{"gene":"PPP1R15A","run_date":"2026-04-28T19:45:44","timeline":{"discoveries":[{"year":2001,"finding":"GADD34 (PPP1R15A) forms a complex with the catalytic subunit of protein phosphatase 1 (PP1c) that specifically promotes dephosphorylation of eIF2α in vitro, acting as a negative feedback regulator of the unfolded protein response and stress-induced translational repression.","method":"Co-immunoprecipitation, in vitro phosphatase assay, retroviral overexpression with CHOP::GFP reporter, PP1c-binding mutants","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution plus mutagenesis plus cellular reporter assay; foundational paper with >1000 citations","pmids":["11381086"],"is_preprint":false},{"year":2001,"finding":"GADD34 assembles a novel signaling complex containing PP1 and inhibitor 1 (I-1); the GADD34/PP1 complex retains eIF2α phosphatase activity while the GADD34-bound PP1 is inhibited for dephosphorylation of phosphorylase a, demonstrating substrate selectivity.","method":"Yeast two-hybrid screen, recombinant protein pulldown, affinity isolation of cellular complexes, in vitro phosphatase assay with eIF2α and phosphorylase a substrates","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 — in vitro assay with multiple substrates demonstrating selectivity, replicated with endogenous brain extracts","pmids":["11564868"],"is_preprint":false},{"year":2003,"finding":"GADD34 contains a bipartite C-terminal PP1-binding domain (canonical KVRF motif plus novel RARA sequence) required for PP1 binding; its N-terminal 180 residues direct ER localization and target PP1α to the ER, and N-terminal sequences are required beyond PP1 binding for eIF2α dephosphorylation in cells.","method":"Structure-function deletion analysis, GFP-GADD34 live-cell imaging, eIF2α phosphorylation reversal assay in thapsigargin/tunicamycin-treated cells","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 — structure-function mutagenesis combined with live imaging and cellular functional assay","pmids":["12556489"],"is_preprint":false},{"year":2003,"finding":"GADD34-deficient mouse embryonic fibroblasts show delayed recovery from eIF2α phosphorylation and protein synthesis shutoff induced by thapsigargin or DTT, establishing GADD34 as required in vivo for recovery from ER stress-induced translational arrest.","method":"GADD34 knockout mice/MEFs, eIF2α phosphorylation Western blot, protein synthesis recovery assay after ER stress","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 — clean genetic KO with defined molecular phenotype (eIF2α phosphorylation) and functional readout (protein synthesis recovery)","pmids":["12824288"],"is_preprint":false},{"year":2004,"finding":"Smad7 acts as an adaptor recruiting the GADD34–PP1c complex to the TGFβ type I receptor (TβRI), leading to dephosphorylation of TβRI and negative feedback inhibition of TGFβ signaling; SARA enhances PP1c recruitment to the Smad7–GADD34 complex.","method":"Co-immunoprecipitation, RNAi knockdown of Smad7, TβRI phosphorylation assay, cell cycle arrest functional assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, RNAi epistasis, and defined functional outcome (TGFβ resistance)","pmids":["14718519"],"is_preprint":false},{"year":2015,"finding":"Crystal/structural and functional analysis of the GADD34:PP1 holoenzyme revealed that GADD34 functions as a scaffold with independent binding sites for PP1 and eIF2α, demonstrating that eIF2α recruitment to the complex is distinct from PP1 binding.","method":"Structural analysis (NMR/biochemical), in vitro reconstitution, mutagenesis, cellular functional assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 — detailed structural and functional analysis with mutagenesis, reconstitution in vitro and in cells","pmids":["26095357"],"is_preprint":false},{"year":2015,"finding":"A novel eIF2α-binding motif in the C-terminus of GADD34 (consensus Rx[Gnl]x(1-2)Wxxx[Arlv]x[Dn][Rg]xRFxx[Rlvk][Ivc]), distinct from the PP1-binding site, is required for eIF2α interaction, eIF2α dephosphorylation promotion, and suppression of PKR toxicity; this motif is conserved in viral GADD34 orthologs (HSV ICP34.5, ASFV, Canarypox).","method":"Point mutagenesis, Co-IP/pulldown, eIF2α dephosphorylation assays, yeast PKR toxicity suppression assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis of defined motif with multiple functional readouts, validated in multiple viral orthologs","pmids":["26100893"],"is_preprint":false},{"year":2017,"finding":"Reconstituted human recombinant R15A(GADD34)–PP1 and R15B(CReP)–PP1 holophosphatases showed that Guanabenz and Sephin1 selectively induce a conformational change in R15A detected by limited proteolysis, altering eIF2α recruitment and preventing its dephosphorylation without disrupting the R15A–PP1 interaction.","method":"In vitro reconstitution of recombinant holophosphatases, limited proteolysis, eIF2α dephosphorylation assay, inhibitor binding studies","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with recombinant proteins, mechanistically distinct from prior studies; multiple orthogonal assays","pmids":["28759048"],"is_preprint":false},{"year":2017,"finding":"In vitro, Guanabenz and Sephin1 do not affect stability of the PP1–PPP1R15A complex nor substrate-specific eIF2α dephosphorylation; in cells, eIF2α-P dephosphorylation after kinase shutoff proceeds normally in Sephin1-treated cells; Sephin1's effect on IRE1 branch is independent of PPP1R15A and eIF2α phosphorylation status.","method":"In vitro phosphatase assay with reconstituted complex, kinase shut-off experiment, CRISPR-edited Ppp1r15a-deleted cells and eIF2α-S51A knock-in cells","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1–2 — rigorous in vitro reconstitution plus genetic controls challenging proposed mechanism; independent of prior studies","pmids":["28447936"],"is_preprint":false},{"year":2008,"finding":"GADD34 is degraded by the 26S proteasome via polyubiquitination; an N-terminal degron drives this rapid turnover; PEST repeat deletions modulate PP1 binding and activity; stabilization of GADD34 by proteasome inhibition enhances eIF2α dephosphorylation and promotes accumulation/aggregation of misfolded CFTRΔF508.","method":"Proteasomal inhibitor treatment, polyubiquitination assay, N-terminal deletion/epitope-tag stabilization, eIF2α phosphorylation assay, CFTR aggregation assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (ubiquitination, inhibitor, mutagenesis, functional readout) in single study","pmids":["18794359"],"is_preprint":false},{"year":2011,"finding":"GADD34's N-terminal amphipathic helix (with hydrophobic residues V25 and L29) mediates monotopic insertion into the ER outer membrane, while the same helix's polar surface mediates mitochondrial association; ER-associated GADD34 has reduced mobility (FRAP) and enhanced proteasomal degradation compared to cytosolic mutant V25R; both WT and V25R scaffold PP1α for eIF2α dephosphorylation, but only WT modifies ER morphology.","method":"Deletion mutagenesis, GFP-GADD34 live imaging, fluorescence protease protection, FRAP, cysteine chemical modification, eIF2α dephosphorylation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods including FRAP, protease protection, and mutagenesis with functional readouts","pmids":["21518769"],"is_preprint":false},{"year":2006,"finding":"Gadd34-null mice display reduced hemoglobin content in erythrocytes due to reduced initiation of globin translation machinery in reticulocytes, revealing a physiological role for Gadd34/PP1c in eIF2α dephosphorylation to counterbalance heme-regulated inhibitor kinase during hemoglobin synthesis.","method":"Gadd34-null mouse analysis, erythrocyte/reticulocyte biochemical analysis of hemoglobin and globin translation initiation","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with defined molecular mechanism (eIF2α dephosphorylation, HRI kinase counterbalance) and clear phenotype","pmids":["16478986"],"is_preprint":false},{"year":2009,"finding":"GADD34 mRNA translation is preferentially induced during eIF2α phosphorylation via upstream ORFs (uORFs) in its 5' UTR; the downstream uORF mediates repression of basal translation and redirects translation during stress, allowing maximal GADD34 expression when needed for negative feedback.","method":"Polysome fractionation, 5'UTR reporter constructs, uORF mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — mechanistic dissection of translational regulation with reporter mutagenesis and polysome profiling","pmids":["19131336"],"is_preprint":false},{"year":2013,"finding":"GADD34 upregulation following traumatic brain injury (TBI) is induced by ATF4 binding to the GADD34 promoter; GADD34 then binds TRAF6, preventing TRAF6-mediated ubiquitination-coupled Akt phosphorylation at T308, retaining Akt in the cytosol and reducing cell survival; in vivo lentiviral knockdown of GADD34 rescues Akt activation and attenuates TBI-induced cell death.","method":"Controlled cortical impact TBI mouse model, Co-IP (GADD34-TRAF6 interaction), lentiviral shRNA knockdown, Akt phosphorylation assay, cell death quantification","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP plus in vivo KD with defined phenotype, single lab","pmids":["23907468"],"is_preprint":false},{"year":2012,"finding":"GADD34/Ppp1r15a is absolutely required for type I IFN and IL-6 production by mouse embryonic fibroblasts in response to dsRNA; GADD34 expression depends on PKR activation linking cytosolic microbial sensing to the ATF4 branch of the UPR; GADD34-deficient mice are extremely susceptible to Chikungunya virus infection.","method":"GADD34-deficient MEFs and neonatal mice, dsRNA stimulation, cytokine measurement, viral infection survival assay","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with defined cellular and in vivo phenotype, PKR pathway epistasis established","pmids":["22615568"],"is_preprint":false},{"year":2014,"finding":"GADD34 acts as a regulatory subunit directing PP1 to dephosphorylate TAK1 at serine 412, attenuating TLR-triggered NF-κB and MAPK signaling; GADD34 depletion abolishes the PP1–TAK1 interaction and enhances pro-inflammatory cytokine production.","method":"Co-IP (GADD34-PP1-TAK1), GADD34 siRNA knockdown, TAK1 S412A mutant, NF-κB/MAPK activation assays, LPS endotoxin shock in vivo","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, mutagenesis of TAK1 Ser412, siRNA epistasis, and in vivo validation","pmids":["24534530"],"is_preprint":false},{"year":2007,"finding":"GADD34 forms a stable complex with TSC1/TSC2 and promotes dephosphorylation of TSC2 at Thr1462, thereby inhibiting mTOR signaling; this mechanism protects cells from apoptosis during energy depletion.","method":"Co-IP (GADD34-TSC1/TSC2 complex), TSC2 phosphorylation assay, mTOR downstream readouts (S6K, 4EBP1), cell viability assay","journal":"International journal of molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP plus phosphorylation assay, replicated in related studies; single lab","pmids":["17273797"],"is_preprint":false},{"year":2011,"finding":"Starvation-induced GADD34 suppresses mTOR by binding and dephosphorylating TSC2 at Thr1462, promoting autophagy; autophagy induction is absent in Gadd34 KO mice under starvation.","method":"Gadd34 KO mice, starvation model, Co-IP (Gadd34-TSC2), TSC2 Thr1462 phosphorylation assay, autophagy marker analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with defined molecular mechanism (TSC2 dephosphorylation), replicates TSC-mTOR finding","pmids":["21439266"],"is_preprint":false},{"year":2017,"finding":"Oxidative stress promotes recruitment of SIRT1 to the GADD34/PP1α complex in the cytoplasm; GADD34-scaffolded PP1α dephosphorylates both eIF2α (pSer51) and SIRT1 (pSer47); SIRT1 dephosphorylation increases its deacetylase activity; GADD34-/- MEFs show persistent phosphorylation of both eIF2α and SIRT1 after arsenite exposure.","method":"Mass spectrometry of GADD34 interactome, Co-IP, GADD34 KO MEFs, SIRT1 deacetylase activity assay in vitro and in cells, WT vs PP1-binding mutant rescue","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 — MS interactome plus reciprocal Co-IP, KO cells, in vitro enzyme assay, and genetic rescue; multiple orthogonal methods","pmids":["28984870"],"is_preprint":false},{"year":2017,"finding":"In response to chronic oxidative stress (arsenite), GADD34 functions as a kinase scaffold by recruiting TDP-43 and casein kinase-1ε (CK1ε); GADD34-bound CK1ε phosphorylates TDP-43 at serines 409/410 (pathological phosphorylation); these phosphorylations are diminished in GADD34-/- cells.","method":"Co-IP (GADD34-TDP-43-CK1ε), GADD34 KO MEFs, TDP-43 phosphorylation assay at S409/410, arsenite vs. ER stress comparison","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — Co-IP with multiple partners, KO cells with defined molecular phenotype, mechanistically distinct scaffold function demonstrated","pmids":["29109149"],"is_preprint":false},{"year":2013,"finding":"HTLV-1 HBZ protein is exported from the nucleus via CRM1-dependent NES, interacts with the C-terminal region of GADD34 in the cytoplasm, and inhibits GADD34 function to activate mTOR signaling (increased S6K phosphorylation) and suppress starvation-induced autophagy.","method":"Co-IP (HBZ-GADD34), NES mutagenesis, CRM1 inhibitor (leptomycin B), S6K phosphorylation assay, autophagy assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP with mutagenesis and functional readout; single lab","pmids":["23708656"],"is_preprint":false},{"year":2017,"finding":"GADD34/PP1 phosphatase activity reverses hyperosmotic-stress-induced Golgi fragmentation, promotes cis-to-trans Golgi trafficking of the neutral amino acid transporter SNAT2, and enables SNAT2 plasma membrane localization and function, independent of GADD34's ISR role.","method":"GADD34 KO cells, Golgi morphology imaging, SNAT2 trafficking assay, amino acid uptake functional assay, PP1 phosphatase inhibitor treatment","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 — KO/rescue with functional trafficking and transport readouts, single lab","pmids":["29212034"],"is_preprint":false},{"year":2002,"finding":"hSNF5/INI1 binds GADD34 (partly through the PP1-docking domain homologous to HSV ICP34.5), forms a stable heterotrimeric complex with GADD34 and PP1, and weakly stimulates PP1 phosphatase activity; EBNA2 disrupts hSNF5/INI1-GADD34 interaction and partially reverses GADD34-mediated growth suppression.","method":"Co-IP, affinity pulldown, in vitro PP1 phosphatase activity assay, colony formation assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP with in vitro functional assay; single lab, moderate evidence","pmids":["12016208"],"is_preprint":false},{"year":2003,"finding":"Human BAG-1 cochaperone proteins interact with GADD34 in cells undergoing apoptosis; BAG-1 negatively modulates GADD34-bound PP1 activity; Hsp70/Hsc70 and PP1 associate reversibly with the GADD34-BAG-1 complex in an ATP-dependent manner; BAG-1 expression masks GADD34-mediated growth suppression and apoptosis.","method":"Yeast two-hybrid screen, Co-IP in SW480 cells, in vitro PP1 phosphatase activity assay, colony formation suppression assay","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2–3 — yeast two-hybrid plus Co-IP plus in vitro enzymatic assay; single lab","pmids":["12724406"],"is_preprint":false},{"year":2009,"finding":"Disruption of the PP1/GADD34 complex (by a competing GADD34-derived peptide fused to a membrane-translocation domain) is sufficient to stimulate eIF2α phosphorylation and trigger calreticulin surface exposure on tumor cells, dissociating CRT exposure from cell death.","method":"Molecular modeling-guided peptide design, cellular eIF2α phosphorylation assay, CRT surface exposure assay, Co-IP to verify PP1/GADD34 complex disruption","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic peptide disruption with functional readout; single lab, moderate evidence","pmids":["19901557"],"is_preprint":false},{"year":2013,"finding":"GADD34 promotes MCL-1 protein stability in hepatocellular carcinoma cells by inhibiting proteasomal degradation of MCL-1 through a TRAF6–TAB1–ERK signaling axis; GADD34 overexpression promotes ERK phosphorylation via TRAF6, which stabilizes MCL-1 and protects against TRAIL-induced apoptosis.","method":"Immunoblotting, GADD34 overexpression/knockdown, ERK phosphorylation assay, proteasome inhibitor (MG132) rescue, TRAF6 and GADD34 siRNA co-knockdown","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 — multiple knockdowns/overexpressions with mechanistic pathway placement; single lab","pmids":["30782845"],"is_preprint":false},{"year":2013,"finding":"TC-PTP (PTPN2) is a phosphatase that dephosphorylates GADD34 at tyrosine 262 (identified by substrate-trapping); phosphorylation at Y262 enhances GADD34 protein turnover; TC-PTP-null MEFs show reduced GADD34 protein after ER stress and increased susceptibility to ER stress-induced apoptosis rescued by ectopic GADD34.","method":"Mass spectrometry (GADD34 phosphosite identification), substrate-trapping Co-IP (TC-PTP-GADD34), TC-PTP-null MEFs, GADD34 turnover assay, apoptosis assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — MS phosphosite identification plus substrate-trapping plus genetic KO cells; single lab","pmids":["24092754"],"is_preprint":false},{"year":2020,"finding":"TFEB directly activates GADD34 expression during starvation; GADD34 in turn dephosphorylates eIF2α to permit translation of the TFEB-driven lysosomal biogenesis program, enabling sustained autophagic flux; GADD34 thus integrates the mTORC1 and ISR pathways during starvation.","method":"GADD34 KO cells, TFEB ChIP/reporter assays, eIF2α phosphorylation assay, autophagic flux measurement (lysosomal biogenesis markers)","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with TFEB-GADD34 transcriptional epistasis established by ChIP and functional autophagy readout","pmids":["32978159"],"is_preprint":false},{"year":2024,"finding":"The 3' UTR of PPP1R15A mRNA contains an AU-rich element (ARE) recognized by ZFP36 family RNA-binding proteins, promoting rapid mRNA decay under normal conditions and mRNA stabilization during stress; this post-transcriptional control of PPP1R15A mRNA stability functions as a component of ISR memory, setting the threshold for stress responsiveness and adaptation.","method":"3'UTR reporter assays, ZFP36 family protein binding assays, mRNA stability assays, ISR memory experiments with repeated stress exposure","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic dissection of ARE-mediated decay with functional ISR readouts; single paper","pmids":["38602876"],"is_preprint":false},{"year":1999,"finding":"GADD34 interacts with HRX (MLL) proteins; leukemic HRX fusion proteins (HRX-ENL, HRX-AF9, HRX-ELL) bind GADD34 and abrogate GADD34-induced apoptosis after ionizing radiation; wild-type HRX does not inhibit this apoptosis; GADD34 also binds hSNF5/INI1.","method":"Yeast two-hybrid, Co-IP in human cells, apoptosis assay (nuclear fragmentation) after ionizing radiation","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP plus functional apoptosis assay, single lab","pmids":["10490642"],"is_preprint":false},{"year":2000,"finding":"GADD34 interacts with GAHSP40 (a DnaJ/Hsp40 family member); interaction requires the ICP34.5-homology domain of GADD34 and the C-terminus of GAHSP40; interaction confirmed by Co-IP in cultured cells.","method":"Yeast two-hybrid, Co-IP, in vitro binding assay","journal":"The Biochemical journal","confidence":"Low","confidence_rationale":"Tier 3 — single lab, Co-IP/pulldown without functional mechanistic follow-up","pmids":["11104688"],"is_preprint":false},{"year":2000,"finding":"GADD34 interacts with KIF3A (kinesin superfamily motor protein) via KIF3A's C-terminal tail domain, identified by yeast two-hybrid and confirmed by in vivo two-hybrid in NIH3T3 cells.","method":"Yeast two-hybrid, in vivo two-hybrid in NIH3T3 cells","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 — single yeast/cell-based interaction assay, no functional follow-up","pmids":["10631107"],"is_preprint":false},{"year":1999,"finding":"GADD34 interacts with Translin (a DNA translocation-associated RNA-binding protein); interaction was confirmed by in vitro binding assay and in vivo two-hybrid in NIH3T3 cells.","method":"Yeast two-hybrid, in vitro binding assay, in vivo two-hybrid","journal":"Biochimica et biophysica acta","confidence":"Low","confidence_rationale":"Tier 3 — single lab, interaction assays without mechanistic follow-up","pmids":["10434033"],"is_preprint":false},{"year":2016,"finding":"GADD34-containing eIF2α phosphatase drives substantial translational changes in unstressed cells targeting the secretome; upon UPR activation, rapid GADD34 translation is essential for UPR progression — in GADD34-absence eIF2α phosphorylation is persistently elevated and UPR translational program is significantly attenuated; compensatory AKT-mediated PERK suppression and CReP induction partially restore protein synthesis.","method":"GADD34 KO cells, polysome profiling, translational analysis, AKT/PERK signaling assays, CReP expression measurement","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 — KO with multiple molecular readouts; single lab","pmids":["27161320"],"is_preprint":false},{"year":2022,"finding":"In sepsis-induced acute kidney injury, Ppp1r15a/GADD34 expression is blunted by its own 5' upstream ORF (uORF); antisense oligonucleotides targeting the uORF enable Ppp1r15a overexpression, rescuing eIF2α dephosphorylation, restoring translation, and improving kidney function in a murine endotoxemia model.","method":"Ribosome profiling (Ribo-seq), proteomics, polyribosome profiling, antisense oligonucleotides, Ppp1r15a knock-in mouse model, mutant cell lines","journal":"Journal of the American Society of Nephrology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (Ribo-seq, proteomics) plus genetic and ASO rescue with functional organ readout","pmids":["36283811"],"is_preprint":false},{"year":2016,"finding":"HES1 (hairy and enhancer of split 1) binds to the GADD34 promoter and represses its transcription during ER stress; HES1 depletion leads to GADD34 upregulation and increased cell death during ER stress in a GADD34-dependent manner.","method":"HES1 depletion (siRNA), GADD34 promoter ChIP, cell death assay, epistasis with GADD34 KD","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP plus siRNA epistasis showing HES1 as transcriptional repressor of GADD34; single lab","pmids":["29491143"],"is_preprint":false}],"current_model":"PPP1R15A (GADD34) functions primarily as a stress-induced scaffolding protein that recruits the catalytic subunit of protein phosphatase 1 (PP1c/PP1α) via a bipartite C-terminal domain and simultaneously engages eIF2α through a separate C-terminal docking motif, directing the assembled holophosphatase to dephosphorylate eIF2α at Ser51 at the ER membrane — thereby providing negative feedback to terminate the integrated stress response and restore protein synthesis; beyond its canonical eIF2α phosphatase-organizing role, GADD34 also scaffolds additional substrates (TβRI via Smad7, TAK1, TSC2, SIRT1) and, in response to chronic oxidative stress, acts as a kinase scaffold recruiting CK1ε to phosphorylate TDP-43, while its own levels are tightly regulated by proteasomal degradation (driven by an N-terminal degron, ER-association, and phosphorylation at Tyr262 by TC-PTP), by translational control through 5' UTR uORFs during stress, and by post-transcriptional mRNA stability via ZFP36-family ARE-binding proteins."},"narrative":{"teleology":[{"year":2001,"claim":"The foundational question of how cells recover from stress-induced translational arrest was answered by showing that GADD34 recruits PP1c to form a holophosphatase that specifically dephosphorylates eIF2α, establishing GADD34 as the negative-feedback node of the ISR.","evidence":"Co-immunoprecipitation, in vitro phosphatase assays with PP1c-binding mutants, and CHOP::GFP reporter in cells","pmids":["11381086","11564868"],"confidence":"High","gaps":["Structural basis of PP1–GADD34 interaction unresolved","Substrate selectivity mechanism unknown","In vivo requirement not yet demonstrated"]},{"year":2003,"claim":"Domain-mapping and genetic ablation established that GADD34 contains a bipartite C-terminal PP1-binding module and an N-terminal ER-targeting region, and that GADD34 is required in vivo for timely recovery of protein synthesis after ER stress.","evidence":"Structure-function deletion mutagenesis with GFP imaging, GADD34 knockout MEFs with eIF2α phosphorylation and translation recovery assays","pmids":["12556489","12824288"],"confidence":"High","gaps":["Identity of the eIF2α-binding site on GADD34 unknown","Physiological consequences of GADD34 loss in whole organisms not yet explored beyond MEFs"]},{"year":2004,"claim":"The discovery that Smad7 recruits the GADD34–PP1c complex to TβRI for dephosphorylation revealed that GADD34 is not exclusively an eIF2α phosphatase scaffold but can be redirected to diverse substrates via adaptor proteins.","evidence":"Reciprocal Co-IP, Smad7 RNAi, TβRI phosphorylation assays, and TGFβ-dependent cell-cycle-arrest readouts","pmids":["14718519"],"confidence":"High","gaps":["Whether GADD34–PP1 acts on TβRI in vivo under physiological stress not tested","Structural basis of Smad7-mediated substrate redirection unknown"]},{"year":2006,"claim":"Analysis of Gadd34-null mice revealed a physiological requirement for GADD34-mediated eIF2α dephosphorylation in erythropoiesis, where it counterbalances HRI kinase to permit globin translation in reticulocytes.","evidence":"Gadd34-null mouse phenotyping with erythrocyte hemoglobin quantification and reticulocyte translation analysis","pmids":["16478986"],"confidence":"High","gaps":["Whether additional tissues show translational defects in Gadd34-null mice not systematically examined"]},{"year":2008,"claim":"Identification of an N-terminal degron driving proteasomal polyubiquitination and rapid turnover of GADD34 explained how GADD34 protein levels are kept low basally, with functional consequences: stabilized GADD34 enhances eIF2α dephosphorylation and promotes misfolded-protein aggregation.","evidence":"Proteasome inhibitor treatment, polyubiquitination assays, N-terminal deletion mutagenesis, CFTRΔF508 aggregation readout","pmids":["18794359"],"confidence":"High","gaps":["E3 ubiquitin ligase responsible for GADD34 ubiquitination not identified","Relationship between ER localization and degradation not fully resolved"]},{"year":2009,"claim":"Demonstration that 5′ UTR uORFs mediate translational derepression of GADD34 mRNA during eIF2α phosphorylation revealed the feed-forward mechanism by which the ISR auto-induces its own negative regulator.","evidence":"Polysome fractionation with 5′ UTR reporter constructs and uORF mutagenesis","pmids":["19131336"],"confidence":"High","gaps":["Relative contribution of transcriptional (ATF4) vs. translational (uORF) induction under different stresses not quantified"]},{"year":2011,"claim":"The N-terminal amphipathic helix was shown to mediate monotopic ER membrane insertion, controlling GADD34 mobility and proteasomal degradation rate, linking subcellular localization to protein turnover and function.","evidence":"GFP-GADD34 live imaging, FRAP, fluorescence protease protection, cysteine chemical modification, V25R mutagenesis","pmids":["21518769"],"confidence":"High","gaps":["Whether ER anchoring affects substrate access beyond eIF2α not tested"]},{"year":2007,"claim":"GADD34's substrate repertoire was expanded to mTOR regulation when it was shown to scaffold PP1-mediated dephosphorylation of TSC2 at Thr1462, inhibiting mTOR signaling during energy depletion and starvation-induced autophagy.","evidence":"Co-IP of GADD34–TSC1/TSC2 complex, TSC2 phosphorylation assays, mTOR readouts, confirmed in Gadd34 KO mice under starvation","pmids":["17273797","21439266"],"confidence":"Medium","gaps":["Whether GADD34-mediated TSC2 dephosphorylation involves direct PP1 catalysis or indirect signaling not fully distinguished","Structural basis of TSC2 recruitment unknown"]},{"year":2012,"claim":"GADD34 was shown to be essential for type I IFN and IL-6 production in response to dsRNA via the PKR–ATF4 axis, establishing GADD34 as a critical node linking innate immune sensing to translational recovery needed for cytokine production.","evidence":"GADD34-deficient MEFs and neonatal mice challenged with dsRNA and Chikungunya virus; cytokine measurement and survival analysis","pmids":["22615568"],"confidence":"High","gaps":["Which specific mRNAs require GADD34-mediated eIF2α dephosphorylation for translation during antiviral response not identified"]},{"year":2014,"claim":"GADD34 was found to direct PP1 to dephosphorylate TAK1 at Ser412, attenuating TLR-triggered NF-κB and MAPK activation, thereby functioning as an anti-inflammatory phosphatase scaffold.","evidence":"Reciprocal Co-IP of GADD34–PP1–TAK1, TAK1 S412A mutant, siRNA epistasis, in vivo LPS endotoxin shock model","pmids":["24534530"],"confidence":"High","gaps":["Whether GADD34-mediated TAK1 dephosphorylation is PP1α-specific or involves other PP1 isoforms not tested"]},{"year":2015,"claim":"Structural and functional studies resolved how GADD34 simultaneously but independently engages PP1 and eIF2α through separate binding motifs, explaining how a single scaffold achieves substrate specificity; a conserved C-terminal eIF2α-binding motif was defined by mutagenesis.","evidence":"NMR/biochemical structural analysis, in vitro reconstitution, point mutagenesis across GADD34 and viral orthologs, yeast PKR suppression assay","pmids":["26095357","26100893"],"confidence":"High","gaps":["Full atomic-resolution structure of the ternary GADD34–PP1–eIF2α complex not available","Conformational dynamics during catalysis not characterized"]},{"year":2017,"claim":"Pharmacological studies with Guanabenz and Sephin1 revealed that these compounds induce conformational changes in GADD34 that alter eIF2α recruitment, though an independent study found no effect of these drugs on reconstituted holophosphatase activity or cellular eIF2α dephosphorylation kinetics, leaving the mechanism of these inhibitors unresolved.","evidence":"In vitro reconstituted holophosphatases with limited proteolysis (PMID:28759048); independent reconstitution plus CRISPR-edited Ppp1r15a-deleted and eIF2α-S51A cells (PMID:28447936)","pmids":["28759048","28447936"],"confidence":"High","gaps":["Contradictory findings on Sephin1/Guanabenz selectivity for GADD34 not resolved","In vivo target engagement of these drugs not definitively demonstrated"]},{"year":2017,"claim":"GADD34 was revealed to have dual scaffolding functions under oxidative stress: directing PP1α to dephosphorylate SIRT1 (activating its deacetylase function) and simultaneously acting as a kinase scaffold recruiting CK1ε to phosphorylate TDP-43 at pathological sites.","evidence":"Mass spectrometry interactome, reciprocal Co-IP, GADD34 KO MEFs, SIRT1 activity assays, TDP-43 S409/410 phosphorylation in KO vs WT cells","pmids":["28984870","29109149"],"confidence":"High","gaps":["Whether GADD34-mediated TDP-43 phosphorylation contributes to ALS/FTLD pathology in vivo not tested","Structural basis for dual phosphatase/kinase scaffold switching unknown"]},{"year":2020,"claim":"TFEB was identified as a direct transcriptional activator of GADD34 during starvation, establishing that GADD34 integrates the mTORC1 and ISR pathways by dephosphorylating eIF2α to permit translation of the TFEB-driven lysosomal biogenesis program.","evidence":"GADD34 KO cells, TFEB ChIP and reporter assays, eIF2α phosphorylation and autophagic flux measurements","pmids":["32978159"],"confidence":"Medium","gaps":["Whether other transcription factors cooperate with TFEB at the GADD34 promoter not examined","Quantitative contribution of TFEB vs ATF4 to GADD34 induction during starvation unclear"]},{"year":2024,"claim":"Post-transcriptional regulation of GADD34 was shown to involve ZFP36-family-mediated recognition of an ARE in the 3′ UTR, promoting rapid mRNA decay basally and stabilization during stress, functioning as a mechanism of ISR memory that tunes stress responsiveness.","evidence":"3′ UTR reporter assays, ZFP36 protein binding assays, mRNA stability measurements, repeated stress-exposure ISR memory experiments","pmids":["38602876"],"confidence":"Medium","gaps":["Identity of kinase(s) that inactivate ZFP36 to allow GADD34 mRNA stabilization not determined","Whether ARE-mediated regulation differs across cell types not tested"]},{"year":null,"claim":"A full atomic-resolution structure of the ternary GADD34–PP1–eIF2α complex is lacking, the E3 ligase(s) responsible for GADD34 ubiquitination remain unidentified, and whether GADD34's kinase-scaffold function (CK1ε–TDP-43) contributes to neurodegenerative disease in vivo has not been tested.","evidence":"","pmids":[],"confidence":"Low","gaps":["No ternary complex structure available","E3 ubiquitin ligase for GADD34 degradation unknown","In vivo disease relevance of GADD34-mediated TDP-43 phosphorylation untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,5,6,7]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,4,15,18,19]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[2,10]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[18,19]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,3,5,6,11,12]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,12,33]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[14,15]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[17,27]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,16]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[3,9,10]}],"complexes":["GADD34–PP1c holophosphatase","Smad7–GADD34–PP1c complex","GADD34–PP1–TAK1 complex"],"partners":["PPP1CA","EIF2S1","SMAD7","MAP3K7","TSC2","SIRT1","CSNK1E","TARDBP"],"other_free_text":[]},"mechanistic_narrative":"PPP1R15A (GADD34) is a stress-inducible regulatory subunit of protein phosphatase 1 (PP1) that serves as the principal negative-feedback effector of the integrated stress response (ISR) by scaffolding PP1c and eIF2α into a holophosphatase complex at the endoplasmic reticulum, thereby directing dephosphorylation of eIF2α at Ser51 and restoring global protein synthesis after stress [PMID:11381086, PMID:26095357, PMID:12824288]. The protein employs a bipartite C-terminal PP1-binding domain (KVRF and RARA motifs) and a separate conserved eIF2α-docking motif for independent substrate recruitment, while an N-terminal amphipathic helix mediates monotopic ER membrane insertion and controls proteasomal turnover via an N-terminal degron [PMID:12556489, PMID:26100893, PMID:21518769, PMID:18794359]. Beyond eIF2α, GADD34 redirects PP1 to additional substrates including TAK1 (attenuating NF-κB/MAPK signaling), TSC2 (inhibiting mTOR to promote autophagy), TβRI (via Smad7, dampening TGFβ signaling), and SIRT1, and under chronic oxidative stress it acts as a kinase scaffold recruiting CK1ε to phosphorylate TDP-43 at pathological sites [PMID:24534530, PMID:21439266, PMID:14718519, PMID:28984870, PMID:29109149]. GADD34 expression is tightly controlled at multiple levels: transcriptionally by ATF4 and TFEB, translationally by 5′ UTR upstream ORFs that permit preferential translation during eIF2α phosphorylation, and post-transcriptionally by ZFP36-family-mediated ARE-dependent mRNA decay that establishes ISR memory [PMID:19131336, PMID:32978159, PMID:38602876]."},"prefetch_data":{"uniprot":{"accession":"O75807","full_name":"Protein phosphatase 1 regulatory subunit 15A","aliases":["Growth arrest and DNA damage-inducible protein GADD34","Myeloid differentiation primary response protein MyD116 homolog"],"length_aa":674,"mass_kda":73.5,"function":"Recruits the serine/threonine-protein phosphatase PPP1CA to prevents excessive phosphorylation of the translation initiation factor eIF-2A/EIF2S1, thereby reversing the shut-off of protein synthesis initiated by stress-inducible kinases and facilitating recovery of cells from stress (PubMed:26095357, PubMed:26742780). Down-regulates the TGF-beta signaling pathway by promoting dephosphorylation of TGFB1 by PP1 (PubMed:14718519). May promote apoptosis by inducing p53/TP53 phosphorylation on 'Ser-15' (PubMed:14635196). Plays an essential role in autophagy by tuning translation during starvation, thus enabling lysosomal biogenesis and a sustained autophagic flux (PubMed:32978159). Also acts a viral restriction factor by attenuating HIV-1 replication (PubMed:31778897). Mechanistically, mediates the inhibition of HIV-1 TAR RNA-mediated translation (PubMed:31778897) (Microbial infection) Promotes enterovirus 71 replication by mediating the internal ribosome entry site (IRES) activity of viral 5'-UTR","subcellular_location":"Endoplasmic reticulum membrane; Mitochondrion outer membrane","url":"https://www.uniprot.org/uniprotkb/O75807/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PPP1R15A","classification":"Not Classified","n_dependent_lines":25,"n_total_lines":1208,"dependency_fraction":0.020695364238410598},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PPP1R15A","total_profiled":1310},"omim":[{"mim_id":"611048","title":"PROTEIN PHOSPHATASE 1, REGULATORY SUBUNIT 15A; PPP1R15A","url":"https://www.omim.org/entry/611048"},{"mim_id":"604683","title":"KINESIN FAMILY MEMBER 3A; KIF3A","url":"https://www.omim.org/entry/604683"},{"mim_id":"604378","title":"BECLIN 1; BECN1","url":"https://www.omim.org/entry/604378"},{"mim_id":"604064","title":"ACTIVATING TRANSCRIPTION FACTOR 4; ATF4","url":"https://www.omim.org/entry/604064"},{"mim_id":"604032","title":"EUKARYOTIC TRANSLATION INITIATION FACTOR 2-ALPHA KINASE 3; EIF2AK3","url":"https://www.omim.org/entry/604032"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Vesicles","reliability":"Uncertain"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"bone marrow","ntpm":529.2}],"url":"https://www.proteinatlas.org/search/PPP1R15A"},"hgnc":{"alias_symbol":["GADD34"],"prev_symbol":[]},"alphafold":{"accession":"O75807","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75807","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75807-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75807-F1-predicted_aligned_error_v6.png","plddt_mean":49.47},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PPP1R15A","jax_strain_url":"https://www.jax.org/strain/search?query=PPP1R15A"},"sequence":{"accession":"O75807","fasta_url":"https://rest.uniprot.org/uniprotkb/O75807.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75807/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75807"}},"corpus_meta":[{"pmid":"11381086","id":"PMC_11381086","title":"Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2alpha.","date":"2001","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/11381086","citation_count":1166,"is_preprint":false},{"pmid":"12556489","id":"PMC_12556489","title":"Growth arrest and DNA damage-inducible protein GADD34 targets protein phosphatase 1 alpha to the endoplasmic reticulum and promotes dephosphorylation of the alpha subunit of eukaryotic translation initiation factor 2.","date":"2003","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/12556489","citation_count":318,"is_preprint":false},{"pmid":"11564868","id":"PMC_11564868","title":"Growth arrest and DNA damage-inducible protein GADD34 assembles a novel signaling complex containing protein phosphatase 1 and inhibitor 1.","date":"2001","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/11564868","citation_count":227,"is_preprint":false},{"pmid":"14718519","id":"PMC_14718519","title":"GADD34-PP1c recruited by Smad7 dephosphorylates TGFbeta type I receptor.","date":"2004","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/14718519","citation_count":208,"is_preprint":false},{"pmid":"12824288","id":"PMC_12824288","title":"The function of GADD34 is a recovery from a shutoff of protein synthesis induced by ER stress: elucidation by GADD34-deficient mice.","date":"2003","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/12824288","citation_count":200,"is_preprint":false},{"pmid":"19131336","id":"PMC_19131336","title":"An upstream open reading frame regulates translation of GADD34 during cellular stresses that induce eIF2alpha phosphorylation.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19131336","citation_count":200,"is_preprint":false},{"pmid":"9153226","id":"PMC_9153226","title":"Mammalian GADD34, an apoptosis- and DNA damage-inducible gene.","date":"1997","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9153226","citation_count":155,"is_preprint":false},{"pmid":"8887567","id":"PMC_8887567","title":"A herpesvirus genetic element which affects translation in the absence of the viral GADD34 function.","date":"1996","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/8887567","citation_count":136,"is_preprint":false},{"pmid":"10490642","id":"PMC_10490642","title":"Leukemic HRX fusion proteins inhibit GADD34-induced apoptosis and associate with the GADD34 and hSNF5/INI1 proteins.","date":"1999","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/10490642","citation_count":132,"is_preprint":false},{"pmid":"26095357","id":"PMC_26095357","title":"Structural and Functional Analysis of the GADD34:PP1 eIF2α Phosphatase.","date":"2015","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/26095357","citation_count":122,"is_preprint":false},{"pmid":"11163539","id":"PMC_11163539","title":"Peroxynitrite induces GADD34, 45, and 153 VIA p38 MAPK in human neuroblastoma SH-SY5Y cells.","date":"2001","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/11163539","citation_count":114,"is_preprint":false},{"pmid":"26163091","id":"PMC_26163091","title":"Is there a causal relationship between genetic changes and radiomics-based image features? An in vivo preclinical experiment with doxycycline inducible GADD34 tumor cells.","date":"2015","source":"Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/26163091","citation_count":109,"is_preprint":false},{"pmid":"22615568","id":"PMC_22615568","title":"Induction of GADD34 is necessary for dsRNA-dependent interferon-β production and participates in the control of Chikungunya virus infection.","date":"2012","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/22615568","citation_count":99,"is_preprint":false},{"pmid":"19776135","id":"PMC_19776135","title":"Inhibition of protein kinase R activation and upregulation of GADD34 expression play a synergistic role in facilitating coronavirus replication by maintaining de novo protein synthesis in virus-infected cells.","date":"2009","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/19776135","citation_count":89,"is_preprint":false},{"pmid":"9371605","id":"PMC_9371605","title":"The herpes simplex virus virulence factor ICP34.5 and the cellular protein MyD116 complex with proliferating cell nuclear antigen through the 63-amino-acid domain conserved in ICP34.5, MyD116, and GADD34.","date":"1997","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/9371605","citation_count":86,"is_preprint":false},{"pmid":"28447936","id":"PMC_28447936","title":"PPP1R15A-mediated dephosphorylation of eIF2α is unaffected by Sephin1 or Guanabenz.","date":"2017","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/28447936","citation_count":81,"is_preprint":false},{"pmid":"9811446","id":"PMC_9811446","title":"Myc suppresses induction of the growth arrest genes gadd34, gadd45, and gadd153 by DNA-damaging agents.","date":"1998","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/9811446","citation_count":80,"is_preprint":false},{"pmid":"28759048","id":"PMC_28759048","title":"Decoding the selectivity of eIF2α holophosphatases and PPP1R15A inhibitors.","date":"2017","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/28759048","citation_count":74,"is_preprint":false},{"pmid":"26100893","id":"PMC_26100893","title":"An eIF2α-binding motif in protein phosphatase 1 subunit GADD34 and its viral orthologs is required to promote dephosphorylation of eIF2α.","date":"2015","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/26100893","citation_count":73,"is_preprint":false},{"pmid":"23907468","id":"PMC_23907468","title":"GADD34 induces cell death through inactivation of Akt following traumatic brain injury.","date":"2013","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/23907468","citation_count":68,"is_preprint":false},{"pmid":"10074192","id":"PMC_10074192","title":"A herpesvirus ribosome-associated, RNA-binding protein confers a growth advantage upon mutants deficient in a GADD34-related function.","date":"1999","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/10074192","citation_count":67,"is_preprint":false},{"pmid":"22315398","id":"PMC_22315398","title":"Protein phosphatase 1 subunit Ppp1r15a/GADD34 regulates cytokine production in polyinosinic:polycytidylic acid-stimulated dendritic cells.","date":"2012","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/22315398","citation_count":66,"is_preprint":false},{"pmid":"18794359","id":"PMC_18794359","title":"Control of cellular GADD34 levels by the 26S proteasome.","date":"2008","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18794359","citation_count":60,"is_preprint":false},{"pmid":"28100675","id":"PMC_28100675","title":"Protein synthesis inhibition and GADD34 control IFN-β heterogeneous expression in response to dsRNA.","date":"2017","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/28100675","citation_count":60,"is_preprint":false},{"pmid":"15059970","id":"PMC_15059970","title":"Up-regulation of GADD34 mediates the synergistic anticancer activity of mitomycin C and a gamma134.5 deleted oncolytic herpes virus (G207).","date":"2004","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/15059970","citation_count":59,"is_preprint":false},{"pmid":"11241327","id":"PMC_11241327","title":"Activation of Gadd34 by diverse apoptotic signals and suppression of its growth inhibitory effects by apoptotic inhibitors.","date":"2001","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/11241327","citation_count":56,"is_preprint":false},{"pmid":"14675157","id":"PMC_14675157","title":"Ischaemic preconditioning in the rat brain: effect on the activity of several initiation factors, Akt and extracellular signal-regulated protein kinase phosphorylation, and GRP78 and GADD34 expression.","date":"2004","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/14675157","citation_count":55,"is_preprint":false},{"pmid":"16294031","id":"PMC_16294031","title":"Cisplatin-induced GADD34 upregulation potentiates oncolytic viral therapy in the treatment of malignant pleural mesothelioma.","date":"2006","source":"Cancer biology & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/16294031","citation_count":54,"is_preprint":false},{"pmid":"32978159","id":"PMC_32978159","title":"GADD34 is a modulator of autophagy during starvation.","date":"2020","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/32978159","citation_count":54,"is_preprint":false},{"pmid":"29511029","id":"PMC_29511029","title":"Toxicity and Efficacy of a Novel GADD34-expressing Oncolytic HSV-1 for the Treatment of Experimental Glioblastoma.","date":"2018","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/29511029","citation_count":49,"is_preprint":false},{"pmid":"14635196","id":"PMC_14635196","title":"GADD34 induces p53 phosphorylation and p21/WAF1 transcription.","date":"2003","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/14635196","citation_count":49,"is_preprint":false},{"pmid":"9878749","id":"PMC_9878749","title":"Activation of MYD116 (gadd34) expression following transient forebrain ischemia of rat: implications for a role of disturbances of endoplasmic reticulum calcium homeostasis.","date":"1999","source":"Brain research. Molecular brain research","url":"https://pubmed.ncbi.nlm.nih.gov/9878749","citation_count":46,"is_preprint":false},{"pmid":"19134553","id":"PMC_19134553","title":"Overexpression of GADD34 enhances production of recombinant human antithrombin III in Chinese hamster ovary cells.","date":"2008","source":"Journal of bioscience and bioengineering","url":"https://pubmed.ncbi.nlm.nih.gov/19134553","citation_count":44,"is_preprint":false},{"pmid":"26070242","id":"PMC_26070242","title":"Quercetin reduces eIF2α phosphorylation by GADD34 induction.","date":"2015","source":"Neurobiology of aging","url":"https://pubmed.ncbi.nlm.nih.gov/26070242","citation_count":43,"is_preprint":false},{"pmid":"24534530","id":"PMC_24534530","title":"Phosphatase holoenzyme PP1/GADD34 negatively regulates TLR response by inhibiting TAK1 serine 412 phosphorylation.","date":"2014","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/24534530","citation_count":42,"is_preprint":false},{"pmid":"27171261","id":"PMC_27171261","title":"GADD34 suppresses lipopolysaccharide-induced sepsis and tissue injury through the regulation of macrophage activation.","date":"2016","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/27171261","citation_count":40,"is_preprint":false},{"pmid":"17273797","id":"PMC_17273797","title":"GADD34 inhibits mammalian target of rapamycin signaling via tuberous sclerosis complex and controls cell survival under bioenergetic stress.","date":"2007","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/17273797","citation_count":40,"is_preprint":false},{"pmid":"12016208","id":"PMC_12016208","title":"The human SNF5/INI1 protein facilitates the function of the growth arrest and DNA damage-inducible protein (GADD34) and modulates GADD34-bound protein phosphatase-1 activity.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12016208","citation_count":39,"is_preprint":false},{"pmid":"23708656","id":"PMC_23708656","title":"HTLV-1 HBZ positively regulates the mTOR signaling pathway via inhibition of GADD34 activity in the cytoplasm.","date":"2013","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/23708656","citation_count":38,"is_preprint":false},{"pmid":"19901557","id":"PMC_19901557","title":"Disruption of the PP1/GADD34 complex induces calreticulin exposure.","date":"2009","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/19901557","citation_count":38,"is_preprint":false},{"pmid":"27161320","id":"PMC_27161320","title":"Complementary Roles of GADD34- and CReP-Containing Eukaryotic Initiation Factor 2α Phosphatases during the Unfolded Protein Response.","date":"2016","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/27161320","citation_count":37,"is_preprint":false},{"pmid":"21439266","id":"PMC_21439266","title":"Gadd34 induces autophagy through the suppression of the mTOR pathway during starvation.","date":"2011","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/21439266","citation_count":37,"is_preprint":false},{"pmid":"12813455","id":"PMC_12813455","title":"Gadd34 functional domains involved in growth suppression and apoptosis.","date":"2003","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/12813455","citation_count":36,"is_preprint":false},{"pmid":"21925170","id":"PMC_21925170","title":"GADD34 mediates cytoprotective autophagy in mutant huntingtin expressing cells via the mTOR pathway.","date":"2011","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/21925170","citation_count":36,"is_preprint":false},{"pmid":"10066455","id":"PMC_10066455","title":"Cloning of a GADD34-like gene that interacts with the zinc-finger transcription factor which binds to the p21(WAF) promoter.","date":"1999","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/10066455","citation_count":36,"is_preprint":false},{"pmid":"28984870","id":"PMC_28984870","title":"Oxidative stress promotes SIRT1 recruitment to the GADD34/PP1α complex to activate its deacetylase function.","date":"2017","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/28984870","citation_count":35,"is_preprint":false},{"pmid":"12099899","id":"PMC_12099899","title":"Specific expression of the cell cycle regulation proteins, GADD34 and PCNA, in the peri-infarct zone after focal cerebral ischaemia in the rat.","date":"2002","source":"The European journal of neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/12099899","citation_count":35,"is_preprint":false},{"pmid":"29109149","id":"PMC_29109149","title":"Chronic oxidative stress promotes GADD34-mediated phosphorylation of the TAR DNA-binding protein TDP-43, a modification linked to neurodegeneration.","date":"2017","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29109149","citation_count":33,"is_preprint":false},{"pmid":"12724406","id":"PMC_12724406","title":"Human BAG-1 proteins bind to the cellular stress response protein GADD34 and interfere with GADD34 functions.","date":"2003","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/12724406","citation_count":32,"is_preprint":false},{"pmid":"16478986","id":"PMC_16478986","title":"Gadd34 requirement for normal hemoglobin synthesis.","date":"2006","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/16478986","citation_count":31,"is_preprint":false},{"pmid":"25821552","id":"PMC_25821552","title":"Enhancement of the acrolein-induced production of reactive oxygen species and lung injury by GADD34.","date":"2015","source":"Oxidative medicine and cellular longevity","url":"https://pubmed.ncbi.nlm.nih.gov/25821552","citation_count":30,"is_preprint":false},{"pmid":"20043261","id":"PMC_20043261","title":"Selenium decreases thyroid cancer cell growth by increasing expression of GADD153 and GADD34.","date":"2010","source":"Nutrition and cancer","url":"https://pubmed.ncbi.nlm.nih.gov/20043261","citation_count":30,"is_preprint":false},{"pmid":"17670836","id":"PMC_17670836","title":"Suppression of viral replication by stress-inducible GADD34 protein via the mammalian serine/threonine protein kinase mTOR pathway.","date":"2007","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/17670836","citation_count":29,"is_preprint":false},{"pmid":"29212034","id":"PMC_29212034","title":"GADD34 Function in Protein Trafficking Promotes Adaptation to Hyperosmotic Stress in Human Corneal Cells.","date":"2017","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/29212034","citation_count":28,"is_preprint":false},{"pmid":"21518769","id":"PMC_21518769","title":"Association with endoplasmic reticulum promotes proteasomal degradation of GADD34 protein.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21518769","citation_count":28,"is_preprint":false},{"pmid":"11104688","id":"PMC_11104688","title":"Interaction between DNA-damage protein GADD34 and a new member of the Hsp40 family of heat shock proteins that is induced by a DNA-damaging reagent.","date":"2000","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/11104688","citation_count":28,"is_preprint":false},{"pmid":"25386686","id":"PMC_25386686","title":"Inhibition of GADD34, the stress-inducible regulatory subunit of the endoplasmic reticulum stress response, does not enhance functional recovery after spinal cord injury.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25386686","citation_count":25,"is_preprint":false},{"pmid":"38139150","id":"PMC_38139150","title":"The PPP1R15 Family of eIF2-alpha Phosphatase Targeting Subunits (GADD34 and CReP).","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38139150","citation_count":24,"is_preprint":false},{"pmid":"30782845","id":"PMC_30782845","title":"The regulatory protein GADD34 inhibits TRAIL-induced apoptosis via TRAF6/ERK-dependent stabilization of myeloid cell leukemia 1 in liver cancer cells.","date":"2019","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30782845","citation_count":23,"is_preprint":false},{"pmid":"25659802","id":"PMC_25659802","title":"GADD34 inhibits activation-induced apoptosis of macrophages through enhancement of autophagy.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/25659802","citation_count":23,"is_preprint":false},{"pmid":"25832002","id":"PMC_25832002","title":"Growth arrest and DNA damage-inducible protein (GADD34) enhanced liver inflammation and tumorigenesis in a diethylnitrosamine (DEN)-treated murine model.","date":"2015","source":"Cancer immunology, immunotherapy : CII","url":"https://pubmed.ncbi.nlm.nih.gov/25832002","citation_count":23,"is_preprint":false},{"pmid":"36283811","id":"PMC_36283811","title":"Translation Rescue by Targeting Ppp1r15a through Its Upstream Open Reading Frame in Sepsis-Induced Acute Kidney Injury in a Murine Model.","date":"2022","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/36283811","citation_count":22,"is_preprint":false},{"pmid":"27992581","id":"PMC_27992581","title":"GADD34 Keeps the mTOR Pathway Inactivated in Endoplasmic Reticulum Stress Related Autophagy.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/27992581","citation_count":22,"is_preprint":false},{"pmid":"36097827","id":"PMC_36097827","title":"A systems biological analysis of the ATF4-GADD34-CHOP regulatory triangle upon endoplasmic reticulum stress.","date":"2022","source":"FEBS open bio","url":"https://pubmed.ncbi.nlm.nih.gov/36097827","citation_count":22,"is_preprint":false},{"pmid":"26316333","id":"PMC_26316333","title":"GADD34-deficient mice develop obesity, nonalcoholic fatty liver disease, hepatic carcinoma and insulin resistance.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26316333","citation_count":22,"is_preprint":false},{"pmid":"20349333","id":"PMC_20349333","title":"N-terminally truncated GADD34 proteins are convenient translation enhancers in a human cell-derived in vitro protein synthesis system.","date":"2010","source":"Biotechnology letters","url":"https://pubmed.ncbi.nlm.nih.gov/20349333","citation_count":22,"is_preprint":false},{"pmid":"10434033","id":"PMC_10434033","title":"Evidence for the interaction between Translin and GADD34 in mammalian cells.","date":"1999","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/10434033","citation_count":22,"is_preprint":false},{"pmid":"26869028","id":"PMC_26869028","title":"Regulation of de novo translation of host cells by manipulation of PERK/PKR and GADD34-PP1 activity during Newcastle disease virus infection.","date":"2016","source":"The Journal of general virology","url":"https://pubmed.ncbi.nlm.nih.gov/26869028","citation_count":22,"is_preprint":false},{"pmid":"31837419","id":"PMC_31837419","title":"Knockdown of GADD34 in neonatal mutant SOD1 mice ameliorates ALS.","date":"2019","source":"Neurobiology of disease","url":"https://pubmed.ncbi.nlm.nih.gov/31837419","citation_count":20,"is_preprint":false},{"pmid":"26142647","id":"PMC_26142647","title":"Increased GADD34 in oligodendrocytes in Alzheimer's disease.","date":"2015","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/26142647","citation_count":20,"is_preprint":false},{"pmid":"10631107","id":"PMC_10631107","title":"Interaction between GADD34 and kinesin superfamily, KIF3A.","date":"2000","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/10631107","citation_count":19,"is_preprint":false},{"pmid":"26196182","id":"PMC_26196182","title":"Effects of growth arrest and DNA damage-inducible protein 34 (GADD34) on inflammation-induced colon cancer in mice.","date":"2015","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/26196182","citation_count":19,"is_preprint":false},{"pmid":"26829377","id":"PMC_26829377","title":"Unfolded protein response gene GADD34 is overexpressed in rheumatoid arthritis and related to the presence of circulating anti-citrullinated protein antibodies.","date":"2016","source":"Autoimmunity","url":"https://pubmed.ncbi.nlm.nih.gov/26829377","citation_count":19,"is_preprint":false},{"pmid":"38602876","id":"PMC_38602876","title":"Turnover of PPP1R15A mRNA encoding GADD34 controls responsiveness and adaptation to cellular stress.","date":"2024","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/38602876","citation_count":18,"is_preprint":false},{"pmid":"35985062","id":"PMC_35985062","title":"Salidroside attenuates sepsis-associated acute lung injury through PPP1R15A mediated endoplasmic reticulum stress inhibition.","date":"2022","source":"Bioorganic & medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/35985062","citation_count":18,"is_preprint":false},{"pmid":"15255948","id":"PMC_15255948","title":"GADD34 protein levels increase after transient ischemia in the cortex but not in the CA1 subfield: implications for post-ischemic recovery of protein synthesis in ischemia-resistant cells.","date":"2004","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15255948","citation_count":18,"is_preprint":false},{"pmid":"29363586","id":"PMC_29363586","title":"Guanabenz inhibits TLR9 signaling through a pathway that is independent of eIF2α dephosphorylation by the GADD34/PP1c complex.","date":"2018","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/29363586","citation_count":18,"is_preprint":false},{"pmid":"27129771","id":"PMC_27129771","title":"Nuclear Matrix Protein 4 Is a Novel Regulator of Ribosome Biogenesis and Controls the Unfolded Protein Response via Repression of Gadd34 Expression.","date":"2016","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27129771","citation_count":18,"is_preprint":false},{"pmid":"34732748","id":"PMC_34732748","title":"Sensitization of the UPR by loss of PPP1R15A promotes fibrosis and senescence in IPF.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/34732748","citation_count":17,"is_preprint":false},{"pmid":"35501353","id":"PMC_35501353","title":"Mxi1 participates in the progression of lung cancer via the microRNA-300/KLF9/GADD34 Axis.","date":"2022","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/35501353","citation_count":16,"is_preprint":false},{"pmid":"25204313","id":"PMC_25204313","title":"Induction of GADD34 Regulates the Neurotoxicity of Amyloid β.","date":"2014","source":"American journal of Alzheimer's disease and other dementias","url":"https://pubmed.ncbi.nlm.nih.gov/25204313","citation_count":15,"is_preprint":false},{"pmid":"38882672","id":"PMC_38882672","title":"PPP1R15A-expressing monocytic MDSCs promote immunosuppressive liver microenvironment in fibrosis-associated hepatocellular carcinoma.","date":"2024","source":"JHEP reports : innovation in hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/38882672","citation_count":15,"is_preprint":false},{"pmid":"28825160","id":"PMC_28825160","title":"Functional validation of ATF4 and GADD34 in Neuro2a cells by CRISPR/Cas9-mediated genome editing.","date":"2017","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/28825160","citation_count":15,"is_preprint":false},{"pmid":"26041779","id":"PMC_26041779","title":"Coordinated Regulation of the Neutral Amino Acid Transporter SNAT2 and the Protein Phosphatase Subunit GADD34 Promotes Adaptation to Increased Extracellular Osmolarity.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26041779","citation_count":15,"is_preprint":false},{"pmid":"20040105","id":"PMC_20040105","title":"EBNA3C interacts with Gadd34 and counteracts the unfolded protein response.","date":"2009","source":"Virology journal","url":"https://pubmed.ncbi.nlm.nih.gov/20040105","citation_count":14,"is_preprint":false},{"pmid":"29491143","id":"PMC_29491143","title":"Hairy and enhancer of split 1 (HES1) protects cells from endoplasmic reticulum stress-induced apoptosis through repression of .","date":"2018","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29491143","citation_count":14,"is_preprint":false},{"pmid":"34930429","id":"PMC_34930429","title":"GADD34-mediated dephosphorylation of eIF2α facilitates pseudorabies virus replication by maintaining de novo protein synthesis.","date":"2021","source":"Veterinary research","url":"https://pubmed.ncbi.nlm.nih.gov/34930429","citation_count":13,"is_preprint":false},{"pmid":"26408692","id":"PMC_26408692","title":"GADD34 Facilitates Cell Death Resulting from Proteasome Inhibition.","date":"2015","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/26408692","citation_count":13,"is_preprint":false},{"pmid":"34098025","id":"PMC_34098025","title":"Growth arrest and DNA damage-inducible protein 34 (GADD34) contributes to cerebral ischemic injury and can be detected in plasma exosomes.","date":"2021","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/34098025","citation_count":13,"is_preprint":false},{"pmid":"36718369","id":"PMC_36718369","title":"Single-cell RNA sequencing reveals the suppressive effect of PPP1R15A inhibitor Sephin1 in antitumor immunity.","date":"2023","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/36718369","citation_count":12,"is_preprint":false},{"pmid":"15541008","id":"PMC_15541008","title":"Up-regulation of a growth arrest and DNA damage protein (GADD34) in the ischaemic human brain: implications for protein synthesis regulation and DNA repair.","date":"2004","source":"Neuropathology and applied neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/15541008","citation_count":12,"is_preprint":false},{"pmid":"24092754","id":"PMC_24092754","title":"Phosphorylation at tyrosine 262 promotes GADD34 protein turnover.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24092754","citation_count":11,"is_preprint":false},{"pmid":"39948597","id":"PMC_39948597","title":"Protein phosphatase 1 regulatory subunit 15 A (PPP1R15A) promoted the progression of gastric cancer by activating cell autophagy under energy stress.","date":"2025","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/39948597","citation_count":10,"is_preprint":false},{"pmid":"17487408","id":"PMC_17487408","title":"GADD34 induces p21 expression and cellular senescence.","date":"2007","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/17487408","citation_count":10,"is_preprint":false},{"pmid":"31366879","id":"PMC_31366879","title":"Capsaicin Induces ATF4 Translation with Upregulation of CHOP, GADD34 and PUMA.","date":"2019","source":"Biological & pharmaceutical bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/31366879","citation_count":10,"is_preprint":false},{"pmid":"27177629","id":"PMC_27177629","title":"Feasibility of novel PPP1R15A and proposed ANXA11 single nucleotide polymorphisms as predictive markers for bevacizumab regimen in metastatic colorectal cancer.","date":"2016","source":"Journal of cancer research and clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/27177629","citation_count":10,"is_preprint":false},{"pmid":"15713259","id":"PMC_15713259","title":"Evolution of GADD34 expression after focal cerebral ischaemia.","date":"2005","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/15713259","citation_count":10,"is_preprint":false},{"pmid":"31778897","id":"PMC_31778897","title":"GADD34 attenuates HIV-1 replication by viral 5'-UTR TAR RNA-mediated translational inhibition.","date":"2019","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/31778897","citation_count":9,"is_preprint":false},{"pmid":"33410111","id":"PMC_33410111","title":"Guanabenz Sensitizes Glioblastoma Cells to Sunitinib by Inhibiting GADD34-Mediated Autophagic Signaling.","date":"2021","source":"Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/33410111","citation_count":9,"is_preprint":false},{"pmid":"31337709","id":"PMC_31337709","title":"The antibiotic robenidine exhibits guanabenz-like cytoprotective properties by a mechanism independent of protein phosphatase PP1:PPP1R15A.","date":"2019","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31337709","citation_count":9,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49765,"output_tokens":8756,"usd":0.140318},"stage2":{"model":"claude-opus-4-6","input_tokens":12856,"output_tokens":4225,"usd":0.254858},"total_usd":0.395176,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"GADD34 (PPP1R15A) forms a complex with the catalytic subunit of protein phosphatase 1 (PP1c) that specifically promotes dephosphorylation of eIF2α in vitro, acting as a negative feedback regulator of the unfolded protein response and stress-induced translational repression.\",\n      \"method\": \"Co-immunoprecipitation, in vitro phosphatase assay, retroviral overexpression with CHOP::GFP reporter, PP1c-binding mutants\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution plus mutagenesis plus cellular reporter assay; foundational paper with >1000 citations\",\n      \"pmids\": [\"11381086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"GADD34 assembles a novel signaling complex containing PP1 and inhibitor 1 (I-1); the GADD34/PP1 complex retains eIF2α phosphatase activity while the GADD34-bound PP1 is inhibited for dephosphorylation of phosphorylase a, demonstrating substrate selectivity.\",\n      \"method\": \"Yeast two-hybrid screen, recombinant protein pulldown, affinity isolation of cellular complexes, in vitro phosphatase assay with eIF2α and phosphorylase a substrates\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro assay with multiple substrates demonstrating selectivity, replicated with endogenous brain extracts\",\n      \"pmids\": [\"11564868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"GADD34 contains a bipartite C-terminal PP1-binding domain (canonical KVRF motif plus novel RARA sequence) required for PP1 binding; its N-terminal 180 residues direct ER localization and target PP1α to the ER, and N-terminal sequences are required beyond PP1 binding for eIF2α dephosphorylation in cells.\",\n      \"method\": \"Structure-function deletion analysis, GFP-GADD34 live-cell imaging, eIF2α phosphorylation reversal assay in thapsigargin/tunicamycin-treated cells\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — structure-function mutagenesis combined with live imaging and cellular functional assay\",\n      \"pmids\": [\"12556489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"GADD34-deficient mouse embryonic fibroblasts show delayed recovery from eIF2α phosphorylation and protein synthesis shutoff induced by thapsigargin or DTT, establishing GADD34 as required in vivo for recovery from ER stress-induced translational arrest.\",\n      \"method\": \"GADD34 knockout mice/MEFs, eIF2α phosphorylation Western blot, protein synthesis recovery assay after ER stress\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic KO with defined molecular phenotype (eIF2α phosphorylation) and functional readout (protein synthesis recovery)\",\n      \"pmids\": [\"12824288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Smad7 acts as an adaptor recruiting the GADD34–PP1c complex to the TGFβ type I receptor (TβRI), leading to dephosphorylation of TβRI and negative feedback inhibition of TGFβ signaling; SARA enhances PP1c recruitment to the Smad7–GADD34 complex.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown of Smad7, TβRI phosphorylation assay, cell cycle arrest functional assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, RNAi epistasis, and defined functional outcome (TGFβ resistance)\",\n      \"pmids\": [\"14718519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Crystal/structural and functional analysis of the GADD34:PP1 holoenzyme revealed that GADD34 functions as a scaffold with independent binding sites for PP1 and eIF2α, demonstrating that eIF2α recruitment to the complex is distinct from PP1 binding.\",\n      \"method\": \"Structural analysis (NMR/biochemical), in vitro reconstitution, mutagenesis, cellular functional assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — detailed structural and functional analysis with mutagenesis, reconstitution in vitro and in cells\",\n      \"pmids\": [\"26095357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"A novel eIF2α-binding motif in the C-terminus of GADD34 (consensus Rx[Gnl]x(1-2)Wxxx[Arlv]x[Dn][Rg]xRFxx[Rlvk][Ivc]), distinct from the PP1-binding site, is required for eIF2α interaction, eIF2α dephosphorylation promotion, and suppression of PKR toxicity; this motif is conserved in viral GADD34 orthologs (HSV ICP34.5, ASFV, Canarypox).\",\n      \"method\": \"Point mutagenesis, Co-IP/pulldown, eIF2α dephosphorylation assays, yeast PKR toxicity suppression assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis of defined motif with multiple functional readouts, validated in multiple viral orthologs\",\n      \"pmids\": [\"26100893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Reconstituted human recombinant R15A(GADD34)–PP1 and R15B(CReP)–PP1 holophosphatases showed that Guanabenz and Sephin1 selectively induce a conformational change in R15A detected by limited proteolysis, altering eIF2α recruitment and preventing its dephosphorylation without disrupting the R15A–PP1 interaction.\",\n      \"method\": \"In vitro reconstitution of recombinant holophosphatases, limited proteolysis, eIF2α dephosphorylation assay, inhibitor binding studies\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with recombinant proteins, mechanistically distinct from prior studies; multiple orthogonal assays\",\n      \"pmids\": [\"28759048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In vitro, Guanabenz and Sephin1 do not affect stability of the PP1–PPP1R15A complex nor substrate-specific eIF2α dephosphorylation; in cells, eIF2α-P dephosphorylation after kinase shutoff proceeds normally in Sephin1-treated cells; Sephin1's effect on IRE1 branch is independent of PPP1R15A and eIF2α phosphorylation status.\",\n      \"method\": \"In vitro phosphatase assay with reconstituted complex, kinase shut-off experiment, CRISPR-edited Ppp1r15a-deleted cells and eIF2α-S51A knock-in cells\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — rigorous in vitro reconstitution plus genetic controls challenging proposed mechanism; independent of prior studies\",\n      \"pmids\": [\"28447936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"GADD34 is degraded by the 26S proteasome via polyubiquitination; an N-terminal degron drives this rapid turnover; PEST repeat deletions modulate PP1 binding and activity; stabilization of GADD34 by proteasome inhibition enhances eIF2α dephosphorylation and promotes accumulation/aggregation of misfolded CFTRΔF508.\",\n      \"method\": \"Proteasomal inhibitor treatment, polyubiquitination assay, N-terminal deletion/epitope-tag stabilization, eIF2α phosphorylation assay, CFTR aggregation assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (ubiquitination, inhibitor, mutagenesis, functional readout) in single study\",\n      \"pmids\": [\"18794359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"GADD34's N-terminal amphipathic helix (with hydrophobic residues V25 and L29) mediates monotopic insertion into the ER outer membrane, while the same helix's polar surface mediates mitochondrial association; ER-associated GADD34 has reduced mobility (FRAP) and enhanced proteasomal degradation compared to cytosolic mutant V25R; both WT and V25R scaffold PP1α for eIF2α dephosphorylation, but only WT modifies ER morphology.\",\n      \"method\": \"Deletion mutagenesis, GFP-GADD34 live imaging, fluorescence protease protection, FRAP, cysteine chemical modification, eIF2α dephosphorylation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods including FRAP, protease protection, and mutagenesis with functional readouts\",\n      \"pmids\": [\"21518769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Gadd34-null mice display reduced hemoglobin content in erythrocytes due to reduced initiation of globin translation machinery in reticulocytes, revealing a physiological role for Gadd34/PP1c in eIF2α dephosphorylation to counterbalance heme-regulated inhibitor kinase during hemoglobin synthesis.\",\n      \"method\": \"Gadd34-null mouse analysis, erythrocyte/reticulocyte biochemical analysis of hemoglobin and globin translation initiation\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with defined molecular mechanism (eIF2α dephosphorylation, HRI kinase counterbalance) and clear phenotype\",\n      \"pmids\": [\"16478986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"GADD34 mRNA translation is preferentially induced during eIF2α phosphorylation via upstream ORFs (uORFs) in its 5' UTR; the downstream uORF mediates repression of basal translation and redirects translation during stress, allowing maximal GADD34 expression when needed for negative feedback.\",\n      \"method\": \"Polysome fractionation, 5'UTR reporter constructs, uORF mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — mechanistic dissection of translational regulation with reporter mutagenesis and polysome profiling\",\n      \"pmids\": [\"19131336\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"GADD34 upregulation following traumatic brain injury (TBI) is induced by ATF4 binding to the GADD34 promoter; GADD34 then binds TRAF6, preventing TRAF6-mediated ubiquitination-coupled Akt phosphorylation at T308, retaining Akt in the cytosol and reducing cell survival; in vivo lentiviral knockdown of GADD34 rescues Akt activation and attenuates TBI-induced cell death.\",\n      \"method\": \"Controlled cortical impact TBI mouse model, Co-IP (GADD34-TRAF6 interaction), lentiviral shRNA knockdown, Akt phosphorylation assay, cell death quantification\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus in vivo KD with defined phenotype, single lab\",\n      \"pmids\": [\"23907468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"GADD34/Ppp1r15a is absolutely required for type I IFN and IL-6 production by mouse embryonic fibroblasts in response to dsRNA; GADD34 expression depends on PKR activation linking cytosolic microbial sensing to the ATF4 branch of the UPR; GADD34-deficient mice are extremely susceptible to Chikungunya virus infection.\",\n      \"method\": \"GADD34-deficient MEFs and neonatal mice, dsRNA stimulation, cytokine measurement, viral infection survival assay\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with defined cellular and in vivo phenotype, PKR pathway epistasis established\",\n      \"pmids\": [\"22615568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"GADD34 acts as a regulatory subunit directing PP1 to dephosphorylate TAK1 at serine 412, attenuating TLR-triggered NF-κB and MAPK signaling; GADD34 depletion abolishes the PP1–TAK1 interaction and enhances pro-inflammatory cytokine production.\",\n      \"method\": \"Co-IP (GADD34-PP1-TAK1), GADD34 siRNA knockdown, TAK1 S412A mutant, NF-κB/MAPK activation assays, LPS endotoxin shock in vivo\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, mutagenesis of TAK1 Ser412, siRNA epistasis, and in vivo validation\",\n      \"pmids\": [\"24534530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"GADD34 forms a stable complex with TSC1/TSC2 and promotes dephosphorylation of TSC2 at Thr1462, thereby inhibiting mTOR signaling; this mechanism protects cells from apoptosis during energy depletion.\",\n      \"method\": \"Co-IP (GADD34-TSC1/TSC2 complex), TSC2 phosphorylation assay, mTOR downstream readouts (S6K, 4EBP1), cell viability assay\",\n      \"journal\": \"International journal of molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus phosphorylation assay, replicated in related studies; single lab\",\n      \"pmids\": [\"17273797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Starvation-induced GADD34 suppresses mTOR by binding and dephosphorylating TSC2 at Thr1462, promoting autophagy; autophagy induction is absent in Gadd34 KO mice under starvation.\",\n      \"method\": \"Gadd34 KO mice, starvation model, Co-IP (Gadd34-TSC2), TSC2 Thr1462 phosphorylation assay, autophagy marker analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with defined molecular mechanism (TSC2 dephosphorylation), replicates TSC-mTOR finding\",\n      \"pmids\": [\"21439266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Oxidative stress promotes recruitment of SIRT1 to the GADD34/PP1α complex in the cytoplasm; GADD34-scaffolded PP1α dephosphorylates both eIF2α (pSer51) and SIRT1 (pSer47); SIRT1 dephosphorylation increases its deacetylase activity; GADD34-/- MEFs show persistent phosphorylation of both eIF2α and SIRT1 after arsenite exposure.\",\n      \"method\": \"Mass spectrometry of GADD34 interactome, Co-IP, GADD34 KO MEFs, SIRT1 deacetylase activity assay in vitro and in cells, WT vs PP1-binding mutant rescue\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — MS interactome plus reciprocal Co-IP, KO cells, in vitro enzyme assay, and genetic rescue; multiple orthogonal methods\",\n      \"pmids\": [\"28984870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In response to chronic oxidative stress (arsenite), GADD34 functions as a kinase scaffold by recruiting TDP-43 and casein kinase-1ε (CK1ε); GADD34-bound CK1ε phosphorylates TDP-43 at serines 409/410 (pathological phosphorylation); these phosphorylations are diminished in GADD34-/- cells.\",\n      \"method\": \"Co-IP (GADD34-TDP-43-CK1ε), GADD34 KO MEFs, TDP-43 phosphorylation assay at S409/410, arsenite vs. ER stress comparison\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with multiple partners, KO cells with defined molecular phenotype, mechanistically distinct scaffold function demonstrated\",\n      \"pmids\": [\"29109149\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"HTLV-1 HBZ protein is exported from the nucleus via CRM1-dependent NES, interacts with the C-terminal region of GADD34 in the cytoplasm, and inhibits GADD34 function to activate mTOR signaling (increased S6K phosphorylation) and suppress starvation-induced autophagy.\",\n      \"method\": \"Co-IP (HBZ-GADD34), NES mutagenesis, CRM1 inhibitor (leptomycin B), S6K phosphorylation assay, autophagy assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP with mutagenesis and functional readout; single lab\",\n      \"pmids\": [\"23708656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"GADD34/PP1 phosphatase activity reverses hyperosmotic-stress-induced Golgi fragmentation, promotes cis-to-trans Golgi trafficking of the neutral amino acid transporter SNAT2, and enables SNAT2 plasma membrane localization and function, independent of GADD34's ISR role.\",\n      \"method\": \"GADD34 KO cells, Golgi morphology imaging, SNAT2 trafficking assay, amino acid uptake functional assay, PP1 phosphatase inhibitor treatment\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO/rescue with functional trafficking and transport readouts, single lab\",\n      \"pmids\": [\"29212034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"hSNF5/INI1 binds GADD34 (partly through the PP1-docking domain homologous to HSV ICP34.5), forms a stable heterotrimeric complex with GADD34 and PP1, and weakly stimulates PP1 phosphatase activity; EBNA2 disrupts hSNF5/INI1-GADD34 interaction and partially reverses GADD34-mediated growth suppression.\",\n      \"method\": \"Co-IP, affinity pulldown, in vitro PP1 phosphatase activity assay, colony formation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP with in vitro functional assay; single lab, moderate evidence\",\n      \"pmids\": [\"12016208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Human BAG-1 cochaperone proteins interact with GADD34 in cells undergoing apoptosis; BAG-1 negatively modulates GADD34-bound PP1 activity; Hsp70/Hsc70 and PP1 associate reversibly with the GADD34-BAG-1 complex in an ATP-dependent manner; BAG-1 expression masks GADD34-mediated growth suppression and apoptosis.\",\n      \"method\": \"Yeast two-hybrid screen, Co-IP in SW480 cells, in vitro PP1 phosphatase activity assay, colony formation suppression assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — yeast two-hybrid plus Co-IP plus in vitro enzymatic assay; single lab\",\n      \"pmids\": [\"12724406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Disruption of the PP1/GADD34 complex (by a competing GADD34-derived peptide fused to a membrane-translocation domain) is sufficient to stimulate eIF2α phosphorylation and trigger calreticulin surface exposure on tumor cells, dissociating CRT exposure from cell death.\",\n      \"method\": \"Molecular modeling-guided peptide design, cellular eIF2α phosphorylation assay, CRT surface exposure assay, Co-IP to verify PP1/GADD34 complex disruption\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic peptide disruption with functional readout; single lab, moderate evidence\",\n      \"pmids\": [\"19901557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"GADD34 promotes MCL-1 protein stability in hepatocellular carcinoma cells by inhibiting proteasomal degradation of MCL-1 through a TRAF6–TAB1–ERK signaling axis; GADD34 overexpression promotes ERK phosphorylation via TRAF6, which stabilizes MCL-1 and protects against TRAIL-induced apoptosis.\",\n      \"method\": \"Immunoblotting, GADD34 overexpression/knockdown, ERK phosphorylation assay, proteasome inhibitor (MG132) rescue, TRAF6 and GADD34 siRNA co-knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — multiple knockdowns/overexpressions with mechanistic pathway placement; single lab\",\n      \"pmids\": [\"30782845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TC-PTP (PTPN2) is a phosphatase that dephosphorylates GADD34 at tyrosine 262 (identified by substrate-trapping); phosphorylation at Y262 enhances GADD34 protein turnover; TC-PTP-null MEFs show reduced GADD34 protein after ER stress and increased susceptibility to ER stress-induced apoptosis rescued by ectopic GADD34.\",\n      \"method\": \"Mass spectrometry (GADD34 phosphosite identification), substrate-trapping Co-IP (TC-PTP-GADD34), TC-PTP-null MEFs, GADD34 turnover assay, apoptosis assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — MS phosphosite identification plus substrate-trapping plus genetic KO cells; single lab\",\n      \"pmids\": [\"24092754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TFEB directly activates GADD34 expression during starvation; GADD34 in turn dephosphorylates eIF2α to permit translation of the TFEB-driven lysosomal biogenesis program, enabling sustained autophagic flux; GADD34 thus integrates the mTORC1 and ISR pathways during starvation.\",\n      \"method\": \"GADD34 KO cells, TFEB ChIP/reporter assays, eIF2α phosphorylation assay, autophagic flux measurement (lysosomal biogenesis markers)\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with TFEB-GADD34 transcriptional epistasis established by ChIP and functional autophagy readout\",\n      \"pmids\": [\"32978159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The 3' UTR of PPP1R15A mRNA contains an AU-rich element (ARE) recognized by ZFP36 family RNA-binding proteins, promoting rapid mRNA decay under normal conditions and mRNA stabilization during stress; this post-transcriptional control of PPP1R15A mRNA stability functions as a component of ISR memory, setting the threshold for stress responsiveness and adaptation.\",\n      \"method\": \"3'UTR reporter assays, ZFP36 family protein binding assays, mRNA stability assays, ISR memory experiments with repeated stress exposure\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic dissection of ARE-mediated decay with functional ISR readouts; single paper\",\n      \"pmids\": [\"38602876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"GADD34 interacts with HRX (MLL) proteins; leukemic HRX fusion proteins (HRX-ENL, HRX-AF9, HRX-ELL) bind GADD34 and abrogate GADD34-induced apoptosis after ionizing radiation; wild-type HRX does not inhibit this apoptosis; GADD34 also binds hSNF5/INI1.\",\n      \"method\": \"Yeast two-hybrid, Co-IP in human cells, apoptosis assay (nuclear fragmentation) after ionizing radiation\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP plus functional apoptosis assay, single lab\",\n      \"pmids\": [\"10490642\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"GADD34 interacts with GAHSP40 (a DnaJ/Hsp40 family member); interaction requires the ICP34.5-homology domain of GADD34 and the C-terminus of GAHSP40; interaction confirmed by Co-IP in cultured cells.\",\n      \"method\": \"Yeast two-hybrid, Co-IP, in vitro binding assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, Co-IP/pulldown without functional mechanistic follow-up\",\n      \"pmids\": [\"11104688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"GADD34 interacts with KIF3A (kinesin superfamily motor protein) via KIF3A's C-terminal tail domain, identified by yeast two-hybrid and confirmed by in vivo two-hybrid in NIH3T3 cells.\",\n      \"method\": \"Yeast two-hybrid, in vivo two-hybrid in NIH3T3 cells\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single yeast/cell-based interaction assay, no functional follow-up\",\n      \"pmids\": [\"10631107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"GADD34 interacts with Translin (a DNA translocation-associated RNA-binding protein); interaction was confirmed by in vitro binding assay and in vivo two-hybrid in NIH3T3 cells.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding assay, in vivo two-hybrid\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, interaction assays without mechanistic follow-up\",\n      \"pmids\": [\"10434033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"GADD34-containing eIF2α phosphatase drives substantial translational changes in unstressed cells targeting the secretome; upon UPR activation, rapid GADD34 translation is essential for UPR progression — in GADD34-absence eIF2α phosphorylation is persistently elevated and UPR translational program is significantly attenuated; compensatory AKT-mediated PERK suppression and CReP induction partially restore protein synthesis.\",\n      \"method\": \"GADD34 KO cells, polysome profiling, translational analysis, AKT/PERK signaling assays, CReP expression measurement\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO with multiple molecular readouts; single lab\",\n      \"pmids\": [\"27161320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In sepsis-induced acute kidney injury, Ppp1r15a/GADD34 expression is blunted by its own 5' upstream ORF (uORF); antisense oligonucleotides targeting the uORF enable Ppp1r15a overexpression, rescuing eIF2α dephosphorylation, restoring translation, and improving kidney function in a murine endotoxemia model.\",\n      \"method\": \"Ribosome profiling (Ribo-seq), proteomics, polyribosome profiling, antisense oligonucleotides, Ppp1r15a knock-in mouse model, mutant cell lines\",\n      \"journal\": \"Journal of the American Society of Nephrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Ribo-seq, proteomics) plus genetic and ASO rescue with functional organ readout\",\n      \"pmids\": [\"36283811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"HES1 (hairy and enhancer of split 1) binds to the GADD34 promoter and represses its transcription during ER stress; HES1 depletion leads to GADD34 upregulation and increased cell death during ER stress in a GADD34-dependent manner.\",\n      \"method\": \"HES1 depletion (siRNA), GADD34 promoter ChIP, cell death assay, epistasis with GADD34 KD\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus siRNA epistasis showing HES1 as transcriptional repressor of GADD34; single lab\",\n      \"pmids\": [\"29491143\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PPP1R15A (GADD34) functions primarily as a stress-induced scaffolding protein that recruits the catalytic subunit of protein phosphatase 1 (PP1c/PP1α) via a bipartite C-terminal domain and simultaneously engages eIF2α through a separate C-terminal docking motif, directing the assembled holophosphatase to dephosphorylate eIF2α at Ser51 at the ER membrane — thereby providing negative feedback to terminate the integrated stress response and restore protein synthesis; beyond its canonical eIF2α phosphatase-organizing role, GADD34 also scaffolds additional substrates (TβRI via Smad7, TAK1, TSC2, SIRT1) and, in response to chronic oxidative stress, acts as a kinase scaffold recruiting CK1ε to phosphorylate TDP-43, while its own levels are tightly regulated by proteasomal degradation (driven by an N-terminal degron, ER-association, and phosphorylation at Tyr262 by TC-PTP), by translational control through 5' UTR uORFs during stress, and by post-transcriptional mRNA stability via ZFP36-family ARE-binding proteins.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PPP1R15A (GADD34) is a stress-inducible regulatory subunit of protein phosphatase 1 (PP1) that serves as the principal negative-feedback effector of the integrated stress response (ISR) by scaffolding PP1c and eIF2α into a holophosphatase complex at the endoplasmic reticulum, thereby directing dephosphorylation of eIF2α at Ser51 and restoring global protein synthesis after stress [PMID:11381086, PMID:26095357, PMID:12824288]. The protein employs a bipartite C-terminal PP1-binding domain (KVRF and RARA motifs) and a separate conserved eIF2α-docking motif for independent substrate recruitment, while an N-terminal amphipathic helix mediates monotopic ER membrane insertion and controls proteasomal turnover via an N-terminal degron [PMID:12556489, PMID:26100893, PMID:21518769, PMID:18794359]. Beyond eIF2α, GADD34 redirects PP1 to additional substrates including TAK1 (attenuating NF-κB/MAPK signaling), TSC2 (inhibiting mTOR to promote autophagy), TβRI (via Smad7, dampening TGFβ signaling), and SIRT1, and under chronic oxidative stress it acts as a kinase scaffold recruiting CK1ε to phosphorylate TDP-43 at pathological sites [PMID:24534530, PMID:21439266, PMID:14718519, PMID:28984870, PMID:29109149]. GADD34 expression is tightly controlled at multiple levels: transcriptionally by ATF4 and TFEB, translationally by 5′ UTR upstream ORFs that permit preferential translation during eIF2α phosphorylation, and post-transcriptionally by ZFP36-family-mediated ARE-dependent mRNA decay that establishes ISR memory [PMID:19131336, PMID:32978159, PMID:38602876].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"The foundational question of how cells recover from stress-induced translational arrest was answered by showing that GADD34 recruits PP1c to form a holophosphatase that specifically dephosphorylates eIF2α, establishing GADD34 as the negative-feedback node of the ISR.\",\n      \"evidence\": \"Co-immunoprecipitation, in vitro phosphatase assays with PP1c-binding mutants, and CHOP::GFP reporter in cells\",\n      \"pmids\": [\"11381086\", \"11564868\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of PP1–GADD34 interaction unresolved\", \"Substrate selectivity mechanism unknown\", \"In vivo requirement not yet demonstrated\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Domain-mapping and genetic ablation established that GADD34 contains a bipartite C-terminal PP1-binding module and an N-terminal ER-targeting region, and that GADD34 is required in vivo for timely recovery of protein synthesis after ER stress.\",\n      \"evidence\": \"Structure-function deletion mutagenesis with GFP imaging, GADD34 knockout MEFs with eIF2α phosphorylation and translation recovery assays\",\n      \"pmids\": [\"12556489\", \"12824288\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the eIF2α-binding site on GADD34 unknown\", \"Physiological consequences of GADD34 loss in whole organisms not yet explored beyond MEFs\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"The discovery that Smad7 recruits the GADD34–PP1c complex to TβRI for dephosphorylation revealed that GADD34 is not exclusively an eIF2α phosphatase scaffold but can be redirected to diverse substrates via adaptor proteins.\",\n      \"evidence\": \"Reciprocal Co-IP, Smad7 RNAi, TβRI phosphorylation assays, and TGFβ-dependent cell-cycle-arrest readouts\",\n      \"pmids\": [\"14718519\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether GADD34–PP1 acts on TβRI in vivo under physiological stress not tested\", \"Structural basis of Smad7-mediated substrate redirection unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Analysis of Gadd34-null mice revealed a physiological requirement for GADD34-mediated eIF2α dephosphorylation in erythropoiesis, where it counterbalances HRI kinase to permit globin translation in reticulocytes.\",\n      \"evidence\": \"Gadd34-null mouse phenotyping with erythrocyte hemoglobin quantification and reticulocyte translation analysis\",\n      \"pmids\": [\"16478986\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether additional tissues show translational defects in Gadd34-null mice not systematically examined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identification of an N-terminal degron driving proteasomal polyubiquitination and rapid turnover of GADD34 explained how GADD34 protein levels are kept low basally, with functional consequences: stabilized GADD34 enhances eIF2α dephosphorylation and promotes misfolded-protein aggregation.\",\n      \"evidence\": \"Proteasome inhibitor treatment, polyubiquitination assays, N-terminal deletion mutagenesis, CFTRΔF508 aggregation readout\",\n      \"pmids\": [\"18794359\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ubiquitin ligase responsible for GADD34 ubiquitination not identified\", \"Relationship between ER localization and degradation not fully resolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstration that 5′ UTR uORFs mediate translational derepression of GADD34 mRNA during eIF2α phosphorylation revealed the feed-forward mechanism by which the ISR auto-induces its own negative regulator.\",\n      \"evidence\": \"Polysome fractionation with 5′ UTR reporter constructs and uORF mutagenesis\",\n      \"pmids\": [\"19131336\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of transcriptional (ATF4) vs. translational (uORF) induction under different stresses not quantified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"The N-terminal amphipathic helix was shown to mediate monotopic ER membrane insertion, controlling GADD34 mobility and proteasomal degradation rate, linking subcellular localization to protein turnover and function.\",\n      \"evidence\": \"GFP-GADD34 live imaging, FRAP, fluorescence protease protection, cysteine chemical modification, V25R mutagenesis\",\n      \"pmids\": [\"21518769\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ER anchoring affects substrate access beyond eIF2α not tested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"GADD34's substrate repertoire was expanded to mTOR regulation when it was shown to scaffold PP1-mediated dephosphorylation of TSC2 at Thr1462, inhibiting mTOR signaling during energy depletion and starvation-induced autophagy.\",\n      \"evidence\": \"Co-IP of GADD34–TSC1/TSC2 complex, TSC2 phosphorylation assays, mTOR readouts, confirmed in Gadd34 KO mice under starvation\",\n      \"pmids\": [\"17273797\", \"21439266\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether GADD34-mediated TSC2 dephosphorylation involves direct PP1 catalysis or indirect signaling not fully distinguished\", \"Structural basis of TSC2 recruitment unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"GADD34 was shown to be essential for type I IFN and IL-6 production in response to dsRNA via the PKR–ATF4 axis, establishing GADD34 as a critical node linking innate immune sensing to translational recovery needed for cytokine production.\",\n      \"evidence\": \"GADD34-deficient MEFs and neonatal mice challenged with dsRNA and Chikungunya virus; cytokine measurement and survival analysis\",\n      \"pmids\": [\"22615568\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which specific mRNAs require GADD34-mediated eIF2α dephosphorylation for translation during antiviral response not identified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"GADD34 was found to direct PP1 to dephosphorylate TAK1 at Ser412, attenuating TLR-triggered NF-κB and MAPK activation, thereby functioning as an anti-inflammatory phosphatase scaffold.\",\n      \"evidence\": \"Reciprocal Co-IP of GADD34–PP1–TAK1, TAK1 S412A mutant, siRNA epistasis, in vivo LPS endotoxin shock model\",\n      \"pmids\": [\"24534530\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether GADD34-mediated TAK1 dephosphorylation is PP1α-specific or involves other PP1 isoforms not tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Structural and functional studies resolved how GADD34 simultaneously but independently engages PP1 and eIF2α through separate binding motifs, explaining how a single scaffold achieves substrate specificity; a conserved C-terminal eIF2α-binding motif was defined by mutagenesis.\",\n      \"evidence\": \"NMR/biochemical structural analysis, in vitro reconstitution, point mutagenesis across GADD34 and viral orthologs, yeast PKR suppression assay\",\n      \"pmids\": [\"26095357\", \"26100893\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full atomic-resolution structure of the ternary GADD34–PP1–eIF2α complex not available\", \"Conformational dynamics during catalysis not characterized\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Pharmacological studies with Guanabenz and Sephin1 revealed that these compounds induce conformational changes in GADD34 that alter eIF2α recruitment, though an independent study found no effect of these drugs on reconstituted holophosphatase activity or cellular eIF2α dephosphorylation kinetics, leaving the mechanism of these inhibitors unresolved.\",\n      \"evidence\": \"In vitro reconstituted holophosphatases with limited proteolysis (PMID:28759048); independent reconstitution plus CRISPR-edited Ppp1r15a-deleted and eIF2α-S51A cells (PMID:28447936)\",\n      \"pmids\": [\"28759048\", \"28447936\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Contradictory findings on Sephin1/Guanabenz selectivity for GADD34 not resolved\", \"In vivo target engagement of these drugs not definitively demonstrated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"GADD34 was revealed to have dual scaffolding functions under oxidative stress: directing PP1α to dephosphorylate SIRT1 (activating its deacetylase function) and simultaneously acting as a kinase scaffold recruiting CK1ε to phosphorylate TDP-43 at pathological sites.\",\n      \"evidence\": \"Mass spectrometry interactome, reciprocal Co-IP, GADD34 KO MEFs, SIRT1 activity assays, TDP-43 S409/410 phosphorylation in KO vs WT cells\",\n      \"pmids\": [\"28984870\", \"29109149\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether GADD34-mediated TDP-43 phosphorylation contributes to ALS/FTLD pathology in vivo not tested\", \"Structural basis for dual phosphatase/kinase scaffold switching unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"TFEB was identified as a direct transcriptional activator of GADD34 during starvation, establishing that GADD34 integrates the mTORC1 and ISR pathways by dephosphorylating eIF2α to permit translation of the TFEB-driven lysosomal biogenesis program.\",\n      \"evidence\": \"GADD34 KO cells, TFEB ChIP and reporter assays, eIF2α phosphorylation and autophagic flux measurements\",\n      \"pmids\": [\"32978159\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether other transcription factors cooperate with TFEB at the GADD34 promoter not examined\", \"Quantitative contribution of TFEB vs ATF4 to GADD34 induction during starvation unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Post-transcriptional regulation of GADD34 was shown to involve ZFP36-family-mediated recognition of an ARE in the 3′ UTR, promoting rapid mRNA decay basally and stabilization during stress, functioning as a mechanism of ISR memory that tunes stress responsiveness.\",\n      \"evidence\": \"3′ UTR reporter assays, ZFP36 protein binding assays, mRNA stability measurements, repeated stress-exposure ISR memory experiments\",\n      \"pmids\": [\"38602876\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of kinase(s) that inactivate ZFP36 to allow GADD34 mRNA stabilization not determined\", \"Whether ARE-mediated regulation differs across cell types not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A full atomic-resolution structure of the ternary GADD34–PP1–eIF2α complex is lacking, the E3 ligase(s) responsible for GADD34 ubiquitination remain unidentified, and whether GADD34's kinase-scaffold function (CK1ε–TDP-43) contributes to neurodegenerative disease in vivo has not been tested.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No ternary complex structure available\", \"E3 ubiquitin ligase for GADD34 degradation unknown\", \"In vivo disease relevance of GADD34-mediated TDP-43 phosphorylation untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 5, 6, 7]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 4, 15, 18, 19]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [2, 10]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [18, 19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 3, 5, 6, 11, 12]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 12, 33]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [14, 15]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [17, 27]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 16]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [3, 9, 10]}\n    ],\n    \"complexes\": [\n      \"GADD34–PP1c holophosphatase\",\n      \"Smad7–GADD34–PP1c complex\",\n      \"GADD34–PP1–TAK1 complex\"\n    ],\n    \"partners\": [\n      \"PPP1CA\",\n      \"EIF2S1\",\n      \"SMAD7\",\n      \"MAP3K7\",\n      \"TSC2\",\n      \"SIRT1\",\n      \"CSNK1E\",\n      \"TARDBP\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}