Affinage

MAPK1

Mitogen-activated protein kinase 1 · UniProt P28482

Length
360 aa
Mass
41.4 kDa
Annotated
2026-06-10
100 papers in source corpus 36 papers cited in narrative 37 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

MAPK1/ERK2 is a serine/threonine kinase that serves as a terminal effector of the ERK MAP kinase module, converting mitogenic and mechanical inputs into transcriptional, metabolic, and cytoskeletal outputs (PMID:10969079, PMID:32187556). Activation is governed by MEK1-mediated dual phosphorylation, which releases conformational constraints at the hinge between the N- and C-terminal lobes to drive global two-state conformational exchange throughout the catalytic core and promote activity (PMID:24550275), with catalysis proceeding through rapid-equilibrium ATP binding followed by rate-limiting phosphoryl transfer (PMID:10821702). Substrate and regulator engagement is directed by a docking site distinct from the catalytic pocket—an acidic patch and hydrophobic groove that bind KIM/linear motifs of partners such as the phosphatase MKP3 and the kinase RSK1, the latter captured in a precatalytic heterodimeric state (PMID:16567630, PMID:25730857); proximity-based docking increases the effective concentration of phosphoacceptor motifs near the active site (PMID:16045329). Subcellular targeting is tightly controlled: a C-terminal retention sequence (residues 312–320) holds ERK2 in the cytosol via MEK1 association in resting cells, while activation promotes homodimerization and carrier-independent nuclear entry through direct nucleoporin binding (PMID:9604935, PMID:10521408, PMID:12032311). ERK2 phosphorylates a broad substrate repertoire to control diverse processes—PFAS to stimulate de novo purine synthesis (PMID:32485148), ULK1 to trigger its ubiquitin-dependent degradation and restrain mitophagy (PMID:33213267), Par3 to regulate axonal transport and neuronal polarity (PMID:23946386), CPEB4 to control its phase behavior and mRNA-translation activity (PMID:27802129), Shank3 and PAK1 to drive their degradation or feedback inhibition (PMID:30696942, PMID:15542607), and transcriptional regulators including Bcl3 and the IEG machinery via PARP1 (PMID:28689659, PMID:27121568). ERK2 activity is spatially organized by scaffolds and tethers including IQGAP1, MEKK1, and nesprin-2 at PML nuclear bodies (PMID:14970219, PMID:10969079, PMID:19861416), and counter-regulated by phosphatases whose dephosphorylation efficiency depends on ERK2 conformational state (PMID:31311868, PMID:24691442). ERK2-specific signaling drives epithelial-mesenchymal plasticity, invasion, and BRAF-inhibitor-resistant melanoma phenotypes, frequently distinguishing it functionally from ERK1 (PMID:28976960, PMID:22328529, PMID:30728292).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1998 High

    Established how active ERK2 reaches the nucleus, resolving whether nuclear accumulation required oligomerization—dimerization of phospho-ERK2 was shown to be necessary for ligand-dependent nuclear translocation.

    Evidence Microinjection, site-directed mutagenesis, and crystal structure of phospho-ERK2

    PMID:9604935

    Open questions at the time
    • Did not identify the nuclear import machinery used
    • Dimerization-independent functions not addressed
  2. 1999 High

    Defined the molecular basis for cytoplasmic retention versus nuclear targeting, mapping a C-terminal retention sequence that anchors ERK2 to MEK1 in resting cells and a separate segment required for translocation.

    Evidence GFP-ERK2 fusions in CHO cells with alanine-scanning mutagenesis and MEK1 co-expression

    PMID:10521408

    Open questions at the time
    • How activation overrides retention not mechanistically resolved
    • Did not address the translocation machinery
  3. 2000 High

    Addressed how ERK2 catalysis is timed and how the kinase module assembles—kinetic dissection set phosphoryl transfer as rate-limiting, and MEKK1 was shown to bind ERK2, MEK1, and Raf-1 as a candidate scaffold.

    Evidence Steady-state kinetics with viscosimetry on purified ERK2; endogenous co-immunoprecipitation

    PMID:10821702 PMID:10969079

    Open questions at the time
    • MEKK1 scaffold stoichiometry and cellular requirement not established
    • Kinetics on physiological substrates beyond MBP/peptide limited
  4. 2002 High

    Determined the mechanism of ERK2 nuclear import, showing it occurs by carrier- and energy-independent direct binding to nucleoporins rather than canonical import factors.

    Evidence Reconstituted in vitro import assay with WGA inhibition, transport-factor competition, and direct nucleoporin binding

    PMID:12032311

    Open questions at the time
    • Reconciliation with dimerization requirement for import not fully integrated
    • Which nucleoporins are physiologically rate-limiting unclear
  5. 2006 High

    Resolved the structural basis of substrate/regulator selection, showing a docking site (acidic patch plus hydrophobic groove) distinct from the catalytic pocket engages KIM motifs.

    Evidence X-ray crystallography of ERK2:MKP3 KIM peptide complex

    PMID:16567630

    Open questions at the time
    • Does not capture full-length phosphatase or substrate complex dynamics
    • Selectivity determinants among different KIM motifs not exhaustively defined
  6. 2005 High

    Clarified how docking translates into catalytic efficiency, demonstrating proximity-induced catalysis where substrate domains dock outside the active site to raise effective concentration of the phosphoacceptor motif.

    Evidence In vitro kinase assays with domain/point mutants of EtsDelta138 and binding measurements

    PMID:16045329

    Open questions at the time
    • Generality across all substrate classes not tested
    • In vitro reconstitution only
  7. 2014 High

    Explained how phosphorylation activates the kinase at the conformational level, showing TEY phosphorylation releases hinge constraints to drive global two-state exchange that reaches the catalytic pocket.

    Evidence NMR 13C relaxation dispersion with hinge-mutant ERK2 engineering

    PMID:24550275

    Open questions at the time
    • Direct link between specific conformer and substrate turnover rates not fully quantified
  8. 2019 High

    Connected ERK2 conformational state to drug action and regulation, showing inhibitors stabilizing distinct L/R states differentially affect phosphatase-mediated dephosphorylation.

    Evidence X-ray crystallography and HX-MS of 2P-ERK2 inhibitor complexes

    PMID:31311868

    Open questions at the time
    • In-cell consequences of conformation-selective dephosphorylation not measured
    • Effect on individual substrate selection unclear
  9. 2004 High

    Identified ERK2 scaffolds and feedback substrates, establishing IQGAP1 as a direct binding partner modulating ERK1/2 activity and PAK1 as an adhesion-dependent substrate forming a negative feedback loop.

    Evidence In vitro pull-down, reciprocal Co-IP, knockdown/overexpression, far-Western, in vitro kinase and reporter assays

    PMID:14970219 PMID:15542607

    Open questions at the time
    • Quantitative contribution of IQGAP1 scaffolding to physiological ERK output unclear
    • PAK1 feedback magnitude in vivo not defined
  10. 2003 High

    Expanded the ERK2 substrate landscape using chemical genetics, identifying the E3 ligase EDD and the nucleoporin Tpr as direct substrates.

    Evidence Engineered ERK2(Q103G) with bulky ATP analog, in vitro and in vivo phosphorylation validation

    PMID:12594221

    Open questions at the time
    • Functional consequences of EDD/Tpr phosphorylation not defined
  11. 2015 High

    Linked ERK2 to upstream activating receptors and to a downstream kinase, defining the SHP2→GAB1→ERK2 axis and capturing the ERK2–RSK1 precatalytic complex.

    Evidence Crystallography with MD simulation (RSK1); phosphatase/kinase assays and dominant-negative GAB1 epistasis (SHP2/GAB1)

    PMID:10593929 PMID:14974085 PMID:25730857

    Open questions at the time
    • Dynamics of transition to fully catalytic RSK1 complex inferred from structure
    • GAB1 axis studied largely via overexpression/mutants
  12. 2011 Medium

    Demonstrated that ERK2 regulatory complexes are conformationally dynamic, with resting ERK2:HePTP extended and the active complex compact in solution.

    Evidence SAXS with EROS ensemble refinement on purified complexes

    PMID:21985012

    Open questions at the time
    • No orthogonal functional validation
    • Single structural method
  13. 2016 Medium

    Defined ERK2 control of regulated proteins via degradation and phase behavior, and its role in chromatin-based gene activation, showing ULK1/Shank3 degradation, CPEB4 monomerization, and PARP1-dependent recruitment to IEG promoters.

    Evidence In vitro kinase/ubiquitination and phase-separation assays, Co-IP, ChIP, knockout mice, LTP electrophysiology

    PMID:27121568 PMID:27802129 PMID:30696942 PMID:33213267

    Open questions at the time
    • Several pathways rest on single-lab Co-IP plus rescue
    • Direct vs. indirect contributions in vivo not fully separated
  14. 2020 High

    Established ERK2 as a metabolic and organelle regulator, phosphorylating PFAS to boost de novo purine synthesis and modulating mitochondrial dynamics through PACS-2/MAM control.

    Evidence In vitro kinase assay, 13C metabolic flux analysis, phosphomutant xenografts; diabetic mouse/HK-2 models with MAPK1 inhibition and PACS-2 rescue

    PMID:32485148 PMID:38169625

    Open questions at the time
    • PACS-2 regulation mechanism (direct vs. indirect) not fully defined
    • ERK1 vs. ERK2 specificity for PACS-2 effect untested
  15. 2020 Medium

    Revealed kinase-independent and isoform-specific ERK2 functions, including bidirectional transcription-factor activity at gastric cancer promoters and mechanically activated ERK2 remodeling cytoskeletal junctions.

    Evidence ChIP-seq/RNA-seq with functional assays; Xenopus mechanical stimulation with phosphoproteomics and FGFR1 inhibition

    PMID:32187556 PMID:37817112

    Open questions at the time
    • Kinase-independent transcriptional role shown in a single cell line
    • Direct DNA-binding mechanism not structurally defined
  16. 2017 High

    Connected ERK2-specific activity to disease-relevant phenotypes, showing ERK2 drives EMT, invasion, and BRAF-inhibitor-resistant melanoma drug addiction distinct from ERK1.

    Evidence CRISPR knockout screens, isoform-specific rescue, 3D invasion assays, mouse models, patient tissue analysis

    PMID:22328529 PMID:24691442 PMID:28689659 PMID:28976960 PMID:30728292

    Open questions at the time
    • Molecular basis of ERK2 vs ERK1 functional divergence incompletely defined
    • Some downstream pathways established by epistasis rather than direct substrate phosphorylation

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ERK2 achieves substrate-specific outputs from a single conformationally dynamic active site—integrating docking, scaffolding, localization, and kinase-independent functions—remains incompletely defined.
  • No unified model linking conformational state to substrate selection in cells
  • Kinase-independent transcription-factor role mechanistically unresolved
  • Determinants of ERK1 vs ERK2 isoform specificity unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 9 GO:0016740 transferase activity 3 GO:0003677 DNA binding 2 GO:0140110 transcription regulator activity 1 GO:0140657 ATP-dependent activity 1
Localization
GO:0005634 nucleus 3 GO:0005739 mitochondrion 2 GO:0005829 cytosol 2 GO:0000228 nuclear chromosome 1 GO:0005635 nuclear envelope 1 GO:0005811 lipid droplet 1
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-1430728 Metabolism 3 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-9612973 Autophagy 3
Partners
GAB1IQGAP1MEK1MEKK1MKP3/DUSP6PAK1PAR3RSK1

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 Phosphorylated ERK2 forms homodimers with both phosphorylated and unphosphorylated ERK2 partners; disruption of dimerization by mutagenesis reduces nuclear accumulation, establishing that dimerization is required for ligand-dependent nuclear translocation. Crystal structure of phosphorylated ERK2 reveals the structural basis for dimerization. Microinjection of ERK2 into cells, site-directed mutagenesis, crystal structure of phospho-ERK2 Cell High 9604935
1999 Residues 312–320 of ERK2 constitute a cytoplasmic-retention sequence that mediates association with MEK1, keeping ERK2 in the cytosol in resting cells; residues 321–327 are required for nuclear translocation upon mitogenic stimulation. Key acidic residues at positions 316, 319, and 320 are essential for cytosolic retention. GFP-ERK2 fusion constructs expressed in CHO cells, alanine-scanning mutagenesis, co-expression with MEK1, fluorescence microscopy The Journal of biological chemistry High 10521408
2002 ERK2 enters the nucleus by a carrier- and energy-independent mechanism involving direct binding to nucleoporins of the nuclear pore complex, competing with canonical transport factors for pore access. In vitro nuclear import assay with GFP-ERK2, wheat germ agglutinin inhibition, recombinant transport factor competition, direct binding to purified nucleoporin Proceedings of the National Academy of Sciences of the United States of America High 12032311
2000 ERK2 catalytic mechanism proceeds via rapid-equilibrium ATP binding followed by diffusion-limited MBP binding and rate-limiting phosphoryl transfer (kcat ~10 s⁻¹), with product release faster than phosphoryl transfer. Steady-state kinetics and solvent viscosimetry with purified ERK2, MBP, and ERKtide peptide substrates Biochemistry High 10821702
2006 Crystal structure of ERK2 bound to the KIM peptide of MAP kinase phosphatase 3 (MKP3) reveals that the docking site on ERK2 comprises a highly acidic patch and a hydrophobic groove that engage the basic and hydrophobic residues of the KIM sequence; this docking site is distinct from the catalytic pocket. X-ray crystallography of ERK2:KIM peptide complex Proceedings of the National Academy of Sciences of the United States of America High 16567630
2014 Dual phosphorylation of ERK2 by MEK1 releases conformational constraints at the hinge between N- and C-terminal domains, inducing global two-state conformational exchange (kex ~300 s⁻¹) throughout the kinase core including the catalytic pocket, thereby promoting catalytic activity. NMR ¹³C relaxation dispersion (Ile/Leu/Val methyl side chains), hinge-mutant ERK2 engineering Proceedings of the National Academy of Sciences of the United States of America High 24550275
2019 ERK inhibitors Vertex-11e and SCH772984 exploit two distinct conformational states (L and R) of active 2P-ERK2: Vertex-11e stabilizes the R (domain-closed, catalytically competent) state while a SCH772984 analog blocks domain closure; these conformational differences differentially regulate MAP kinase phosphatase-mediated dephosphorylation of ERK2. X-ray crystallography of 2P-ERK2 complexes, NMR hydrogen-exchange MS (HX-MS), kinase conformation analysis Proceedings of the National Academy of Sciences of the United States of America High 31311868
2004 IQGAP1 directly binds ERK2 in vitro and co-immunoprecipitates with endogenous ERK2 from human breast epithelial cells; manipulation of IQGAP1 levels modulates growth-factor-stimulated ERK1/2 activity, and an IQGAP1 construct lacking the ERK2-binding region fails to interfere with ERK activation. In vitro pull-down with purified proteins, co-immunoprecipitation from cell lysates, overexpression/knockdown of IQGAP1, kinase activity assays The Journal of biological chemistry High 14970219
2000 Endogenous MEKK1 binds endogenous ERK2, MEK1, and Raf-1, indicating that MEKK1 can serve as a scaffold assembling all three kinases of the ERK MAP kinase module. Co-immunoprecipitation of endogenous proteins from cell lysates The Journal of biological chemistry Medium 10969079
2003 Using an engineered ERK2 (Q103G) that accepts a bulky ATP analog, EDD (ubiquitin E3 ligase) and nucleoporin Tpr were identified as novel direct ERK2 substrates; EDD phosphorylation by ERK2 was confirmed both in vitro and in vivo. Chemical genetics (engineered kinase + ATP analog), phosphorylation of ERK2-associated proteins in COS-1 cells, in vitro kinase assay, in vivo phosphorylation validation The Journal of biological chemistry High 12594221
1999 Phosphorylated (active) ERK2 directly associates with GAB1 via its MET-binding domain without requiring a third protein; ERK2 phosphorylates GAB1 in vitro and in cells, with new phosphorylation sites appearing upon MEK1 co-transfection. GST pull-down with bacterially expressed proteins, co-immunoprecipitation in A293 cells, in vitro kinase assay, phosphopeptide mapping The Journal of biological chemistry Medium 10593929
2004 Adhesion stimulates a direct physical interaction between PAK1 and ERK2; ERK2 phosphorylates PAK1 at Thr212 in vitro and in PDGF-treated smooth muscle cells in an adhesion- and MEK/ERK-dependent manner; a phosphomimic PAK1-T212E attenuates downstream ERK signaling, suggesting a negative feedback loop. Co-immunoprecipitation, far-Western analysis, peptide mapping of ERK2 binding site, in vitro kinase assay, SRE-luciferase reporter, immunofluorescence co-localization The Journal of biological chemistry High 15542607
2005 ERK2 mediates proximity-induced (docking-dependent) catalysis: the pnt domain of substrate EtsDelta138 docks outside the active site, increasing effective concentration of the phosphorylatable TP motif near the catalytic pocket; disruption of the pnt-domain interaction (F120A) reduces binding 10-fold without affecting kcat, while mutagenesis of the TP motif decreases kcat without affecting docking. In vitro kinase assays with ERK2 and domain/point mutants of EtsDelta138, equilibrium binding measurements Journal of the American Chemical Society High 16045329
2015 Crystal structure of the ERK2–RSK1 heterodimeric complex captures a precatalytic state where the RSK1 activation loop faces the ERK2 catalytic site; the MAPK-binding linear motif of RSK1 interacting with the ERK2 docking groove is the primary determinant of complex formation, and domain contacts between the kinase cores shift the complex into a catalytically competent state. X-ray crystallography, molecular dynamics simulation, biochemical assays, cellular signaling studies Proceedings of the National Academy of Sciences of the United States of America High 25730857
2011 SAXS analysis shows the resting-state ERK2:HePTP complex is extended and dynamic, whereas the active-state complex is compact and ordered, demonstrating that these regulatory complexes undergo significant dynamic structural rearrangement in solution. Small-angle X-ray scattering (SAXS) with EROS ensemble refinement Journal of the American Chemical Society Medium 21985012
2006 ERK2 (but not ERK1, JNK1, JNK2, p38α, or p38β) is required for cytosolic lipid droplet formation; ERK2 acts downstream of PLD1, and ERK2 increases phosphorylation of dynein, which increases dynein association with ADRP-containing lipid droplets; antibody inhibition of dynein strongly blocks lipid droplet formation. Overexpression, siRNA knockdown, microinjection of ERK2 and PLD1, pharmacological inhibition, dynein phosphorylation assay, antibody microinjection Journal of cell science Medium 16723731
2013 ERK2 directly interacts with Par3 and phosphorylates it at Ser-1116; phosphorylated Par3 accumulates at axonal tips but its interaction with KIF3A is inhibited, slowing axonal transport and impairing neuronal polarization in cultured hippocampal neurons and mouse cortical neurons in vivo. Co-immunoprecipitation, in vitro kinase assay, phosphomimic/phospho-null mutants, RNAi rescue experiments in cultured neurons and in vivo cortical neurons The Journal of neuroscience High 23946386
2020 ERK2 (but not ERK1) phosphorylates PFAS (phosphoribosylformylglycinamidine synthase) at Thr619 to stimulate de novo purine synthesis flux; non-phosphorylatable PFAS-T619A decreases purine synthesis and reduces RAS-dependent cancer cell colony formation and tumor growth. In vitro kinase assay with purified ERK2, ¹³C metabolic flux analysis, phosphomutant expression, colony formation and xenograft tumor assays Molecular cell High 32485148
2020 MAPK1/ERK2 phosphorylates ULK1, triggering its interaction with the E3 ligase BTRC and subsequent K48-linked ubiquitination and proteasomal degradation, thereby attenuating mitophagy and promoting NLRP3 inflammasome activation and breast cancer bone metastasis. Co-immunoprecipitation, in vitro ubiquitination assay, MEK inhibitor (trametinib) rescue, xenograft mouse model, human breast cancer tissue correlation Autophagy Medium 33213267
2017 ERK2, together with Akt and IKK1/2, phosphorylates Bcl3 at Ser114 and Ser446; ERK2/IKK1/2-mediated phosphorylation converts Bcl3 from an IκB-like inhibitor into a transcriptional co-regulator by facilitating its recruitment to DNA; cells expressing S114A/S446A Bcl3 show proliferation and migration defects. In vitro kinase assays, phosphomutant expression, co-immunoprecipitation, DNA-binding assays, cellular proliferation/migration assays Molecular cell High 28689659
2016 ERK2 and Cdk1 hyperphosphorylate CPEB4 in M-phase to maintain it as a monomer and activate its mRNA-translation regulatory function; unphosphorylated CPEB4 phase-separates into inactive liquid-like droplets through its intrinsically disordered N-terminal domain. In vitro phosphorylation assays, phosphomutant analysis, phase-separation assays, cell cycle synchronization, fluorescence microscopy eLife Medium 27802129
2019 ERK2 (but not ERK1) binds Shank3 and phosphorylates it at three residues to promote poly-ubiquitination-dependent proteasomal degradation of Shank3; genetic deletion or pharmacological inhibition of ERK2 increases Shank3 abundance in vivo. Kinome-wide siRNA screen, co-immunoprecipitation, in vitro kinase assay, ERK2 knockout mice, pharmacological inhibition Molecular psychiatry High 30696942
2019 ERK2 induces EMT by upregulating Dock10 (a Rac1/Cdc42 GEF), which activates Rac1/JNK signaling, leading to increased FoxO1 expression; ERK2-dependent FoxO1 regulation promotes epithelial-to-mesenchymal plasticity. Global gene expression analysis (ERK2-specific), co-immunoprecipitation, RNAi, reporter assays, cell migration assays Proceedings of the National Academy of Sciences of the United States of America Medium 30728292
2015 Under sustained metabolic (low-glucose) stress, MEK1/ERK2 isoform-specific signaling induces GCN2/eIF2α phosphorylation and ATF4 expression, which overrides PERK/Akt-mediated survival and induces apoptosis through ATF4-dependent pro-apoptotic factors (Bid, Trb3); ERK2 activation also alters TCA cycle and amino acid metabolism. Isoform-specific knockdown/overexpression, phosphoprotein analysis, metabolomics (TCA cycle, amino acid profiling), apoptosis assays Molecular cell Medium 26190261
2008 Mitochondrial localization of active ERK2 (but not kinase-dead ERK2) is sufficient to induce mitophagy and autophagic cell death; constitutively active ERK2 localizes more strongly to mitochondria than WT ERK2, and these mitochondria-associated ERK2 granules undergo autophagic degradation. GFP-ERK2 fusion constructs (WT, CA, KD), live-cell fluorescence microscopy, co-localization with mitochondrial and autophagolysosomal markers, bafilomycin-A inhibitor experiments, LC3 autophagy marker analysis Autophagy Medium 18594198
2017 ERK2 kinase activity drives a specific phenotype switch (transcriptional reprogramming resembling EMT, including shutdown of MITF) that underlies drug addiction in BRAF-inhibitor-resistant melanoma cells; disruption of an ERK2-JUNB-FRA1 signaling pathway allows addicted cells to survive drug withdrawal. Unbiased CRISPR-Cas9 knockout screen, ERK2-specific rescue experiments, in vitro and in vivo (mouse) models, patient tissue analysis Nature High 28976960
2014 PLAC8 directly binds and inactivates the ERK2 phosphatase DUSP6 in vitro, thereby increasing phospho-ERK2 levels; ERK2 knockdown reverses PLAC8-induced EMT features (restored CDH1, suppressed CDH3/VIM/ZEB1), placing ERK2 downstream of PLAC8-DUSP6 in an unconventional EMT pathway in colon cancer. In vitro DUSP6 activity assay with recombinant PLAC8, ERK2 knockdown, xenograft tumor model, MultiOmyx multiplex immunofluorescence The Journal of clinical investigation Medium 24691442
2009 Nesprin-2 acts as a nuclear scaffold that tethers active ERK1/2 at PML nuclear bodies; knockdown or dominant-negative disruption of nesprin-2 augments ERK1/2 nuclear signaling (increased SP1 activity and ELK1 phosphorylation) and increases cell proliferation; this function is mediated by nuclear nesprin-2 isoforms lacking the KASH domain. Immunofluorescence co-localization, GST pull-down, co-immunoprecipitation, siRNA knockdown, dominant-negative overexpression, reporter assays The Journal of biological chemistry Medium 19861416
2016 PARP1 binds phosphorylated ERK2 in neuronal chromatin upon stimulation; ERK2-induced PARP1 activation renders immediate early gene (IEG) promoters accessible to phospho-ERK2, mediating IEG expression required for LTP; PARP1 inhibition or deletion abrogates ERK2 recruitment to IEG promoters and prevents LTP generation. Co-immunoprecipitation of chromatin-bound proteins, PARP1 inhibition/knockdown/knockout, ERK2 chromatin-immunoprecipitation, LTP electrophysiology in hippocampal slices Scientific reports Medium 27121568
2004 Noonan syndrome PTPN11 (SHP2) gain-of-function mutants cause prolonged ERK2/MAPK1 activation in a ligand (EGF)-dependent, GAB1-docking-dependent manner; co-expression of GAB1-FF (lacking SHP2-binding motifs) dramatically reduces ERK2 activation, establishing the SHP2→GAB1→ERK2 pathway axis. Phosphatase activity assays, ERK2 kinase assays, co-immunoprecipitation of SHP2 with GAB1, dominant-negative GAB1 epistasis, cell proliferation assays Human mutation Medium 14974085
2020 In Xenopus embryos, mechanical forces (centrifugal, compression, stretching) activate ERK2 via FGFR1 independently of FGF ligands; ERK2 activation remodels cytoskeletal proteins (F-actin, C-cadherin, ZO-1) to enhance cellular junctions and tissue stiffening. Xenopus embryo mechanical stimulation, phosphoproteome analysis, FGFR1 inhibition, fluorescence imaging of cytoskeletal markers Cell reports Medium 32187556
2012 ERK2 (but not ERK1) silencing inhibits invasive migration in 3D matrices; ERK2 re-expression (not ERK1) restores invasion; ERK2 suppresses expression of Rab17 and liprin-β2, which inhibit invasion; knockdown of either Rab17 or liprin-β2 restores invasiveness of ERK2-depleted cells. siRNA knockdown, isoform-specific rescue, 3D matrix migration assays, gene expression arrays, secondary knockdown epistasis Journal of cell science Medium 22328529
2013 ERK2 directly interacts with and phosphorylates Par3 at Ser-1116, inhibiting Par3–KIF3A interaction; phosphomimic Par3-S1116D shows reduced KIF3A binding and slower axonal transport, impairing neuronal polarization in hippocampal neurons and cortical projection neurons in vivo. Co-immunoprecipitation, in vitro kinase assay, phosphomimic/phospho-null mutants expressed in cultured neurons and in vivo mouse cortex via in utero electroporation, RNAi rescue The Journal of neuroscience High 23946386
2005 PEA-15 sequesters ERK2 in the cytoplasm by competing with DEJL-domain-containing substrates/activators for binding to ERK2; the C-terminus of PEA-15 (residues 121–129) constitutes a reverse DEJL domain mediating one arm of a bidentate interaction with ERK2. Fluorescence anisotropy binding assays with purified ERK2 and PEA-15/peptides, competition experiments with DEJL-derived peptides Biochimica et biophysica acta Medium 16324895
2024 High glucose conditions increase MAPK1 activity, which lowers PACS-2 (a MAM tethering protein) levels, causing mitochondria-associated ER membrane (MAM) disruption and mitochondrial fragmentation in renal tubular cells; inhibition of MAPK1 restores PACS-2 and protects against MAM loss and mitochondrial fragmentation in diabetic mice. Diabetic mouse and human kidney tissue analysis, HK-2 cell high-glucose model, MAPK1 inhibition (pharmacological), PACS-2 rescue overexpression International journal of biological sciences Medium 38169625
2016 MAPK1/ERK2 activation ameliorates hepatic steatosis through ATG7-dependent autophagy; knockdown of MAPK1/3 promotes liver steatosis, reduces autophagic flux and ATG7 levels in primary hepatocytes; blockade of autophagy (chloroquine or ATG7 knockdown) reverses the anti-steatosis effect of MAPK1/3 activation. Adenoviral MAPK1/3 activation in db/db mice, siRNA knockdown, autophagic flux assays, ATG7 expression analysis, pharmacological autophagy blockade Autophagy Medium 26760678
2020 MAPK1 binds to promoter regions of target genes in gastric cancer cells and functions as a bidirectional transcription factor (independent of its kinase role), upregulating KRT13, KRT6A, KRT81, MYH15, STARD4, SYTL4, TMEM267 and downregulating FGG, thereby promoting cell motility and invasion. ChIP-seq, RNA-seq, ChIP assays, chromatin immunoprecipitation confirming MAPK1 at promoters, cell proliferation and migration assays BMC cancer Medium 37817112

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 Phosphorylation of the MAP kinase ERK2 promotes its homodimerization and nuclear translocation. Cell 581 9604935
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 244 18594198
2003 Essential role for ERK2 mitogen-activated protein kinase in placental development. Genes to cells : devoted to molecular & cellular mechanisms 241 14622137
2016 ERK1 and ERK2 Map Kinases: Specific Roles or Functional Redundancy? Frontiers in cell and developmental biology 228 27376062
2004 MEK1-ERK2 signaling pathway protects myocardium from ischemic injury in vivo. Circulation 203 15096454
2004 IQGAP1 binds ERK2 and modulates its activity. The Journal of biological chemistry 189 14970219
2020 MAPK1/3 kinase-dependent ULK1 degradation attenuates mitophagy and promotes breast cancer bone metastasis. Autophagy 177 33213267
2008 The Erk2 MAPK regulates CD8 T cell proliferation and survival. Journal of immunology (Baltimore, Md. : 1950) 170 19017950
2004 Noonan syndrome-associated SHP2/PTPN11 mutants cause EGF-dependent prolonged GAB1 binding and sustained ERK2/MAPK1 activation. Human mutation 159 14974085
2009 Erk1 and Erk2 regulate endothelial cell proliferation and migration during mouse embryonic angiogenesis. PloS one 148 20011539
2006 PLD1 and ERK2 regulate cytosolic lipid droplet formation. Journal of cell science 140 16723731
2011 The ERK2 mitogen-activated protein kinase regulates the timing of oligodendrocyte differentiation. The Journal of neuroscience : the official journal of the Society for Neuroscience 138 21248107
1999 Identification of a cytoplasmic-retention sequence in ERK2. The Journal of biological chemistry 128 10521408
1996 Dual leucine zipper-bearing kinase (DLK) activates p46SAPK and p38mapk but not ERK2. The Journal of biological chemistry 126 8798750
2002 ERK2 enters the nucleus by a carrier-independent mechanism. Proceedings of the National Academy of Sciences of the United States of America 125 12032311
2020 CircRNA_101237 promotes NSCLC progression via the miRNA-490-3p/MAPK1 axis. Scientific reports 124 32494004
2017 Cancer drug addiction is relayed by an ERK2-dependent phenotype switch. Nature 121 28976960
2006 Structural basis of docking interactions between ERK2 and MAP kinase phosphatase 3. Proceedings of the National Academy of Sciences of the United States of America 114 16567630
2000 ERK5 and ERK2 cooperate to regulate NF-kappaB and cell transformation. The Journal of biological chemistry 112 11118448
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 101 10969079
2003 Identification of novel ERK2 substrates through use of an engineered kinase and ATP analogs. The Journal of biological chemistry 100 12594221
2015 Functional Redundancy of ERK1 and ERK2 MAP Kinases during Development. Cell reports 82 26235619
2015 ERK2 Mediates Metabolic Stress Response to Regulate Cell Fate. Molecular cell 81 26190261
2004 Alternative, nonapoptotic programmed cell death: mediation by arrestin 2, ERK2, and Nur77. The Journal of biological chemistry 78 14769794
1994 Functional divergence of the MAP kinase pathway. ERK1 and ERK2 activate specific transcription factors. FEBS letters 78 8013639
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
2020 Enhanced MAPK1 Function Causes a Neurodevelopmental Disorder within the RASopathy Clinical Spectrum. American journal of human genetics 73 32721402
2005 Leptin activates STAT and ERK2 pathways and induces gastric cancer cell proliferation. Biochemical and biophysical research communications 73 15882975
2019 ERK2 regulates epithelial-to-mesenchymal plasticity through DOCK10-dependent Rac1/FoxO1 activation. Proceedings of the National Academy of Sciences of the United States of America 69 30728292
2012 ERK2 drives tumour cell migration in three-dimensional microenvironments by suppressing expression of Rab17 and liprin-β2. Journal of cell science 66 22328529
2020 ERK2 Phosphorylates PFAS to Mediate Posttranslational Control of De Novo Purine Synthesis. Molecular cell 65 32485148
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
2014 Phosphorylation releases constraints to domain motion in ERK2. Proceedings of the National Academy of Sciences of the United States of America 60 24550275
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
2016 CPEB4 is regulated during cell cycle by ERK2/Cdk1-mediated phosphorylation and its assembly into liquid-like droplets. eLife 53 27802129
2000 Catalytic reaction pathway for the mitogen-activated protein kinase ERK2. Biochemistry 49 10821702
2017 ERK1 and ERK2 activation modulates diet-induced obesity in mice. Biochimie 48 28302472
2018 P2RX7-MAPK1/2-SP1 axis inhibits MTOR independent HSPB1-mediated astroglial autophagy. Cell death & disease 47 29749377
2009 Novel nuclear nesprin-2 variants tether active extracellular signal-regulated MAPK1 and MAPK2 at promyelocytic leukemia protein nuclear bodies and act to regulate smooth muscle cell proliferation. The Journal of biological chemistry 47 19861416
2008 ERK1 and ERK2 MAPK are key regulators of distinct gene sets in zebrafish embryogenesis. BMC genomics 47 18442396
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
2015 Expression of MAPK1 in cervical cancer and effect of MAPK1 gene silencing on epithelial-mesenchymal transition, invasion and metastasis. Asian Pacific journal of tropical medicine 45 26614994
2021 Paeonol inhibits the malignancy of Apatinib-resistant gastric cancer cells via LINC00665/miR-665/MAPK1 axis. Phytomedicine : international journal of phytotherapy and phytopharmacology 44 35026514
2008 ERK2 protein regulates the proliferation of human mesenchymal stem cells without affecting their mobilization and differentiation potential. Experimental cell research 43 18378228
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 41 29335299
2015 ERK1 and ERK2 present functional redundancy in tetrapods despite higher evolution rate of ERK1. BMC evolutionary biology 40 26336084
2005 Proximity-induced catalysis by the protein kinase ERK2. Journal of the American Chemical Society 40 16045329
1997 Activation of the mitogen-activated protein kinase ERK2 by the chemoattractant folic acid in Dictyostelium. The Journal of biological chemistry 40 9295311
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
2013 Erk1 and Erk2 are required for maintenance of hematopoietic stem cells and adult hematopoiesis. Blood 38 23444405
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
2016 MAPK1/3 regulate hepatic lipid metabolism via ATG7-dependent autophagy. Autophagy 35 26760678
2019 MicroRNA-206 facilitates gastric cancer cell apoptosis and suppresses cisplatin resistance by targeting MAPK2 signaling pathway. European review for medical and pharmacological sciences 34 30657558
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 34 31311868
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
2020 Liver Fibrosis and Inflammation under the Control of ERK2. International journal of molecular sciences 32 32471201
1999 Activated ERK2 interacts with and phosphorylates the docking protein GAB1. The Journal of biological chemistry 32 10593929
2024 MAPK1 Mediates MAM Disruption and Mitochondrial Dysfunction in Diabetic Kidney Disease via the PACS-2-Dependent Mechanism. International journal of biological sciences 30 38169625
2013 ERK2-mediated phosphorylation of Par3 regulates neuronal polarization. The Journal of neuroscience : the official journal of the Society for Neuroscience 30 23946386
2016 Naringenin targets ERK2 and suppresses UVB-induced photoaging. Journal of cellular and molecular medicine 29 26861188
2011 Resting and active states of the ERK2:HePTP complex. Journal of the American Chemical Society 28 21985012
2022 EZH2 upregulates the expression of MAPK1 to promote intervertebral disc degeneration via suppression of miR-129-5p. The journal of gene medicine 27 34668273
2022 The role of ERK-1 and ERK-2 gene polymorphisms in PCOS pathogenesis. Reproductive biology and endocrinology : RB&E 27 35768803
2022 LINC00511 promotes cervical cancer progression by regulating the miR-497-5p/MAPK1 axis. Apoptosis : an international journal on programmed cell death 27 36103025
2023 MAPK1 promotes the metastasis and invasion of gastric cancer as a bidirectional transcription factor. BMC cancer 26 37817112
2021 MicroRNA‑186‑5p downregulation inhibits osteoarthritis development by targeting MAPK1. Molecular medicine reports 26 33537828
2017 MAPK1 of Leishmania donovani interacts and phosphorylates HSP70 and HSP90 subunits of foldosome complex. Scientific reports 26 28860596
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
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
2019 A kinome-wide RNAi screen identifies ERK2 as a druggable regulator of Shank3 stability. Molecular psychiatry 23 30696942
2017 siRNA-loaded biodegradable nanocarriers for therapeutic MAPK1 silencing against cisplatin-induced ototoxicity. International journal of pharmaceutics 23 28627458
2009 Clozapine-induced ERK1 and ERK2 signaling in prefrontal cortex is mediated by the EGF receptor. Journal of molecular neuroscience : MN 23 19277491
2016 A PARP1-ERK2 synergism is required for the induction of LTP. Scientific reports 22 27121568
2015 Both ERK1 and ERK2 are required for enterovirus 71 (EV71) efficient replication. Viruses 22 25803100
2020 Loss of the Conserved Alveolate Kinase MAPK2 Decouples Toxoplasma Cell Growth from Cell Division. mBio 21 33173004
2018 Dictyostelium Erk2 is an atypical MAPK required for chemotaxis. Cellular signalling 21 29551366
2017 Synergistic suppression of t(8;21)-positive leukemia cell growth by combining oridonin and MAPK1/ERK2 inhibitors. Oncotarget 21 28915648
2016 MAPK1/ERK2 as novel target genes for pain in head and neck cancer patients. BMC genetics 21 26872611
2024 N6-methyladenosine-modified CircPSMA7 enhances bladder cancer malignancy through the miR-128-3p/MAPK1 axis. Cancer letters 20 38211649
2015 Active ERK2 is sufficient to mediate growth arrest and differentiation signaling. The FEBS journal 20 25639353
2008 COX2 expression and Erk1/Erk2 activity mediate Cot-induced cell migration. Cellular signalling 20 18572386

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