizable unknown
    • Relative contribution of ERK1 vs ERK2 to ULK1 phosphorylation not dissected
  19. 2023 Medium

    ChIP-seq revealed ERK2 binds directly to gene promoters as a bidirectional transcription factor in gastric cancer cells, expanding its role beyond kinase to include direct DNA-binding transcriptional regulation.

    Evidence ChIP-seq, ChIP assay, RNA-seq, cell migration/invasion assays in gastric cancer cells

    PMID:37817112

    Open questions at the time
    • DNA-binding domain or motif within ERK2 not identified
    • Whether this transcription factor function occurs in non-cancer contexts unknown
    • Independent replication in other cell types needed

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major open questions include the structural basis for isoform-specific (ERK2 vs ERK1) substrate selectivity, comprehensive identification of dimer-dependent versus monomer-dependent substrates, and the mechanism and physiological relevance of ERK2's direct DNA-binding transcription factor activity.
  • Structural explanation for ERK2/ERK1 non-redundancy lacking
  • Complete dimer-specific substrate catalog unavailable
  • ERK2 DNA-binding mechanism unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 21 GO:0016740 transferase activity 4 GO:0140657 ATP-dependent activity 2 GO:0003677 DNA binding 1 GO:0140110 transcription regulator activity 1
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 3 GO:0005654 nucleoplasm 2 GO:0005739 mitochondrion 1 GO:0005811 lipid droplet 1
Pathway
R-HSA-162582 Signal Transduction 10 R-HSA-74160 Gene expression (Transcription) 5 R-HSA-1430728 Metabolism 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-1640170 Cell Cycle 2 R-HSA-1643685 Disease 2 R-HSA-168256 Immune System 2 R-HSA-392499 Metabolism of proteins 2 R-HSA-9612973 Autophagy 2
Partners
DUSP1DUSP6GAB1IQGAP1MAP2K1PARP1PEA15PTPN7
Complex memberships
Raf-MEK-ERK cascade moduleβ-arrestin/ERK2 signalosome

Evidence

Reading pass · 53 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1991 ERK2 (MAPK1) was cloned and identified as a protein-serine/threonine kinase activated by tyrosine phosphorylation in response to insulin and NGF, establishing it as an intermediate that converts tyrosine phosphorylation signals into serine/threonine phosphorylation cascades. Molecular cloning, biochemical kinase assays, phosphorylation analysis Cell High 2032290
1992 ERK2 (42 kDa MAP kinase) is activated by phosphorylation on tyrosine and threonine downstream of oncogenic p21ras, and is constitutively activated in ras-transformed cell lines, placing ERK2 in the signal transduction pathway of the Ras oncoprotein. Scrape-loading of p21ras into cells, kinase activity assays, phosphorylation analysis The EMBO journal High 1371463
1993 cPLA2 is a direct substrate of MAP kinase (ERK); ERK phosphorylates cPLA2 at Ser-505, increasing its enzymatic activity, and mutation of Ser-505 to Ala abolishes agonist-stimulated arachidonate release. In vitro kinase assay, site-directed mutagenesis, arachidonate release assay Cell High 8381049
1993 MAP kinase (ERK, p42/p44) phosphorylates the Elk-1 C-terminal region at multiple sites both in vitro and in vivo following growth factor stimulation, and this phosphorylation is required for transcriptional activation by the serum response element. In vitro phosphorylation, co-immunoprecipitation, transcriptional reporter assays, phosphopeptide mapping Cell High 8386592
1993 MKP-1 (3CH134) is a dual-specificity phosphatase that dephosphorylates p42MAPK (ERK2) at both T183 and Y185 in vitro and inactivates it in vivo; a catalytically inactive MKP-1 mutant forms a physical complex with phosphorylated ERK2. In vitro phosphatase assay, co-immunoprecipitation, dominant-negative mutant expression Cell High 8221888
1997 ERK MAP kinases phosphorylate Smad1 at specific serines in the linker region connecting its DNA-binding and effector domains, inhibiting nuclear accumulation of Smad1 and antagonizing BMP signaling. In vitro kinase assay, phosphopeptide mapping, nuclear localization assays Nature High 9335504
1997 Mnk1 and Mnk2 bind directly to ERK1/2 (with Mnk1 complexing more strongly with inactive than active ERK), and ERK phosphorylates Mnk1/2 to stimulate their kinase activity toward eIF-4E at Ser209. Co-immunoprecipitation, in vitro kinase assay, phosphorylation site mapping The EMBO journal High 9155017
1998 MSK1 is directly activated by ERK2 (MAPK2/ERK2) in vitro, and endogenous MSK1 activation by growth factors is prevented by MEK inhibitor PD 98059; MSK1 phosphorylates CREB at Ser133, linking ERK2 signaling to CREB activation. In vitro kinase assay, pharmacological inhibition, CREB phosphorylation assay The EMBO journal High 9687510
1998 Phosphorylated ERK2 forms homodimers with both phosphorylated and unphosphorylated ERK2 partners; nuclear accumulation of ERK2 depends on its phosphorylation state and requires dimerization, as disruption of dimerization by mutagenesis reduces nuclear accumulation. Crystal structure of phosphorylated ERK2 reveals the structural basis for dimerization. Crystal structure determination, site-directed mutagenesis, microinjection, nuclear localization assays Cell High 9604935
1999 ERK2 residues 312–320 constitute a cytoplasmic retention sequence that mediates association with MEK1, retaining ERK2 in the cytosol; residues 316, 319, and 320 (acidic) are most critical. Residues 321–327 are required for nuclear translocation upon mitogenic stimulation. GFP-fusion protein expression, alanine-scanning mutagenesis, subcellular localization imaging The Journal of biological chemistry High 10521408
1999 ERK2 phosphorylates the transcription factor Sp1, and this phosphorylation stimulates Sp1 DNA binding; pretreatment with recombinant ERK2 increased Sp1 binding while dephosphorylation reduced it. Ras and ERK2 activation target the EGF-responsive gERE element via Sp1. In vitro phosphorylation assay, EMSA/DNA-binding assay, cotransfection reporter assay Biochemical and biophysical research communications Medium 9918860
1999 Activated ERK2 directly associates with and phosphorylates the docking protein GAB1; this association is exclusive to phosphorylated ERK2 and does not require a third protein. In intact cells, GAB1 co-immunoprecipitates with active ERK2. Pull-down assay with purified proteins, co-immunoprecipitation, in vitro kinase assay The Journal of biological chemistry High 10593929
1999 ERK2 phosphorylates Smad2 and Smad3 at specific linker-region sites downstream of oncogenic Ras/ERK signaling, causing cytoplasmic retention and inhibiting TGF-β-induced nuclear accumulation and transcription. Ras-resistant Smad3 mutant rescues TGF-β growth inhibitory response. In vitro phosphorylation, site-directed mutagenesis, nuclear translocation assay, transcriptional reporter Genes & development High 10197981
1999 RKIP (Raf kinase inhibitor protein) binds to Raf-1, MEK, and ERK in vitro and co-immunoprecipitates with Raf-1 and MEK from cells, competitively disrupting Raf-1/MEK interaction and suppressing ERK activation. RKIP overexpression inhibits MEK, ERK, and AP-1 activation. Yeast two-hybrid, co-immunoprecipitation, in vitro binding, kinase activity assays Nature High 10490027
2000 MEKK1 binds directly to endogenous ERK2, MEK1, and Raf-1, suggesting it can scaffold all three components of the ERK2 MAP kinase module. Co-immunoprecipitation of endogenous proteins The Journal of biological chemistry Medium 10969079
2001 Dual phosphorylation of ERK2 at Thr-185 and Tyr-187 increases overall catalytic efficiency ~600,000-fold and turnover rate ~50,000-fold, primarily through a ~60,000-fold enhancement of the phosphoryl group transfer step, with only modest decreases in Km for ATP and substrate. In vitro kinase assay, solvent viscosimetry, steady-state kinetics The Journal of biological chemistry High 11016942
2001 ERK2 activation is required for glucose-stimulated insulin gene transcription; ERK2 phosphorylates transcription factors Beta2/NeuroD1 and PDX-1, increasing their functional activity and cumulatively transactivating the insulin promoter. Dominant-negative ERK2 expression, MEK inhibitors, in vitro phosphorylation, transcriptional reporter assays The Journal of biological chemistry High 12810726
2001 ERK2 activation of the c-fos SRE through C/EBPbeta requires phosphorylation of a consensus MAPK site in C/EBPbeta; dominant-negative ERK2 (but not ERK1) blocks Ras-stimulated C/EBPbeta-SRF interaction, and recombinant ERK2 (but not ERK1) phosphorylates C/EBPbeta in vitro. Dominant-negative overexpression, in vitro kinase assay, co-immunoprecipitation, luciferase reporter The Journal of biological chemistry Medium 11500490
2001 MUC1 cytoplasmic domain signaling leads to activation of ERK2 through the Ras-MEK-ERK2 pathway following tyrosine phosphorylation of MUC1; this was blocked by dominant-negative Ras or MEK inhibitor. Immunoblotting, kinase assay, immunocytochemistry, dominant-negative Ras, pharmacological inhibition American journal of physiology. Lung cellular and molecular physiology Medium 11404250
2002 Naf1α binds to ERK2 (confirmed by yeast two-hybrid, pull-down and co-immunoprecipitation); overexpression of Naf1α suppresses ERK2 nuclear translocation and inhibits ERK2-dependent Elk1-driven transcription, identifying Naf1α as an attenuator of activated ERK2 signaling. Yeast two-hybrid, pull-down assay, co-immunoprecipitation, nuclear translocation assay, luciferase reporter Biochemical and biophysical research communications Medium 12220502
2003 MKP3 dephosphorylates ERK2 via an intramolecular mechanism: a 1:1 MKP3:pERK monomer complex forms, and MKP3 within this complex performs intramolecular dephosphorylation, achieving ≥4000-fold rate enhancement through catalytic activation and substrate tethering. In vitro phosphatase assay, chemical cross-linking, binding analyses, engineered mutants Biochemistry High 14690430
2004 IQGAP1 directly binds ERK2 (confirmed by in vitro pull-down with purified proteins and endogenous co-immunoprecipitation); manipulation of IQGAP1 levels significantly reduces growth factor-stimulated ERK1/2 activity, and an IQGAP1 construct lacking the ERK2-binding region does not interfere with ERK activation. In vitro pull-down with purified proteins, co-immunoprecipitation, siRNA knockdown, kinase activity assay The Journal of biological chemistry High 14970219
2004 ERK2 phosphorylates PAK1 at Thr212 in vitro, and Thr212 is phosphorylated in smooth muscle cells after PDGF treatment in an MEK/ERK-dependent manner. PAK1 and ERK1/2 directly associate (Far Western analysis) at an ERK2 binding site within PAK1's autoinhibitory domain, and this association facilitates ERK signaling. A phosphomimic PAK1-T212E variant attenuates downstream ERK signaling, providing negative feedback. In vitro kinase assay, Far Western, co-immunoprecipitation, immunolocalization, luciferase reporter The Journal of biological chemistry High 15542607
2004 Nonapoptotic programmed cell death mediated by the NK1R/Substance P pathway is executed through a MAPK cascade (Raf-1, MEK2, ERK2) recruited by arrestin 2 as scaffold, leading to phosphorylation of the orphan nuclear receptor Nur77. RNAi against ERK2 (but not ERK1) blocks this cell death. RNAi knockdown, dominant-negative constructs, pharmacological inhibition, cell death assays The Journal of biological chemistry Medium 14769794
2004 MEK1-ERK1/2 signaling is required for cardioprotection against ischemia-reperfusion injury; ERK2 heterozygous knockout mice show enhanced infarction, DNA laddering and TUNEL positivity, while MEK1 transgenic mice with activated ERK1/2 are resistant to injury. Gene-targeted knockout mice, transgenic overexpression, ischemia-reperfusion in vivo model, pressure-volume loop recordings, TUNEL assay Circulation High 15096454
2004 Noonan syndrome PTPN11/SHP2 mutants cause prolonged ERK2/MAPK1 activation in a ligand- and GAB1-docking-dependent manner; coexpression of GAB1-FF (lacking SHP2 binding motifs) blocks EGF-mediated increase in SHP2 phosphatase activity and reduces ERK2 activation. Kinase activity assays, co-immunoprecipitation, dominant-negative/mutant overexpression, proliferation assays Human mutation Medium 14974085
2005 ERK2 uses a proximity-mediated catalysis mechanism: docking of a substrate recognition domain (pnt domain of EtsDelta138) outside the active site increases local concentration of the phosphoacceptor TP motif near the catalytic site; mutagenesis of the pnt domain reduces binding 10-fold but kcat is unchanged, while mutagenesis of the TP motif decreases kcat without affecting ternary complex stability. In vitro kinase assay, site-directed mutagenesis, binding studies Journal of the American Chemical Society High 16045329
2005 FR180204, an ERK-selective ATP-competitive inhibitor (Ki 0.14 µM for ERK2), binds within the ATP-binding pocket of ERK2 engaging residues Q105, D106, L156, and C166, as determined by X-ray crystallography of the human ERK2/FR180204 complex. X-ray crystallography, enzyme kinetic assay (Lineweaver-Burk), cell-based reporter assay Biochemical and biophysical research communications High 16139248
2005 PEA-15 sequesters ERK2 in the cytoplasm by binding to ERK2 through a reverse DEJL domain in its C-terminus, thereby blocking ERK2 interactions with DEJL-containing substrates and inhibiting many ERK2-mediated phosphorylations. Fluorescence anisotropy binding assay, peptide displacement studies Biochimica et biophysica acta Medium 16324895
2005 ERK2 is required for cardioprotection, T cell development, positive selection, and CD4/CD8 T cell maturation; conditional and global knockout studies demonstrate ERK2's predominant in vivo roles compared to ERK1. Gene-targeted knockout mice, T cell development analysis, proliferation and survival assays Immunity High 16226508
2005 ERK MAP kinase phosphorylates TSC2 at specific Erk sites, causing dissociation of the TSC1-TSC2 complex and markedly impairing TSC2's ability to inhibit mTOR signaling and cell transformation; an Erk-nonphosphorylatable TSC2 mutant blocks tumorigenicity in vivo. In vitro phosphorylation, co-immunoprecipitation, mutagenesis, xenograft tumor model Cell High 15851026
2006 ERK2 (but not ERK1, JNK, or p38) plays a specific role in cytosolic lipid droplet formation; ERK2 phosphorylates dynein, increasing its localization on ADRP-containing lipid droplets. ERK2 functions downstream of PLD1 in this process, without affecting PLD1 activity. siRNA knockdown, microinjection, overexpression, phosphorylation assay, lipid droplet quantification Journal of cell science Medium 16723731
2007 Phosphorylated ERK2 directly interacts with and activates PARP-1 in a DNA-independent manner in a cell-free system; activated PARP-1 dramatically increases ERK2-catalyzed phosphorylation of Elk1. In cortical neurons and cardiomyocytes, PARP-1 activation enhances ERK-induced Elk1 phosphorylation, histone acetylation, and c-fos transcription. Cell-free reconstitution, co-immunoprecipitation, kinase assay, reporter gene assay, primary cell experiments Molecular cell High 17244536
2007 ERK2 activation in platelets requires simultaneous signaling from both P2Y1 (Gq-coupled) and P2Y12 (Gi-coupled) ADP receptors plus Src kinase activity; ERK2 activation is required for ADP-induced thromboxane A2 generation, and extracellular calcium blocks ADP-induced ERK2 activation. Pharmacological inhibition of specific receptors/kinases, kinase activity assay, thromboxane measurement The Biochemical journal Medium 17298299
2008 Mitochondrially localized ERK2 activity is sufficient to induce mitophagy; active ERK2-CA shows greater localization to mitochondria than WT, and kinase activity (not just localization) correlates with degree of mitophagy. ERK2 localization to mitochondria is triggered by 6-OHDA. GFP-ERK2 fusion constructs (WT, CA, KD), colocalization imaging, autophagy marker analysis (LC3), bafilomycin treatment Autophagy Medium 18594198
2008 ERK2 (but not ERK1) is required for proliferation of CD8 T cells activated without costimulation, and regulates CD8 T cell survival by transcriptionally upregulating Bcl-xL and downregulating Bim; impaired ERK2-deficient CD8 T cell survival can be rescued by genetic ablation of Bim. Conditional Erk2 knockout, viral infection model, in vitro activation, Bim genetic rescue Journal of immunology High 19017950
2008 ERK2 morpholino knockdown in zebrafish blocks initiation of epiboly, actin/tubulin cytoskeleton reorganization, and causes severe anterior-posterior extension defects; ERK2 mRNA cross-rescues ERK1 morphants, but ERK1 mRNA cannot rescue ERK2 morphants, suggesting distinct functions. Morpholino knockdown, mRNA rescue, cell-tracing, cytoskeleton imaging in zebrafish embryos Developmental biology Medium 18514184
2011 Large-scale chemical-genetic screen using analog-sensitive ERK2 identified 80 ERK2 substrates; ETV3 is a novel substrate extensively phosphorylated at canonical and noncanonical ERK motifs, and this phosphorylation prevents ETV3 binding to DNA at promoters of thousands of genes including negative feedback regulators. Analog-sensitive kinase assay (chemical genetics), mass spectrometry, ChIP-seq, reporter assays Science signaling High 22028470
2011 The ERK2:HePTP complex transitions from a highly extended dynamic resting-state conformation to a compact, ordered active-state conformation as determined by SAXS combined with EROS ensemble refinement; HePTP negatively regulates ERK2 via dephosphorylation. Small-angle X-ray scattering (SAXS), EROS ensemble refinement Journal of the American Chemical Society Medium 21985012
2012 ERK1/2-dependent phosphorylation of PKM2 at Ser37 (by ERK2 binding directly to PKM2 Ile429/Leu431 through the ERK2 docking groove) recruits PIN1 for cis-trans isomerization, promotes PKM2 nuclear translocation, and nuclear PKM2 acts as β-catenin coactivator to induce c-Myc and the Warburg effect. In vitro kinase assay, co-immunoprecipitation, mutagenesis, nuclear fractionation, xenograft tumor model Nature cell biology High 23178880
2013 ERK2-mediated phosphorylation of RhoA is required for SCF(FBXL19)-mediated RhoA ubiquitination at Lys135 and proteasomal degradation; RhoA-K135R mutant is resistant to FBXL19-mediated ubiquitination. ERK2 phosphorylation of RhoA is both sufficient and required for this degradation. In vitro kinase assay, ubiquitination assay, mutagenesis, co-immunoprecipitation, protein stability assay Biochimica et biophysica acta High 23871831
2013 PLAC8 directly binds and inactivates the ERK2 phosphatase DUSP6 in vitro, thereby increasing phospho-ERK2 levels and driving an unconventional EMT in colon cancer characterized by increased VIM, ZEB1, and CDH3 without CDH2 upregulation; ERK2 knockdown reverses these EMT features. In vitro protein binding assay, ERK2 knockdown, immunofluorescence, xenograft model The Journal of clinical investigation High 24691442
2014 Dual phosphorylation of ERK2 by MAP kinase kinase 1 induces global conformational exchange dynamics (two-state exchange, kex ≈ 300 s⁻¹) throughout the conserved kinase core, releasing constraints on domain motions; inactive ERK2 shows only localized, uncoupled side-chain dynamics. NMR 13C relaxation dispersion experiments (side-chain methyl dynamics), phosphorylation by MKK1 Proceedings of the National Academy of Sciences of the United States of America High 24550275
2014 ERK2 directly phosphorylates NANOG at multiple sites in vitro; using the MAKS multiplexed kinase assay, ERK2 and CDK1/CyclinA2 were identified as site-specific kinases for human NANOG, linking key signaling pathways to pluripotency regulation. MAKS (multiplexed assay for kinase specificity), mass spectrometry phosphopeptide mapping Stem cell reports Medium 24678451
2015 ERK2 dimerization is essential for extranuclear (but not nuclear) ERK signaling; a small molecule inhibitor of ERK dimerization prevents RAS-ERK oncogene-driven tumorigenesis without affecting ERK phosphorylation, demonstrating that dimerization controls sub-localization-specific ERK signaling. Small molecule inhibitor design, dimerization assays, cancer cell transformation assays, mouse tumor models Cancer cell High 26267534
2015 Crystal structure of ERK2 in complex with RSK1 reveals a precatalytic kinase-kinase heterodimer where the RSK1 activation loop faces ERK2's catalytic site; the MAPK-binding linear motif in RSK1's disordered kinase domain extension docks into ERK2's groove to form the encounter complex, and generic kinase domain surface contacts enable the catalytically competent state. X-ray crystallography, molecular dynamics simulation, biochemical and cellular kinase assays Proceedings of the National Academy of Sciences of the United States of America High 25730857
2015 Under low-glucose metabolic stress, isoform-specific MEK1/ERK2 signaling (not ERK1) activates GCN2/eIF2α phosphorylation and ATF4 expression, which overrides PERK/Akt-mediated adaptation and induces apoptosis through ATF4-dependent pro-apoptotic factor expression including Bid and Trb3. ERK2 activation also alters TCA cycle and amino acid metabolism. Isoform-specific knockdown/overexpression, phosphoproteomics, metabolomics, apoptosis assays Molecular cell High 26190261
2017 Akt, Erk2, and IKK1/2 phosphorylate Bcl3 at distinct sites: Erk2 and IKK1/2 phosphorylate Ser114 and Ser446, converting Bcl3 from an IκB-like inhibitor to a transcriptional coregulator by facilitating its recruitment to DNA. Cells expressing S114A/S446A Bcl3 have proliferation and migration defects. In vitro kinase assay, site-directed mutagenesis, co-immunoprecipitation, ChIP, cell proliferation and migration assays Molecular cell High 28689659
2017 In BRAF-inhibitor-resistant melanoma, ERK2 kinase drives a phenotype switch (resembling EMT with MITF shutdown) upon drug withdrawal, through a pathway involving ERK2, JUNB, and FRA1 transcription factors; CRISPR-Cas9 screen identified this as the core 'drug addiction' pathway. Unbiased CRISPR-Cas9 knockout screen, transcriptomics, mouse tumor models, patient sample analysis Nature High 28976960
2019 ERK inhibitors Vertex-11e and SCH772984 exploit conformational equilibrium in active 2P-ERK2 by shifting exchange between two states (L and R) in opposing directions; X-ray structures and NMR/HX-MS measurements show that the L→R shift in 2P-ERK2 involves active site domain closure for productive nucleotide binding, and these inhibitors differentially affect MAP kinase phosphatase activity toward 2P-ERK2. NMR, X-ray crystallography, hydrogen-exchange mass spectrometry, phosphatase activity assays Proceedings of the National Academy of Sciences of the United States of America High 31311868
2020 MAPK1/ERK2-MAPK3/ERK1 kinase phosphorylates ULK1, triggering ULK1 interaction with BTRC and subsequent K48-linked ubiquitination and proteasomal degradation. ULK1 depletion attenuates mitophagy during hypoxia, causing accumulation of ROS-generating mitochondria and NLRP3 inflammasome activation that promotes breast cancer bone metastasis. Co-immunoprecipitation, in vitro kinase assay, ubiquitination assay, MEK inhibitor (trametinib), xenograft model Autophagy High 33213267
2020 Mechanical force (centrifugal, compression, stretching) rapidly activates Erk2 in Xenopus embryos in an FGFR1-dependent but FGF-ligand-independent manner; Erk2 activation induces cytoskeletal remodeling (F-actin, C-cadherin, ZO-1), enhancing cellular junctions and tissue stiffening during early embryogenesis. Phosphoproteome analysis of Xenopus embryos, force application experiments, FGFR1 inhibition, cytoskeletal protein analysis Cell reports Medium 32187556
2023 MAPK1 binds directly to promoter regions of target genes as a bidirectional transcription factor in gastric cancer cells; ChIP-seq and biochemical assays demonstrate MAPK1 upregulates KRT13, KRT6A, KRT81, MYH15, STARD4, SYTL4, TMEM267 and downregulates FGG, promoting cell invasion and migration. ChIP-seq, ChIP assay, RNA sequencing, protein interaction assays, cell migration/invasion assays BMC cancer Medium 37817112

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 3725 23128233
2006 Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 2861 17081983
2011 Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 2101 21833088
1991 ERKs: a family of protein-serine/threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF. Cell 1747 2032290
1993 cPLA2 is phosphorylated and activated by MAP kinase. Cell 1729 8381049
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
1993 The SRF accessory protein Elk-1 contains a growth factor-regulated transcriptional activation domain. Cell 1219 8386592
2015 High-Resolution CRISPR Screens Reveal Fitness Genes and Genotype-Specific Cancer Liabilities. Cell 1200 26627737
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
1993 MKP-1 (3CH134), an immediate early gene product, is a dual specificity phosphatase that dephosphorylates MAP kinase in vivo. Cell 1086 8221888
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2005 Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell 1067 15851026
2001 Nerve growth factor signaling, neuroprotection, and neural repair. Annual review of neuroscience 1029 11520933
1999 BCL-2 is phosphorylated and inactivated by an ASK1/Jun N-terminal protein kinase pathway normally activated at G(2)/M. Molecular and cellular biology 920 10567572
2004 Immunoaffinity profiling of tyrosine phosphorylation in cancer cells. Nature biotechnology 916 15592455
2007 The ERK1/2 mitogen-activated protein kinase pathway as a master regulator of the G1- to S-phase transition. Oncogene 883 17496918
2020 A reference map of the human binary protein interactome. Nature 849 32296183
1999 A mechanism of repression of TGFbeta/ Smad signaling by oncogenic Ras. Genes & development 843 10197981
1998 Mitogen- and stress-activated protein kinase-1 (MSK1) is directly activated by MAPK and SAPK2/p38, and may mediate activation of CREB. The EMBO journal 842 9687510
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
1997 Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin. Science (New York, N.Y.) 813 9204908
1997 Mitogen-activated protein kinases activate the serine/threonine kinases Mnk1 and Mnk2. The EMBO journal 791 9155017
2012 ERK1/2-dependent phosphorylation and nuclear translocation of PKM2 promotes the Warburg effect. Nature cell biology 769 23178880
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
1997 Opposing BMP and EGF signalling pathways converge on the TGF-beta family mediator Smad1. Nature 752 9335504
1999 Suppression of Raf-1 kinase activity and MAP kinase signalling by RKIP. Nature 723 10490027
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2001 Activation and targeting of extracellular signal-regulated kinases by beta-arrestin scaffolds. Proceedings of the National Academy of Sciences of the United States of America 685 11226259
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1998 Phosphorylation of the MAP kinase ERK2 promotes its homodimerization and nuclear translocation. Cell 580 9604935
1992 Activation of extracellular signal-regulated kinase, ERK2, by p21ras oncoprotein. The EMBO journal 518 1371463
2007 Integrating signals from RTKs to ERK/MAPK. Oncogene 479 17496910
2008 The regulation of extracellular signal-regulated kinase (ERK) in mammalian cells. The international journal of biochemistry & cell biology 378 18562239
2007 DNA-independent PARP-1 activation by phosphorylated ERK2 increases Elk1 activity: a link to histone acetylation. Molecular cell 284 17244536
2005 The role of erk1 and erk2 in multiple stages of T cell development. Immunity 280 16226508
2006 ERK2: a logical AND gate critical for drug-induced plasticity? Current opinion in pharmacology 278 17085074
2008 Mitochondrially localized ERK2 regulates mitophagy and autophagic cell stress: implications for Parkinson's disease. Autophagy 242 18594198
2016 ERK1 and ERK2 Map Kinases: Specific Roles or Functional Redundancy? Frontiers in cell and developmental biology 223 27376062
2005 Identification of a selective ERK inhibitor and structural determination of the inhibitor-ERK2 complex. Biochemical and biophysical research communications 203 16139248
2004 MEK1-ERK2 signaling pathway protects myocardium from ischemic injury in vivo. Circulation 201 15096454
2004 IQGAP1 binds ERK2 and modulates its activity. The Journal of biological chemistry 189 14970219
1999 Sp1 phosphorylation by Erk 2 stimulates DNA binding. Biochemical and biophysical research communications 181 9918860
2015 Mitophagy is primarily due to alternative autophagy and requires the MAPK1 and MAPK14 signaling pathways. Autophagy 175 25831013
2020 MAPK1/3 kinase-dependent ULK1 degradation attenuates mitophagy and promotes breast cancer bone metastasis. Autophagy 174 33213267
2008 The Erk2 MAPK regulates CD8 T cell proliferation and survival. Journal of immunology (Baltimore, Md. : 1950) 165 19017950
2004 Noonan syndrome-associated SHP2/PTPN11 mutants cause EGF-dependent prolonged GAB1 binding and sustained ERK2/MAPK1 activation. Human mutation 158 14974085
2017 A compendium of ERK targets. FEBS letters 145 28675784
2006 PLD1 and ERK2 regulate cytosolic lipid droplet formation. Journal of cell science 140 16723731
2004 Xenoestrogen-induced ERK-1 and ERK-2 activation via multiple membrane-initiated signaling pathways. Environmental health perspectives 136 15531431
2003 Regulation of insulin gene transcription by ERK1 and ERK2 in pancreatic beta cells. The Journal of biological chemistry 134 12810726
1999 Identification of a cytoplasmic-retention sequence in ERK2. The Journal of biological chemistry 128 10521408
1994 The mitogen-activated protein kinases, ERK1 and ERK2. Seminars in cancer biology 127 7803762
2020 CircRNA_101237 promotes NSCLC progression via the miRNA-490-3p/MAPK1 axis. Scientific reports 123 32494004
2017 Cancer drug addiction is relayed by an ERK2-dependent phenotype switch. Nature 121 28976960
2011 Large-scale discovery of ERK2 substrates identifies ERK-mediated transcriptional regulation by ETV3. Science signaling 118 22028470
2015 Small Molecule Inhibition of ERK Dimerization Prevents Tumorigenesis by RAS-ERK Pathway Oncogenes. Cancer cell 114 26267534
2014 Excess PLAC8 promotes an unconventional ERK2-dependent EMT in colon cancer. The Journal of clinical investigation 105 24691442
1998 Expression of dominant negative Erk2 inhibits AP-1 transactivation and neoplastic transformation. Oncogene 104 10030673
2000 MEKK1 binds raf-1 and the ERK2 cascade components. The Journal of biological chemistry 100 10969079
1996 Calcium-dependent activation of Erk-1 and Erk-2 after hypo-osmotic astrocyte swelling. The Biochemical journal 89 8947482
2015 Functional Redundancy of ERK1 and ERK2 MAP Kinases during Development. Cell reports 81 26235619
2015 ERK2 Mediates Metabolic Stress Response to Regulate Cell Fate. Molecular cell 80 26190261
2004 Alternative, nonapoptotic programmed cell death: mediation by arrestin 2, ERK2, and Nur77. The Journal of biological chemistry 78 14769794
2013 A new mechanism of RhoA ubiquitination and degradation: roles of SCF(FBXL19) E3 ligase and Erk2. Biochimica et biophysica acta 77 23871831
2017 A miR-20a/MAPK1/c-Myc regulatory feedback loop regulates breast carcinogenesis and chemoresistance. Cell death and differentiation 76 29125598
2007 Regulation and functional consequences of ADP receptor-mediated ERK2 activation in platelets. The Biochemical journal 75 17298299
2001 Involvement of the MAP kinase ERK2 in MUC1 mucin signaling. American journal of physiology. Lung cellular and molecular physiology 74 11404250
2001 Mechanism of activation of ERK2 by dual phosphorylation. The Journal of biological chemistry 67 11016942
2013 FGF2 stimulates osteogenic differentiation through ERK induced TAZ expression. Bone 66 24125755
2010 Key role of ERK pathway signaling in lupus. Autoimmunity 66 19961364
2023 MAPK-ERK Pathway. International journal of molecular sciences 64 37298618
2010 Blocking of ERK1 and ERK2 sensitizes human mesothelioma cells to doxorubicin. Molecular cancer 64 21159167
2015 ERK1 and ERK2 regulate chondrocyte terminal differentiation during endochondral bone formation. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 62 25401279
2013 Integration of mTOR and estrogen-ERK2 signaling in lymphangioleiomyomatosis pathogenesis. Proceedings of the National Academy of Sciences of the United States of America 61 23983265
2014 Phosphorylation releases constraints to domain motion in ERK2. Proceedings of the National Academy of Sciences of the United States of America 59 24550275
2001 ERK2- and p90(Rsk2)-dependent pathways regulate the CCAAT/enhancer-binding protein-beta interaction with serum response factor. The Journal of biological chemistry 57 11500490
2008 Distinct functions for ERK1 and ERK2 in cell migration processes during zebrafish gastrulation. Developmental biology 56 18514184
2017 MicroRNA-329-3p targets MAPK1 to suppress cell proliferation, migration and invasion in cervical cancer. Oncology reports 55 28393232
2004 Adhesion stimulates direct PAK1/ERK2 association and leads to ERK-dependent PAK1 Thr212 phosphorylation. The Journal of biological chemistry 55 15542607
2015 HOTAIR Interacting with MAPK1 Regulates Ovarian Cancer skov3 Cell Proliferation, Migration, and Invasion. Medical science monitor : international medical journal of experimental and clinical research 54 26117268
2018 ERK Mutations and Amplification Confer Resistance to ERK-Inhibitor Therapy. Clinical cancer research : an official journal of the American Association for Cancer Research 52 29760222
2013 S-nitrosylation of ERK inhibits ERK phosphorylation and induces apoptosis. Scientific reports 52 23657295
2017 ERK1 and ERK2 activation modulates diet-induced obesity in mice. Biochimie 48 28302472
2019 Silencing of spinal Trpv1 attenuates neuropathic pain in rats by inhibiting CAMKII expression and ERK2 phosphorylation. Scientific reports 46 30808963
2017 Bcl3 Phosphorylation by Akt, Erk2, and IKK Is Required for Its Transcriptional Activity. Molecular cell 46 28689659
2005 Differential Involvement of ERK2 and p38 in platelet adhesion to collagen. The Journal of biological chemistry 46 15851480
2008 ERK1 and ERK2 MAPK are key regulators of distinct gene sets in zebrafish embryogenesis. BMC genomics 45 18442396
2014 NANOG is multiply phosphorylated and directly modified by ERK2 and CDK1 in vitro. Stem cell reports 43 24678451
2008 ERK2 protein regulates the proliferation of human mesenchymal stem cells without affecting their mobilization and differentiation potential. Experimental cell research 43 18378228
2018 Outstanding questions in developmental ERK signaling. Development (Cambridge, England) 42 30049820
2017 miR-422a inhibits cell proliferation in colorectal cancer by targeting AKT1 and MAPK1. Cancer cell international 42 29118671
2018 HOTAIR contributes to cell proliferation and metastasis of cervical cancer via targetting miR-23b/MAPK1 axis. Bioscience reports 40 29335299
2010 Genetic targeting of ERK1 suggests a predominant role for ERK2 in murine pain models. The Journal of neuroscience : the official journal of the Society for Neuroscience 40 20739576
2005 Proximity-induced catalysis by the protein kinase ERK2. Journal of the American Chemical Society 40 16045329
2019 miR-141-5p regulate ATF2 via effecting MAPK1/ERK2 signaling to promote preeclampsia. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 39 31075732
2018 Gene Silencing via PDA/ERK2-siRNA-Mediated Electrospun Fibers for Peritendinous Antiadhesion. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 39 30693181
2015 ERK1 and ERK2 present functional redundancy in tetrapods despite higher evolution rate of ERK1. BMC evolutionary biology 39 26336084
2015 MAPK1 up-regulates the expression of MALAT1 to promote the proliferation of cardiomyocytes through PI3K/AKT signaling pathway. International journal of clinical and experimental pathology 39 26884868
2017 MiR-143 inhibits endometrial cancer cell proliferation and metastasis by targeting MAPK1. Oncotarget 37 29137432
2012 Proteomic and functional analyses reveal MAPK1 regulates milk protein synthesis. Molecules (Basel, Switzerland) 36 23271465
2010 ERK1 and ERK2 are required for radial glial maintenance and cortical lamination. Genes to cells : devoted to molecular & cellular mechanisms 36 20825492
2010 Genetic inactivation of ERK1 and ERK2 in chondrocytes promotes bone growth and enlarges the spinal canal. Journal of orthopaedic research : official publication of the Orthopaedic Research Society 36 20922792
2008 TDAG51 is an ERK signaling target that opposes ERK-mediated HME16C mammary epithelial cell transformation. BMC cancer 36 18597688
2020 Circ_0058124 Upregulates MAPK1 Expression to Promote Proliferation, Metastasis and Metabolic Abilities in Thyroid Cancer Through Sponging miR-940. OncoTargets and therapy 34 32110054
2020 Mechanical Stress Regulates Epithelial Tissue Integrity and Stiffness through the FGFR/Erk2 Signaling Pathway during Embryogenesis. Cell reports 33 32187556
2020 Circular RNA MAN2B2 promotes cell proliferation of hepatocellular carcinoma cells via the miRNA-217/MAPK1 axis. Journal of Cancer 33 32231737
2019 Activation loop dynamics are controlled by conformation-selective inhibitors of ERK2. Proceedings of the National Academy of Sciences of the United States of America 33 31311868
2002 A new ERK2 binding protein, Naf1, attenuates the EGF/ERK2 nuclear signaling. Biochemical and biophysical research communications 32 12220502
1999 Activated ERK2 interacts with and phosphorylates the docking protein GAB1. The Journal of biological chemistry 32 10593929
2003 Intramolecular dephosphorylation of ERK by MKP3. Biochemistry 31 14690430
2020 Liver Fibrosis and Inflammation under the Control of ERK2. International journal of molecular sciences 29 32471201
2017 Iodine Promotes Tumorigenesis of Thyroid Cancer by Suppressing Mir-422a and Up-Regulating MAPK1. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 28 28992617
2016 Naringenin targets ERK2 and suppresses UVB-induced photoaging. Journal of cellular and molecular medicine 28 26861188
2011 Resting and active states of the ERK2:HePTP complex. Journal of the American Chemical Society 28 21985012
2017 Activating MAPK1 (ERK2) mutation in an aggressive case of disseminated juvenile xanthogranuloma. Oncotarget 27 28512266
2022 EZH2 upregulates the expression of MAPK1 to promote intervertebral disc degeneration via suppression of miR-129-5p. The journal of gene medicine 26 34668273
2022 LINC00511 promotes cervical cancer progression by regulating the miR-497-5p/MAPK1 axis. Apoptosis : an international journal on programmed cell death 26 36103025
2018 Activation of the SphK1/ERK/p-ERK pathway promotes autophagy in colon cancer cells. Oncology letters 26 29928348
2017 MAPK1 of Leishmania donovani interacts and phosphorylates HSP70 and HSP90 subunits of foldosome complex. Scientific reports 26 28860596
2015 Tetrahydropyrrolo-diazepenones as inhibitors of ERK2 kinase. Bioorganic & medicinal chemistry letters 26 26259804
2013 KRAS and MAPK1 gene amplification in type II ovarian carcinomas. International journal of molecular sciences 26 23820584
2006 ERK2 activation in arteriolar and venular murine thrombosis: platelet receptor GPIb vs. P2X. Journal of thrombosis and haemostasis : JTH 26 16420578
2023 An improved Erk biosensor detects oscillatory Erk dynamics driven by mitotic erasure during early development. Developmental cell 25 37714159
2021 MicroRNA‑186‑5p downregulation inhibits osteoarthritis development by targeting MAPK1. Molecular medicine reports 25 33537828
2015 Structural assembly of the signaling competent ERK2-RSK1 heterodimeric protein kinase complex. Proceedings of the National Academy of Sciences of the United States of America 25 25730857
2001 Defective mitogen-activated protein kinase (ERK2) signaling in gastric mucosa of portal hypertensive rats: potential therapeutic implications. Hepatology (Baltimore, Md.) 25 11679970
2005 Quantifying ERK2-protein interactions by fluorescence anisotropy: PEA-15 inhibits ERK2 by blocking the binding of DEJL domains. Biochimica et biophysica acta 24 16324895
2023 MAPK1 promotes the metastasis and invasion of gastric cancer as a bidirectional transcription factor. BMC cancer 23 37817112
2013 Autophagy is used as a survival program in unfertilized sea urchin eggs that are destined to die by apoptosis after inactivation of MAPK1/3 (ERK2/1). Autophagy 23 23970301