Affinage

ATF2

Cyclic AMP-dependent transcription factor ATF-2 · UniProt P15336

Length
505 aa
Mass
54.5 kDa
Annotated
2026-06-09
100 papers in source corpus 35 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ATF2 is a basic-leucine-zipper transcription factor that binds CRE/ATF DNA elements as homodimers or as heterodimers with Jun-family partners, integrating stress signaling into transcriptional programs governing differentiation, apoptosis, metabolism, and tumor suppression (PMID:2529117, PMID:2139203). Its transactivation domain is the convergence point of stress-activated kinases: JNK phosphorylates Thr69, Thr71, and Ser90, with p38 partially substituting at Thr69/71 and JNK uniquely targeting Ser90 (PMID:7824938, PMID:15304344), while ERK1/2 and MSK1 additionally phosphorylate Thr71 (PMID:15192015); structural analysis shows JNK and p38 dock at distinct sites on the TAD arranged to maximize co-regulation, with a JNK-specific site diminishing p38 binding (PMID:33188182). VRK1 phosphorylates Thr73/Ser62 to stabilize and accumulate nuclear ATF2 (PMID:15105425). DNA binding specificity and activity are tuned by partner choice: Jun heterodimerization confers cooperative CRE binding and nuclear retention required for transactivation (PMID:2139203, PMID:16511568), and ATF2 cooperates with cell-type-specific factors such as MafA/Pdx1/Beta2 at the insulin promoter and c-Jun at the C/EBPβ promoter (PMID:21278380, PMID:12215258). ATF2 also functions independently of transcription: following ionizing radiation, ATM phosphorylates Ser490/498 to recruit ATF2 to DNA-damage foci where it promotes MRN assembly and S-phase checkpoint signaling (PMID:15916964), and it controls TIP60 stability and ATM activation via Cul3 (PMID:18397884). Subcellular localization, governed by PKCε phosphorylation, dictates opposing outcomes—nuclear ATF2 drives transcriptional repression of targets including FUK, IFNβ1, and MITF (via SOX10), whereas mitochondrial/cytosolic ATF2 perturbs the HK1-VDAC1 complex to trigger apoptosis (PMID:22685333, PMID:26645581, PMID:21203491, PMID:25852302). In vivo, ATF2 acts as a tumor suppressor in keratinocytes and liver (PMID:18227516, PMID:25456131) and supports thermogenic gene expression in brown adipose tissue through the scaffold p62 (PMID:32385399). Protein abundance is set by ubiquitin-proteasome degradation involving hUBC9 and the SPOP-CUL3-RBX1 E3 ligase complex (PMID:9488727, PMID:29996942).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1989 High

    Established the founding biochemical identity of ATF2 as a leucine-zipper DNA-binding protein, defining how it recognizes its genomic targets.

    Evidence Expression cloning with multimerized CRE and DNA-binding assays on somatostatin, fibronectin, and E4 promoters

    PMID:2529117

    Open questions at the time
    • Did not define activating signals or dimerization partners
    • No functional readout beyond DNA binding
  2. 1990 High

    Showed ATF2's DNA-binding specificity is determined combinatorially through dimerization, answering how its target repertoire is diversified.

    Evidence Biotinylated Jun pulldown of cDNA library plus dimerization/DNA-binding assays

    PMID:2139203

    Open questions at the time
    • Functional transcriptional consequences of heterodimers not yet established
    • Restriction to Jun-not-Fos partnering mechanism not structurally explained
  3. 1992 High

    Linked ATF2 to growth-control machinery by showing it mediates pRb-dependent transactivation, expanding its role beyond cAMP signaling.

    Evidence High-affinity site mapping in TGF-β2 promoter, GAL4-ATF2 fusion reporter, and co-IP of ATF2 with pRb

    PMID:1641004

    Open questions at the time
    • Mechanism of pRb-ATF2 functional cooperation not detailed
    • Physiological contexts of the interaction unexplored
  4. 1995 High

    Defined the activating event for ATF2 by identifying JNK phosphorylation of Thr69/Thr71 in the activation domain as required for transcriptional activity.

    Evidence In vitro kinase assay, Thr→Ala mutagenesis, dominant-negative JNK, and reporter assays

    PMID:7824938

    Open questions at the time
    • Did not address redundancy with other MAPKs
    • Structural basis of kinase recognition unknown
  5. 1998 Medium

    Identified that ATF2 abundance is controlled by ubiquitin-proteasome degradation, introducing protein turnover as a regulatory layer.

    Evidence Yeast two-hybrid, Far Western, in vivo/in vitro ubiquitination assays, proteasome inhibition in activated T cells

    PMID:9488727

    Open questions at the time
    • E3 ligase responsible not identified
    • Link between phosphorylation and degradation timing not resolved
  6. 2004 High

    Refined the kinase logic of ATF2 activation, establishing JNK as primary with p38 partial redundancy at Thr69/71 and exclusive JNK control of Ser90, and broadening the spectrum to ERK/MSK1.

    Evidence JNK-null fibroblasts with pharmacological inhibitors, phospho-site analysis; separate in vitro kinase/co-IP study with ERK/MSK1

    PMID:15192015 PMID:15304344

    Open questions at the time
    • Stimulus-specific kinase selection in vivo not fully mapped
    • Functional consequence of Ser90 phosphorylation alone unclear
  7. 2004 High

    Showed VRK1 phosphorylates ATF2 at Thr73/Ser62 to stabilize the protein, adding a nuclear kinase that controls ATF2 levels rather than only activity.

    Evidence In vitro kinase assay, K179E and T73A mutants, nuclear co-localization, reporter assays

    PMID:15105425

    Open questions at the time
    • Mechanism by which Thr73 phosphorylation prevents degradation not defined
    • Interplay with proteasomal turnover not resolved
  8. 2005 High

    Revealed a transcription-independent function for ATF2 in the DNA damage response, recasting it as an ATM effector in checkpoint control.

    Evidence Phospho-Ser490/498 antibodies, IRIF colocalization with γ-H2AX/MRN, siRNA checkpoint assays, domain mutants

    PMID:15916964

    Open questions at the time
    • Molecular basis of MRN recruitment by ATF2 not detailed
    • Relationship to its transcriptional pool unclear
  9. 2006 High

    Explained how ATF2 localization is set, showing nucleocytoplasmic shuttling via NES/NLS with Jun-dependent nuclear retention coupling dimerization to activity.

    Evidence NES/NLS mutagenesis, live imaging, BiFC, reporter assays in F9 differentiation/death models

    PMID:16511568

    Open questions at the time
    • Upstream control of the export machinery not defined
    • Did not address mitochondrial targeting
  10. 2008 Medium

    Connected ATF2 to chromatin-modifying control of the DNA damage response by showing it directs Cul3-dependent TIP60 degradation, thereby tuning ATM activation.

    Evidence siRNA, co-IP, ChIP, Western blots for TIP60 stability and ATM activity

    PMID:18397884

    Open questions at the time
    • Direct E3 role of ATF2 versus adaptor role unclear
    • Stoichiometry on chromatin not quantified
  11. 2008 High

    Demonstrated nuclear ATF2 is a tumor suppressor in skin, establishing an in vivo loss-of-function phenotype tied to defined downstream effectors.

    Evidence Keratinocyte-specific conditional knockout, DMBA/TPA carcinogenesis, target Western blots

    PMID:18227516

    Open questions at the time
    • Direct transcriptional targets driving suppression not all defined
    • Tissue specificity of the tumor-suppressor role unexplored
  12. 2009 High

    Defined the c-Jun/ATF2 heterodimer as a pro-apoptotic effector in neurons and showed c-Fos antagonizes its assembly, clarifying partner-dependent outcomes.

    Evidence BiFC in living neurons, dominant-negative mutants, shRNA, decoy oligos, ChIP

    PMID:19255142

    Open questions at the time
    • Target genes mediating apoptosis not fully enumerated
    • Generality beyond neurons unclear
  13. 2012 Medium

    Unified ATF2's opposing functions under PKCε-controlled localization, positing it as the master switch between nuclear transcription and cytosolic/mitochondrial death.

    Evidence Fractionation, live imaging, mitochondrial membrane potential assays, PKCε perturbation (review synthesizing experiments)

    PMID:22685333

    Open questions at the time
    • Direct PKCε phospho-sites and their localization effect summarized from prior work
    • Quantitative threshold separating fates not defined
  14. 2015 Medium

    Provided mechanistic detail for cytosolic ATF2-driven apoptosis, showing it perturbs the HK1-VDAC1 complex upstream of Bim to permeabilize mitochondria.

    Evidence Co-IP with HK1/VDAC1, conformational Bim Western, sequential siRNA epistasis, xenograft

    PMID:25852302

    Open questions at the time
    • How ATF2 physically engages HK1-VDAC1 not structurally defined
    • Trigger for mitochondrial import not resolved
  15. 2015 High

    Established PKCε→ATF2 as a transcriptional repression axis in melanoma, repressing FUK to alter fucosylation/metastasis and repressing IFNβ1 to confer chemoresistance.

    Evidence ChIP at FUK/IFNβ1 promoters, PKCε phospho-mutants, knockdowns, in vivo isograft with dietary fucose; patient tissue correlation

    PMID:25728676 PMID:26645581

    Open questions at the time
    • Repressive co-factors at these promoters not all identified
    • Switch between activator and repressor roles not mechanistically resolved
  16. 2018 Medium

    Identified the SPOP-CUL3-RBX1 complex as the E3 ligase degrading ATF2 via Ser/Thr-rich degrons, linking ATF2 turnover to cancer-associated SPOP mutations.

    Evidence Yeast two-hybrid, co-IP, ubiquitination/stability Westerns, migration assays with SPOP mutants

    PMID:29996942

    Open questions at the time
    • Interplay with hUBC9-mediated ubiquitination unclear
    • Phospho-dependence of degron recognition not fully mapped
  17. 2020 High

    Resolved the structural basis of dual MAPK control, showing JNK and p38 dock at distinct TAD sites whose arrangement maximizes co-regulation and tunes vertebrate JNK/p38 sensitivity.

    Evidence Crystal structures of MAPK-TAD complexes, mechanistic modeling, docking-site mutagenesis, in-cell phosphorylation

    PMID:33188182

    Open questions at the time
    • Functional output of differential JNK/p38 sensitivity in vivo not measured
    • Integration with ERK/MSK1/VRK1 inputs not modeled
  18. 2020 High

    Showed ATF2 requires the scaffold p62 for genomic binding at thermogenic loci, linking ATF2 to brown-fat metabolic control and obesity resistance.

    Evidence Co-IP, ChIP at Ucp1/Pgc-1α, p62 domain-deletion and conditional knockout mice

    PMID:32385399

    Open questions at the time
    • How p62 enables chromatin engagement mechanistically unclear
    • Generality to other ATF2 target loci untested
  19. 2022 Medium

    Demonstrated direct ATF2 repression of TROP2 controls adhesion and invasion in colorectal cancer, extending its repressor tumor-suppressive program.

    Evidence CRISPR/Cas9 knockout, ChIP at TROP2 promoter, NanoString, migration assays, mouse and chicken xenografts

    PMID:35838828

    Open questions at the time
    • Co-repressors at the TROP2 promoter not identified
    • Signal directing ATF2 to repress this locus unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple ATF2 phospho-inputs (JNK/p38/ERK/MSK1/VRK1/PKCε/ATM) are integrated to select among transcriptional activation, repression, DNA-damage signaling, and apoptosis in a given cell remains unresolved.
  • No unified model linking specific phospho-codes to specific localization and target outcomes
  • Quantitative relationship between PKCε levels, localization, and fate not established
  • Direct co-regulators distinguishing activator vs repressor states not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 8 GO:0003677 DNA binding 5 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 3 GO:0000228 nuclear chromosome 2 GO:0005739 mitochondrion 2
Pathway
R-HSA-74160 Gene expression (Transcription) 6 R-HSA-162582 Signal Transduction 4 R-HSA-392499 Metabolism of proteins 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-73894 DNA Repair 2
Partners
JUNMAPK8PKM2RB1SPOPSQSTM1TIP60VRK1
Complex memberships
SPOP-CUL3-RBX1 E3 ubiquitin ligase complex

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 ATF2 is phosphorylated by JNK on two closely spaced threonine residues (Thr69 and Thr71) within its NH2-terminal activation domain; replacement of these sites with alanine inhibited ATF2 transcriptional activity, and dominant-negative JNK inhibited ATF2 transcriptional activity. In vitro kinase assay, site-directed mutagenesis (Thr→Ala substitutions), transcriptional reporter assays, dominant-negative JNK expression Science High 7824938
1989 CRE-BP1 (ATF2) contains a leucine zipper dimerization motif at its carboxy terminus and binds as a protein to cAMP response elements (CRE) of the somatostatin, fibronectin, and adenovirus E4 genes. Lambda gt11 library screening with multimerized CRE, E. coli expression of CRE-BP1, DNA-binding assay The EMBO journal High 2529117
1990 ATF2 (CRE-BP1) forms homodimers that bind CRE and also forms heterodimers with Jun (but not Fos) via its leucine zipper; Jun binds cooperatively to CRE in association with CRE-BP1, demonstrating that the DNA-binding specificity of Jun is modulated by its dimerization partner. Biotinylated Jun polypeptide pulldown screening of lambda gt11 cDNA library, DNA-binding/dimerization assays Oncogene High 2139203
1992 ATF2 binds the ATF site in the TGF-β2 promoter with high affinity; a GAL4-ATF2 fusion protein supports pRb-mediated transcriptional activation, and ATF2 in nuclear extracts physically interacts with the retinoblastoma protein (pRb), mediating pRb-dependent transcriptional activation of TGF-β2. DNA-binding assay (high-affinity site identification), GAL4 fusion transcriptional assay, co-immunoprecipitation of ATF2 with pRb from nuclear extracts Nature High 1641004
1991 ATF2 (CRE-BP1) mediates E1A-induced transactivation; the N-terminal portion of CRE-BP1 containing the putative metal finger structure is essential (but not sufficient) for this activation, demonstrated using a c-Myb-CRE-BP1 fusion protein. c-Myb-CRE-BP1 fusion protein expression, transient transfection/transcriptional reporter assay, deletion mutagenesis Oncogene Medium 1827668
2005 ATM phosphorylates ATF2 on serines 490 and 498 following ionizing radiation (IR); this phosphorylation causes ATF2 to rapidly colocalize with γ-H2AX and MRN components into IR-induced foci (IRIF). Inhibition of ATF2 expression decreased Mre11 recruitment to IRIF, abrogated S-phase checkpoint, and reduced ATM, Chk1, and Chk2 activation. ATF2 requires neither JNK/p38 nor its DNA-binding domain for IRIF recruitment. Phospho-specific antibodies, immunofluorescence colocalization, siRNA knockdown with checkpoint/S-phase assays, domain mutant analysis Molecular cell High 15916964
2008 ATF2 promotes degradation of the histone acetyltransferase TIP60 in cooperation with Cul3 ubiquitin ligase under non-stressed conditions; ATF2 association with TIP60 on chromatin decreases after ionizing radiation, stabilizing TIP60 and increasing ATM activation. Inhibition of ATF2 expression restored TIP60 levels and both basal and IR-induced ATM activity. siRNA knockdown, co-immunoprecipitation, chromatin immunoprecipitation, Western blot for TIP60 stability and ATM activation The Journal of biological chemistry Medium 18397884
2004 VRK1 (vaccinia-related kinase 1) phosphorylates ATF2 primarily on Thr-73 (and Ser-62) in the nucleus, stabilizing ATF2 protein and increasing its intracellular level. VRK1 and JNK have additive effects on ATF2-dependent transcription. Loss of VRK1 kinase activity (K179E mutant) or T73A substitution in ATF2 prevents ATF2 accumulation and transcriptional activation. In vitro kinase assay, mutagenesis (K179E, T73A substitutions), nuclear co-localization by immunofluorescence, functional transcriptional reporter assay The Journal of biological chemistry High 15105425
2004 JNK is the primary kinase phosphorylating ATF2 at Thr69, Thr71, and Ser90 in cells. In JNK-deficient fibroblasts, p38 MAPK can partially substitute for JNK at Thr69 and Thr71, but JNK is the only MAP kinase that phosphorylates Ser90 under conditions examined. Transformed fibroblasts from JNK1/2-deficient mice, pharmacological inhibitors of p38 and ERK, phospho-site-specific analysis FEBS letters High 15304344
2006 ATF2 contains a nuclear export signal (NES) in its leucine zipper region and two nuclear localization signals (NLS) in its basic region, enabling continuous nucleocytoplasmic shuttling. Dimerization with c-Jun in the nucleus prevents ATF2 export and is essential for transcriptional activation of the c-jun promoter; c-Jun-dependent nuclear retention of ATF2 occurs during retinoic acid-induced differentiation and UV-induced cell death. Identification of NES/NLS by mutagenesis, live-cell imaging, transcriptional reporter assay, bimolecular fluorescence complementation, F9 cell differentiation/death models The EMBO journal High 16511568
2012 ATF2 subcellular localization controls its opposing functions: in the nucleus it contributes to transcription and DNA damage response, while translocation to the cytosol following severe genotoxic stress impairs mitochondrial membrane potential and promotes mitochondrial-based cell death. PKCε phosphorylation of ATF2 is the master switch controlling its subcellular localization. Subcellular fractionation, live imaging, mitochondrial membrane potential assays, PKCε knockdown/overexpression, phospho-ATF2 analysis Journal of cell science Medium 22685333
1998 ATF2 is ubiquitinated in vivo and in vitro; ubiquitination in vitro is facilitated by the ubiquitin-conjugating enzyme hUBC9. ATF2 undergoes proteasome-dependent proteolysis, regulated upon T cell activation concomitant with induction of ATF2 phosphorylation. Yeast two-hybrid (ATF2 as bait), Far Western blot (in vitro binding), in vivo and in vitro ubiquitination assays, proteasome inhibitor treatment The Journal of biological chemistry Medium 9488727
2018 SPOP recognizes multiple Ser/Thr-rich degrons in ATF2 and promotes ATF2 ubiquitination and degradation via the SPOP-CUL3-RBX1 E3 ubiquitin ligase complex. Prostate cancer-associated SPOP mutants are defective in promoting ATF2 degradation. Yeast two-hybrid screen, co-immunoprecipitation, Western blot for ubiquitination and protein stability, cell migration/invasion assays with SPOP mutants Journal of experimental & clinical cancer research Medium 29996942
2003 Amino acid starvation-induced transcription of CHOP requires both ATF4 expression and ATF2 phosphorylation. ATF2 binds the amino acid response element (AARE) of the CHOP gene; inhibition of ATF2 expression impairs CHOP transcriptional activation by leucine starvation. ATF4 and ATF2 act in two distinct pathways converging on the AARE. EMSA (electrophoretic mobility shift assay), transient transfection/reporter assays, ATF2/ATF4 siRNA knockdown The Journal of biological chemistry Medium 14630918
2004 Syndecan-4 regulates ATF2 transcriptional activity in a Rac1-dependent manner: syndecan-4-null fibroblasts show elevated Rac1 activity leading to increased p38 MAPK and JNK activation and consequently higher ATF2 phosphorylation and transcriptional activity; re-expression of syndecan-4 or dominant-negative Rac1 (RacN17) abolishes these effects. Syndecan-4-null fibroblasts, dominant-negative Rac1 expression, p38/JNK activity assays, ATF2 phosphorylation and transcriptional reporter assays The Journal of biological chemistry Medium 15371457
2009 c-Jun predominantly heterodimerizes with ATF2 in neurons, and the c-Jun/ATF2 complex promotes apoptosis by triggering ATF activity. Inhibition of c-Jun/ATF2 heterodimerization using dominant negative mutants, shRNAs, or decoy oligonucleotides rescues neurons from apoptosis. c-Fos downregulation facilitates c-Jun/ATF2 heterodimerization, and c-Fos expression prevents c-Jun/ATF2 binding to ATF sites and suppresses their target gene expression. Bimolecular fluorescence complementation (BiFC) in living neurons, dominant-negative mutants, shRNA knockdown, decoy oligonucleotides, chromatin immunoprecipitation (ChIP) Molecular and cellular biology High 19255142
2010 ATF2 directly binds to the Hes-1 promoter (downstream of FGF2 signaling via JNK) in neural progenitors, maintaining Hes-1 expression independently of canonical Notch/CBF1 signaling, thereby maintaining a pool of proliferating neural progenitors. Chromatin immunoprecipitation (ChIP) demonstrating ATF2 binding to Hes-1 promoter, transcriptional reporter assays, siRNA knockdown Journal of neurochemistry Medium 20067572
2011 ATF2 forms a complex with beta-cell-enriched transcription factors MafA, Pdx1, and Beta2; ATF2 alone cannot bind the C1/RIPE3b insulin promoter element but acquires binding capacity upon complex formation with MafA. Co-expression of ATF2, MafA, Pdx1, and Beta2 synergistically activates the insulin promoter; RNAi knockdown of ATF2 in MIN6 cells decreases endogenous insulin mRNA levels. EMSA, co-immunoprecipitation, transient transfection/reporter assay, RNAi knockdown, immunohistochemistry The Journal of biological chemistry Medium 21278380
2011 Neuron-specific inactivation of ATF2 in mouse embryos leads to caspase-dependent and -independent death of motoneurons in the brainstem (hypoglossal, abducens, and facial nuclei), correlating with increased levels of stress-activated MAP kinases JNK and p38 and aberrant accumulation of phosphorylated neurofilament proteins. Conditional ATF2 knockout (neuron-specific), histological analysis, immunostaining for activated caspases, JNK/p38 phosphorylation, and phospho-neurofilament PloS one Medium 21533046
2008 ATF2 selectively deleted in mouse keratinocytes (K14.ATF2f/f) results in increased papilloma formation after DMBA/TPA carcinogenesis, with reduced presenilin1 expression, enhanced β-catenin and cyclin D1, and reduced Notch1, establishing a tumor suppressor role for nuclear ATF2 in skin. Conditional keratinocyte-specific ATF2 knockout (K14-Cre), two-stage chemical carcinogenesis, anchorage-independent growth assays, Western blot for downstream targets Proceedings of the National Academy of Sciences of the United States of America High 18227516
2010 ATF2 transcriptional activity suppresses MITF expression through ATF2-JunB-dependent repression of SOX10 transcription in melanocytes. Reduction of MITF by ATF2 was confirmed in Atf2-/- mice skin and in primary human melanocytes. Gene expression profiling, ChIP, melanocyte-specific ATF2 mutant mouse crossed with melanoma model, shRNA knockdown PLoS genetics Medium 21203491
2015 PKCε-dependent phosphorylation of ATF2 promotes transcriptional repression of the fucokinase (FUK) gene, suppressing global cellular protein fucosylation and promoting melanoma cell migration and invasion. In advanced-stage melanomas, increased PKCε expression leads to phosphorylated ATF2, decreased FUK expression and fucosylation, and increased metastasis. ChIP for ATF2 at FUK promoter, siRNA/shRNA knockdown, overexpression of PKCε phospho-mutants of ATF2, in vivo murine isograft models with dietary fucose supplementation and Fuk genetic manipulation Science signaling High 26645581
2015 PKCε-mediated ATF2 activation transcriptionally represses IFNβ1 expression in melanoma; this repression mechanism confers resistance to chemotherapy. Cytosolic ATF2 (associated with low PKCε) is correlated with IFNβ1 induction and therapeutic responsiveness, while nuclear ATF2 (high PKCε) suppresses IFNβ1 and correlates with chemotherapy resistance. ChIP for ATF2 binding to IFNβ1 promoter, PKCε overexpression/knockdown, chemotherapy treatment experiments, melanoma cell line and tissue microarray analysis Oncogene Medium 25728676
2014 JNK-mediated phosphorylation of ATF2 activates a transcriptional program that suppresses tumor formation; ATF2 is required for JNK-mediated suppression of tumorigenesis in an orthotopic liver cancer model. ATF2-dependent gene expression is frequently downregulated in human cancers. Orthotopic liver cancer model, ATF2 loss-of-function, gene expression profiling for ATF2-dependent transcriptional program, in vitro transformation assays Cell reports Medium 25456131
2020 The ATF2 transactivation domain (TAD) is co-regulated by JNK and p38 through structurally distinct MAPK binding sites. JNK-mediated phosphorylation at an evolutionarily more recent site diminishes p38 binding, making the ATF2 phosphoswitch differentially sensitive to JNK vs. p38 in vertebrates. MAPK-TAD complex structures were determined and mechanistic modeling confirmed that kinase binding motifs and phosphorylation sites are arranged to maximize co-regulation. Crystal/structural determination of MAPK-TAD complexes, mechanistic modeling of ATF2 TAD phosphorylation in cells, mutagenesis of MAPK docking sites, in-cell phosphorylation assays Nature communications High 33188182
2020 The scaffold protein p62 (SQSTM1) binds to ATF2 and is required for ATF2 genomic binding at the Ucp1 enhancer and Pgc-1α promoter in brown adipose tissue (BAT) during β-adrenergic stimulation. p62-deficient mice show reduced ATF2-dependent Ucp1 and Pgc-1α expression, BAT dysfunction, and subsequent obesity despite normal food intake. Co-immunoprecipitation of p62-ATF2, ChIP for ATF2 genomic binding, p62Δ69-251 and p62-/- and BAT-specific p62 conditional knockout mice, gene expression analysis Nature communications High 32385399
2021 PKM2 directly interacts with ATF2 in microglia (identified by mass spectrometry and co-immunoprecipitation). Nuclear translocation of PKM2 promotes ATF2 phosphorylation and activation, linking glycolysis (Warburg effect) to ATF2-mediated pyroptosis in neuroinflammation. Silencing ATF2 reduces LPS-induced pyroptosis. Biological mass spectrometry, co-immunoprecipitation, PKM2 nuclear translocation inhibition (TEPP-46), ATF2 knockdown, LPS neuroinflammation model in vivo and in vitro Molecular immunology Medium 34798593
2004 UVC-stimulated phosphorylation of ATF2 at Thr71 is mediated by ERK1, ERK2, and MSK1 (in addition to p38 and JNK2), as shown by in vitro kinase assays with purified kinases and dominant-negative kinase mutants. Co-immunoprecipitation revealed an intracellular signaling complex containing ATF2, ERKs, and/or MSK1. In vitro kinase assays, dominant-negative kinase mutants (p38β, JNK1, ERK2, MSK1), pharmacological inhibitors (PD98059, H89), co-immunoprecipitation Carcinogenesis Medium 15192015
2002 ATF2 and c-Jun activate the C/EBPβ gene cooperatively through binding to URE2 and URE4 elements in the C/EBPβ promoter. Recombinant ATF2 and c-Jun proteins directly bind URE2 and URE4 in vitro; cotransfection shows cooperative transcriptional activation that is enhanced by anisomycin-induced phosphorylation. DNase I footprinting, EMSA with supershift, recombinant protein binding assays, cotransfection/reporter assays DNA and cell biology Medium 12215258
2015 ATF2 mitochondrial accumulation following genotoxic stress perturbs the HK1-VDAC1 complex, increases mitochondrial permeability, and promotes apoptosis. ATF2 acts upstream of Bim in this pathway: ATF2 inhibition reduces Bim conformational activation, and Bim knockdown abolishes VDAC1 activation but does not affect ATF2 activation. Co-immunoprecipitation of ATF2 with HK1/VDAC1, Western blot for conformational Bim, siRNA knockdown of ATF2 and Bim, flow cytometry apoptosis assay, xenograft in vivo model Cancer cell international Medium 25852302
2020 ATF2 inhibits BET inhibitor-induced ferroptosis by transcriptionally upregulating NRF2 expression; in NRF2-depleted cells, ATF2 cannot attenuate BETi-stimulated ferroptosis, placing NRF2 downstream of ATF2 in this pathway. BET inhibitors activate ATF2 through the JNK1/2 pathway. ATF2 overexpression/knockdown, NRF2 siRNA knockdown, measurement of ferroptosis markers (oxidized glutathione, MDA, lipid ROS), Western blot, xenograft mouse model Biochemical and biophysical research communications Medium 33008584
2022 ATF2 directly represses TROP2 gene transcription in colorectal cancer cells, as confirmed by NanoString gene expression and ChIP analysis. Loss of ATF2 (CRISPR/Cas9 KO) leads to high TROP2 expression, increased cell de-adhesion and migration, and enhanced tumor invasiveness in vivo (mouse and chicken xenograft models), without triggering EMT. CRISPR/Cas9 ATF2 knockout, ChIP for ATF2 at TROP2 promoter, NanoString gene expression, cell migration/invasion assays, in vivo mouse and chicken xenograft models Cellular and molecular life sciences Medium 35838828
2007 Drosophila ATF-2 (dATF-2) positively regulates PEPCK gene transcription via CRE half-sites in the PEPCK promoter in the fat body; dATF-2 knockdown reduces triglyceride stores and decreases glyceroneogenesis activity without major effect on blood sugar levels. RNAi knockdown in Drosophila fat body, PEPCK promoter reporter assay, triglyceride and glyceroneogenesis metabolic assays Molecular biology of the cell Medium 17314398
2007 ATF2 impairs glucocorticoid receptor-mediated transactivation in human CD8+ T cells. ATF2 expression is significantly lower in CD8+ than in CD4+ cells; siRNA-mediated inhibition of ATF2 in CD4+ cells inhibits dexamethasone-induced transactivation, identifying ATF2 as a histone acetyltransferase required for steroid-induced gene expression. siRNA knockdown of ATF2 in CD4+ T cells, dexamethasone-induced histone H4 acetylation assay, glucocorticoid receptor reporter assay, comparison of CD4+ vs. CD8+ T cells Blood Medium 17525285
2008 IRF2-BP1 (Interferon regulatory factor-2-binding protein-1) was isolated as a JDP2-binding protein; as anticipated from its RING-finger domain, IRF2-BP1 promotes polyubiquitination of JDP2 (an ATF2 dimerization partner) and represses ATF2-mediated transcriptional activation from a CRE-containing promoter. Epitope-tag pulldown (isolation of IRF2-BP1), polyubiquitination assay for JDP2, luciferase reporter assay for ATF2-mediated transcription FEBS letters Low 18671972

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 Transcription factor ATF2 regulation by the JNK signal transduction pathway. Science (New York, N.Y.) 1335 7824938
1995 Aplysia CREB2 represses long-term facilitation: relief of repression converts transient facilitation into long-term functional and structural change. Cell 469 8521521
1989 Leucine zipper structure of the protein CRE-BP1 binding to the cyclic AMP response element in brain. The EMBO journal 394 2529117
1992 Retinoblastoma gene product activates expression of the human TGF-beta 2 gene through transcription factor ATF-2. Nature 256 1641004
1990 Direct cloning of leucine zipper proteins: Jun binds cooperatively to the CRE with CRE-BP1. Oncogene 254 2139203
2003 Induction of CHOP expression by amino acid limitation requires both ATF4 expression and ATF2 phosphorylation. The Journal of biological chemistry 231 14630918
2000 The GABAB receptor interacts directly with the related transcription factors CREB2 and ATFx. Proceedings of the National Academy of Sciences of the United States of America 144 11087824
2005 ATM-dependent phosphorylation of ATF2 is required for the DNA damage response. Molecular cell 139 15916964
2010 Biochanin-A, an isoflavon, showed anti-proliferative and anti-inflammatory activities through the inhibition of iNOS expression, p38-MAPK and ATF-2 phosphorylation and blocking NFκB nuclear translocation. European journal of pharmacology 119 21147093
2017 ATF2, a paradigm of the multifaceted regulation of transcription factors in biology and disease. Pharmacological research 116 28212892
2000 Latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus (human herpesvirus-8) binds ATF4/CREB2 and inhibits its transcriptional activation activity. The Journal of general virology 104 11038375
2004 Human vaccinia-related kinase 1 (VRK1) activates the ATF2 transcriptional activity by novel phosphorylation on Thr-73 and Ser-62 and cooperates with JNK. The Journal of biological chemistry 103 15105425
2012 ATF2 - at the crossroad of nuclear and cytosolic functions. Journal of cell science 101 22685333
2008 The role of ATF-2 in oncogenesis. BioEssays : news and reviews in molecular, cellular and developmental biology 100 18348191
2006 Mutual regulation of c-Jun and ATF2 by transcriptional activation and subcellular localization. The EMBO journal 96 16511568
2008 ATF2: a transcription factor that elicits oncogenic or tumor suppressor activities. Cell cycle (Georgetown, Tex.) 88 18677098
2008 Importin-mediated retrograde transport of CREB2 from distal processes to the nucleus in neurons. Proceedings of the National Academy of Sciences of the United States of America 88 18957537
2005 TGF-beta1 induces cardiac hypertrophic responses via PKC-dependent ATF-2 activation. Journal of molecular and cellular cardiology 85 16125722
2007 ATF2 on the double - activating transcription factor and DNA damage response protein. Pigment cell research 81 17935492
2000 Janus kinase 2-dependent activation of p38 mitogen-activated protein kinase by growth hormone. Resultant transcriptional activation of ATF-2 and CHOP, cytoskeletal re-organization and mitogenesis. The Journal of biological chemistry 81 10636915
2008 Suppressor role of activating transcription factor 2 (ATF2) in skin cancer. Proceedings of the National Academy of Sciences of the United States of America 74 18227516
2009 Opposing roles for ATF2 and c-Fos in c-Jun-mediated neuronal apoptosis. Molecular and cellular biology 72 19255142
2004 Signalling pathways involved in multisite phosphorylation of the transcription factor ATF-2. FEBS letters 72 15304344
1998 ATF2 confers radiation resistance to human melanoma cells. Oncogene 72 9484842
2002 An ATF2-derived peptide sensitizes melanomas to apoptosis and inhibits their growth and metastasis. The Journal of clinical investigation 70 12208865
2018 miR-144-5p Enhances the Radiosensitivity of Non-Small-Cell Lung Cancer Cells via Targeting ATF2. BioMed research international 69 29850528
2018 MiR-451a suppressed cell migration and invasion in non-small cell lung cancer through targeting ATF2. European review for medical and pharmacological sciences 69 30229828
1991 Cyclic AMP response element-binding protein, CRE-BP1, mediates the E1A-induced but not the Tax-induced trans-activation. Oncogene 69 1827668
2010 Activating transcription factor 2 (ATF2) controls tolfenamic acid-induced ATF3 expression via MAP kinase pathways. Oncogene 68 20581861
2004 Hippocampal CREB1 but not CREB2 is decreased in aged rats with spatial memory impairments. Neurobiology of learning and memory 68 14670355
1998 Coordinate transactivation of the interleukin-2 CD28 response element by c-Rel and ATF-1/CREB2. The Journal of biological chemistry 67 9417115
2012 The roles of ATF2 (activating transcription factor 2) in tumorigenesis. Biochemical Society transactions 64 22260696
2005 cAMP-response elements in Aplysia creb1, creb2, and Ap-uch promoters: implications for feedback loops modulating long term memory. The Journal of biological chemistry 64 15888447
2017 Activation of the ATF2/CREB-PGC-1α pathway by metformin leads to dopaminergic neuroprotection. Oncotarget 61 28611284
2010 A role for ATF2 in regulating MITF and melanoma development. PLoS genetics 59 21203491
2007 ATF-2 regulates fat metabolism in Drosophila. Molecular biology of the cell 56 17314398
1997 Cell stress-induced phosphorylation of ATF2 and c-Jun transcription factors in rat ventricular myocytes. The Biochemical journal 56 9271103
2016 Resveratrol ameliorates benzo(a)pyrene-induced testicular dysfunction and apoptosis: involvement of p38 MAPK/ATF2/iNOS signaling. The Journal of nutritional biochemistry 55 27162022
2018 Hsa_circ_0001859 Regulates ATF2 Expression by Functioning as an MiR-204/211 Sponge in Human Rheumatoid Arthritis. Journal of immunology research 54 29577053
2019 TRAF6-p38/JNK-ATF2 axis promotes microglial inflammatory activation. Experimental cell research 52 30763583
2000 Enhancement of memory-related long-term facilitation by ApAF, a novel transcription factor that acts downstream from both CREB1 and CREB2. Cell 52 11106730
2018 SPOP promotes ATF2 ubiquitination and degradation to suppress prostate cancer progression. Journal of experimental & clinical cancer research : CR 50 29996942
2005 Role of basic region leucine zipper transcription factors cyclic AMP response element binding protein (CREB), CREB2, activating transcription factor 2 and CAAT/enhancer binding protein alpha in cyclic AMP response element-mediated transcription. Journal of neurochemistry 50 15663480
2008 Regulation of TIP60 by ATF2 modulates ATM activation. The Journal of biological chemistry 49 18397884
1998 Association of activating transcription factor 2 (ATF2) with the ubiquitin-conjugating enzyme hUBC9. Implication of the ubiquitin/proteasome pathway in regulation of ATF2 in T cells. The Journal of biological chemistry 49 9488727
1992 A cyclic AMP-responsive DNA-binding protein (CREB2) is a cellular transactivator of the bovine leukemia virus long terminal repeat. Journal of virology 49 1309910
2014 ATF2 contributes to cisplatin resistance in non-small cell lung cancer and celastrol induces cisplatin resensitization through inhibition of JNK/ATF2 pathway. International journal of cancer 48 25359574
2015 The transcription factor ATF2 promotes melanoma metastasis by suppressing protein fucosylation. Science signaling 47 26645581
2018 β-catenin-independent regulation of Wnt target genes by RoR2 and ATF2/ATF4 in colon cancer cells. Scientific reports 46 29453334
2020 Co-regulation of the transcription controlling ATF2 phosphoswitch by JNK and p38. Nature communications 45 33188182
2021 Pyruvate kinase M2 (PKM2) interacts with activating transcription factor 2 (ATF2) to bridge glycolysis and pyroptosis in microglia. Molecular immunology 43 34798593
2020 Exosomal microRNA-26b-5p down-regulates ATF2 to enhance radiosensitivity of lung adenocarcinoma cells. Journal of cellular and molecular medicine 39 32476275
2019 miR-141-5p regulate ATF2 via effecting MAPK1/ERK2 signaling to promote preeclampsia. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 39 31075732
2014 JNK suppresses tumor formation via a gene-expression program mediated by ATF2. Cell reports 38 25456131
2012 The atf2 gene is involved in triacylglycerol biosynthesis and accumulation in the oleaginous Rhodococcus opacus PD630. Applied microbiology and biotechnology 38 22926642
2016 miR-204 suppresses the development and progression of human glioblastoma by targeting ATF2. Oncotarget 37 27588402
2010 ATF2 maintains a subset of neural progenitors through CBF1/Notch independent Hes-1 expression and synergistically activates the expression of Hes-1 in Notch-dependent neural progenitors. Journal of neurochemistry 37 20067572
2008 The JNK/AP1/ATF2 pathway is involved in H2O2-induced acetylcholinesterase expression during apoptosis. Cellular and molecular life sciences : CMLS 37 18385943
2020 6'-O-galloylpaeoniflorin regulates proliferation and metastasis of non-small cell lung cancer through AMPK/miR-299-5p/ATF2 axis. Respiratory research 35 32014006
2016 miRNA-204 suppresses human non-small cell lung cancer by targeting ATF2. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 35 26935060
2013 Oxidative stress and MAPK involved into ATF2 expression in immortalized human urothelial cells treated by arsenic. Archives of toxicology 35 23591579
2002 Characterization and functional analysis of cAMP response element modulator protein and activating transcription factor 2 (ATF2) isoforms in the human myometrium during pregnancy and labor: identification of a novel ATF2 species with potent transactivation properties. The Journal of clinical endocrinology and metabolism 34 11932306
2017 MicroRNA-451 regulates chemoresistance in renal cell carcinoma by targeting ATF-2 gene. Experimental biology and medicine (Maywood, N.J.) 33 28429654
2011 Loss of ATF2 function leads to cranial motoneuron degeneration during embryonic mouse development. PloS one 33 21533046
2003 Production of isoamyl acetate in ackA-pta and/or ldh mutants of Escherichia coli with overexpression of yeast ATF2. Applied microbiology and biotechnology 32 14586577
1997 Activating transcription factor 2 (ATF2) down-regulates hepatitis B virus X promoter activity by the competition for the activating protein 1 binding site and the formation of the ATF2-Jun heterodimer. The Journal of biological chemistry 32 9202004
2023 Human umbilical cord mesenchymal stem cell-derived exosomes loaded miR-451a targets ATF2 to improve rheumatoid arthritis. International immunopharmacology 30 38104370
2020 circTNFRSF21, a newly identified circular RNA promotes endometrial carcinoma pathogenesis through regulating miR-1227-MAPK13/ATF2 axis. Aging 30 32299063
2011 ATF2 interacts with beta-cell-enriched transcription factors, MafA, Pdx1, and beta2, and activates insulin gene transcription. The Journal of biological chemistry 30 21278380
1999 Isolation and characterization of the ATF2 gene encoding alcohol acetyltransferase II in the bottom fermenting yeast Saccharomyces pastorianus. Yeast (Chichester, England) 30 10219999
1998 Expression of Jun, Fos, and ATF-2 proteins in axotomized explanted and cultured adult rat dorsal root ganglia. Neuroscience 29 9522371
2018 ATF2 promotes urothelial cancer outgrowth via cooperation with androgen receptor signaling. Endocrine connections 28 30521479
2015 cJun and CREB2 in the postsynaptic neuron contribute to persistent long-term facilitation at a behaviorally relevant synapse. The Journal of neuroscience : the official journal of the Society for Neuroscience 28 25568130
2014 Transcriptional regulation of STAT3 by SPTBN1 and SMAD3 in HCC through cAMP-response element-binding proteins ATF3 and CREB2. Carcinogenesis 28 25096061
2004 Syndecan-4 regulates ATF-2 transcriptional activity in a Rac1-dependent manner. The Journal of biological chemistry 28 15371457
2020 The scaffold protein p62 regulates adaptive thermogenesis through ATF2 nuclear target activation. Nature communications 27 32385399
2020 ATF2 inhibits ani-tumor effects of BET inhibitor in a negative feedback manner by attenuating ferroptosis. Biochemical and biophysical research communications 27 33008584
2018 Transcriptional activation of miR-320a by ATF2, ELK1 and YY1 induces cancer cell apoptosis under ionizing radiation conditions. International journal of oncology 27 30066913
2008 Overexpression of phosphorylated-ATF2 and STAT3 in cutaneous angiosarcoma and pyogenic granuloma. Journal of cutaneous pathology 27 18700251
2001 Modular structure of cAMP response element binding protein 2 (CREB2). Neurochemistry international 27 11290385
2022 GLUT3 Promotes Epithelial-Mesenchymal Transition via TGF-β/JNK/ATF2 Signaling Pathway in Colorectal Cancer Cells. Biomedicines 25 36009381
2017 The role of Nrf2 and ATF2 in resistance to platinum-based chemotherapy. Cancer chemotherapy and pharmacology 25 28120035
2022 ATF2 loss promotes tumor invasion in colorectal cancer cells via upregulation of cancer driver TROP2. Cellular and molecular life sciences : CMLS 24 35838828
2018 A CREB2-targeting microRNA is required for long-term memory after single-trial learning. Scientific reports 24 29500383
2007 ATF2 impairs glucocorticoid receptor-mediated transactivation in human CD8+ T cells. Blood 24 17525285
2021 Atorvastatin Attenuates Isoflurane-Induced Activation of ROS-p38MAPK/ATF2 Pathway, Neuronal Degeneration, and Cognitive Impairment of the Aged Mice. Frontiers in aging neuroscience 23 33519423
2013 ATF2 knockdown reinforces oxidative stress-induced apoptosis in TE7 cancer cells. Journal of cellular and molecular medicine 23 23800081
2022 Nuciferine attenuates lipopolysaccharide-stimulated inflammatory responses by inhibiting p38 MAPK/ATF2 signaling pathways. Inflammopharmacology 22 36219321
2024 MAP4K4 and WT1 mediate SOX6-induced cellular senescence by synergistically activating the ATF2-TGFβ2-Smad2/3 signaling pathway in cervical cancer. Molecular oncology 21 38383842
2017 Silencing of ATF2 inhibits growth of pancreatic cancer cells and enhances sensitivity to chemotherapy. Cell biology international 21 28318081
2008 IRF2-binding protein-1 is a JDP2 ubiquitin ligase and an inhibitor of ATF2-dependent transcription. FEBS letters 20 18671972
2020 ATF2 and ATF7 Are Critical Mediators of Intestinal Epithelial Repair. Cellular and molecular gastroenterology and hepatology 19 31958521
2015 Transcriptional repression of IFNβ1 by ATF2 confers melanoma resistance to therapy. Oncogene 19 25728676
2015 Bim and VDAC1 are hierarchically essential for mitochondrial ATF2 mediated cell death. Cancer cell international 19 25852302
2023 Inhibition of JNK/c-Jun-ATF2 Overcomes Cisplatin Resistance in Liver Cancer through down-Regulating Galectin-1. International journal of biological sciences 18 37215991
2020 The interplay between ATF2 and NEAT1 contributes to lung adenocarcinoma progression. Cancer cell international 18 33298086
2011 Serotonin- and training-induced dynamic regulation of CREB2 in Aplysia. Learning & memory (Cold Spring Harbor, N.Y.) 18 21441301
2002 Transcriptional activation of C/EBPbeta gene by c-Jun and ATF2. DNA and cell biology 18 12215258
1999 Nuclear targeting of cAMP response element binding protein 2 (CREB2). European journal of cell biology 18 10535306
2004 Involvement of ERKs and mitogen- and stress-activated protein kinase in UVC-induced phosphorylation of ATF2 in JB6 cells. Carcinogenesis 17 15192015

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