ATF2 (Activating Transcription Factor 2, also known as CRE-BP1 or CREB2) is a phosphorylation-regulated bZIP transcription factor of the ATF/CREB subfamily. It binds CRE (5'-TGACGTCA-3') and AP-1 (5'-TGACTCA-3') DNA elements as homodimers or heterodimers with JUN family members and other bZIP proteins. Its transcriptional activity is activated by MAPK-mediated phosphorylation at Thr-69/Thr-71 downstream of stress, cytokine, and growth factor signaling (JNK, p38, ERK). ATF2 possesses intrinsic histone acetyltransferase (HAT) activity toward histones H2B and H4, though the physiological significance of this activity has been debated. Beyond transcription, ATF2 participates in the DNA damage response through ATM-dependent phosphorylation at Ser-490/Ser-498, which recruits it to IR-induced foci independently of its DNA-binding domain. ATF2 subcellular localization is regulated by PKC-epsilon; under genotoxic stress, ATF2 can translocate to the mitochondrial outer membrane where it perturbs HK1-VDAC1 complexes to promote apoptosis. ATF2 regulates genes involved in stress response, cell proliferation, DNA repair, and redox homeostasis.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
|
GO:0000981
DNA-binding transcription factor activity, RNA polymerase II-specific
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: ATF2 is a well-established bZIP transcription factor that binds CRE and AP-1 elements to regulate RNA polymerase II-dependent transcription. This is a core function supported by extensive evidence (PMID:2529117, PMID:10821277, PMID:17267404).
Reason: Core molecular function of ATF2 as a sequence-specific DNA-binding transcription factor. IBA annotation is well supported phylogenetically and by extensive experimental literature.
|
|
GO:0006357
regulation of transcription by RNA polymerase II
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: ATF2 regulates transcription by RNA polymerase II through binding CRE/AP-1 elements as homo- or heterodimers with JUN family proteins. This is a core biological process (PMID:17267404, PMID:10821277).
Reason: Core biological process for ATF2. Well established by multiple experimental studies.
|
|
GO:0035497
cAMP response element binding
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: ATF2 (also known as CRE-BP1) was originally identified by its ability to bind CRE elements (5-prime-TGACGTCA-3-prime). This is a defining feature of the protein (PMID:2529117, PMID:19861239).
Reason: Core molecular function. ATF2 was named CRE-BP1 precisely because of its CRE-binding activity. IBA is at the right level of specificity.
|
|
GO:0003677
DNA binding
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: ATF2 is a bZIP transcription factor with well-documented DNA binding activity to CRE and AP-1 elements. This IEA is correct but more general than the IBA for cAMP response element binding (GO:0035497).
Reason: Correct but general. More specific terms (GO:0035497 cAMP response element binding) are also annotated. Acceptable as a broader IEA.
|
|
GO:0003700
DNA-binding transcription factor activity
|
IEA
GO_REF:0000002 |
ACCEPT |
Summary: ATF2 is a DNA-binding transcription factor. IEA from InterPro mapping. More specific IBA term (GO:0000981) is also annotated.
Reason: Correct but less specific than GO:0000981. Acceptable as broader IEA.
|
|
GO:0005634
nucleus
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: ATF2 is primarily nuclear as expected for a transcription factor. UniProt confirms nuclear localization (PMID:15105425, PMID:22304920). Also demonstrated by IDA evidence.
Reason: Correct. ATF2 is primarily localized to the nucleus, consistent with its role as a transcription factor.
|
|
GO:0005737
cytoplasm
|
IEA
GO_REF:0000044 |
ACCEPT |
Summary: ATF2 can localize to the cytoplasm under stress conditions and in disease states. PKC-epsilon directs ATF2 nuclear localization; genotoxic stress enables nuclear export and mitochondrial localization (PMID:22304920).
Reason: Correct. UniProt and experimental evidence confirm cytoplasmic localization under specific conditions.
|
|
GO:0005741
mitochondrial outer membrane
|
IEA
GO_REF:0000044 |
ACCEPT |
Summary: ATF2 localizes to the mitochondrial outer membrane under genotoxic stress, where it perturbs HK1-VDAC1 complexes and promotes apoptosis (PMID:22304920).
Reason: Correct. Lau et al. 2012 in Cell demonstrated ATF2 mitochondrial outer membrane localization and its functional consequence.
|
|
GO:0006355
regulation of DNA-templated transcription
|
IEA
GO_REF:0000002 |
ACCEPT |
Summary: ATF2 regulates DNA-templated transcription. IEA from InterPro. More specific term GO:0006357 (regulation of transcription by RNAPII) also annotated.
Reason: Correct but general. Acceptable as broader IEA alongside more specific terms.
|
|
GO:0006974
DNA damage response
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: ATF2 participates in DNA damage response through ATM-dependent phosphorylation at Ser-490/Ser-498, recruiting to IR-induced foci and activating the intra-S checkpoint (PMID:15916964).
Reason: Correct. ATF2 role in DDR is well established by experimental evidence from Bhoumik et al. 2005.
|
|
GO:0008270
zinc ion binding
|
IEA
GO_REF:0000043 |
ACCEPT |
Summary: ATF2 has a C2H2-type zinc finger domain at residues 25-49 (UniProt FT record). Zinc ion binding is expected from this domain.
Reason: Correct. ATF2 contains a well-annotated C2H2-type zinc finger domain that requires zinc ion coordination.
|
|
GO:0046872
metal ion binding
|
IEA
GO_REF:0000043 |
ACCEPT |
Summary: ATF2 binds metal ions through its C2H2-type zinc finger domain. This is a parent term of zinc ion binding.
Reason: Correct but very general parent of GO:0008270. Acceptable as IEA.
|
|
GO:0005515
protein binding
|
IPI
PMID:10327051 The N-terminal transactivation domain of ATF2 is a target fo... |
MARK AS OVER ANNOTATED |
Summary: Protein binding annotation from PMID:10327051. ATF2 interacts with numerous partners including JUN family, FOS family, ATF family, SMAD proteins, and others (UniProt lists >30 interaction partners). However, "protein binding" is uninformative.
Reason: GO:0005515 (protein binding) is too vague to be informative for ATF2. More specific interaction terms such as leucine zipper domain binding (GO:0043522), protein heterodimerization activity (GO:0046982), or specific binding activities should be used instead.
Supporting Evidence:
PMID:10327051
The N-terminal transactivation domain of ATF2 is a target for the co-operative activation of the c-jun promoter by p300 and 12S E1A.
|
|
GO:0005515
protein binding
|
IPI
PMID:15105425 Human vaccinia-related kinase 1 (VRK1) activates the ATF2 tr... |
MARK AS OVER ANNOTATED |
Summary: Protein binding annotation from PMID:15105425. ATF2 interacts with numerous partners including JUN family, FOS family, ATF family, SMAD proteins, and others (UniProt lists >30 interaction partners). However, "protein binding" is uninformative.
Reason: GO:0005515 (protein binding) is too vague to be informative for ATF2. More specific interaction terms such as leucine zipper domain binding (GO:0043522), protein heterodimerization activity (GO:0046982), or specific binding activities should be used instead.
Supporting Evidence:
PMID:15105425
2004 Apr 21. Human vaccinia-related kinase 1 (VRK1) activates the ATF2 transcriptional activity by novel phosphorylation on Thr-73 and Ser-62 and cooperates with JNK.
|
|
GO:0005515
protein binding
|
IPI
PMID:16511568 Mutual regulation of c-Jun and ATF2 by transcriptional activ... |
MARK AS OVER ANNOTATED |
Summary: Protein binding annotation from PMID:16511568. ATF2 interacts with numerous partners including JUN family, FOS family, ATF family, SMAD proteins, and others (UniProt lists >30 interaction partners). However, "protein binding" is uninformative.
Reason: GO:0005515 (protein binding) is too vague to be informative for ATF2. More specific interaction terms such as leucine zipper domain binding (GO:0043522), protein heterodimerization activity (GO:0046982), or specific binding activities should be used instead.
Supporting Evidence:
PMID:16511568
Mutual regulation of c-Jun and ATF2 by transcriptional activation and subcellular localization.
|
|
GO:0005515
protein binding
|
IPI
PMID:20102225 Identification of bZIP interaction partners of viral protein... |
MARK AS OVER ANNOTATED |
Summary: Protein binding annotation from PMID:20102225. ATF2 interacts with numerous partners including JUN family, FOS family, ATF family, SMAD proteins, and others (UniProt lists >30 interaction partners). However, "protein binding" is uninformative.
Reason: GO:0005515 (protein binding) is too vague to be informative for ATF2. More specific interaction terms such as leucine zipper domain binding (GO:0043522), protein heterodimerization activity (GO:0046982), or specific binding activities should be used instead.
Supporting Evidence:
PMID:20102225
Identification of bZIP interaction partners of viral proteins HBZ, MEQ, BZLF1, and K-bZIP using coiled-coil arrays.
|
|
GO:0005515
protein binding
|
IPI
PMID:20116378 JNK-ATF-2 inhibits thrombomodulin (TM) expression by recruit... |
MARK AS OVER ANNOTATED |
Summary: Protein binding annotation from PMID:20116378. ATF2 interacts with numerous partners including JUN family, FOS family, ATF family, SMAD proteins, and others (UniProt lists >30 interaction partners). However, "protein binding" is uninformative.
Reason: GO:0005515 (protein binding) is too vague to be informative for ATF2. More specific interaction terms such as leucine zipper domain binding (GO:0043522), protein heterodimerization activity (GO:0046982), or specific binding activities should be used instead.
Supporting Evidence:
PMID:20116378
2010 Jan 30. JNK-ATF-2 inhibits thrombomodulin (TM) expression by recruiting histone deacetylase4 (HDAC4) and forming a transcriptional repression complex in the TM promoter.
|
|
GO:0005515
protein binding
|
IPI
PMID:20195357 A comprehensive resource of interacting protein regions for ... |
MARK AS OVER ANNOTATED |
Summary: Protein binding annotation from PMID:20195357. ATF2 interacts with numerous partners including JUN family, FOS family, ATF family, SMAD proteins, and others (UniProt lists >30 interaction partners). However, "protein binding" is uninformative.
Reason: GO:0005515 (protein binding) is too vague to be informative for ATF2. More specific interaction terms such as leucine zipper domain binding (GO:0043522), protein heterodimerization activity (GO:0046982), or specific binding activities should be used instead.
Supporting Evidence:
PMID:20195357
A comprehensive resource of interacting protein regions for refining human transcription factor networks.
|
|
GO:0005515
protein binding
|
IPI
PMID:20211142 An atlas of combinatorial transcriptional regulation in mous... |
MARK AS OVER ANNOTATED |
Summary: Protein binding annotation from PMID:20211142. ATF2 interacts with numerous partners including JUN family, FOS family, ATF family, SMAD proteins, and others (UniProt lists >30 interaction partners). However, "protein binding" is uninformative.
Reason: GO:0005515 (protein binding) is too vague to be informative for ATF2. More specific interaction terms such as leucine zipper domain binding (GO:0043522), protein heterodimerization activity (GO:0046982), or specific binding activities should be used instead.
Supporting Evidence:
PMID:20211142
An atlas of combinatorial transcriptional regulation in mouse and man.
|
|
GO:0005515
protein binding
|
IPI
PMID:20511396 In situ proximity ligation detection of c-Jun/AP-1 dimers re... |
MARK AS OVER ANNOTATED |
Summary: Protein binding annotation from PMID:20511396. ATF2 interacts with numerous partners including JUN family, FOS family, ATF family, SMAD proteins, and others (UniProt lists >30 interaction partners). However, "protein binding" is uninformative.
Reason: GO:0005515 (protein binding) is too vague to be informative for ATF2. More specific interaction terms such as leucine zipper domain binding (GO:0043522), protein heterodimerization activity (GO:0046982), or specific binding activities should be used instead.
Supporting Evidence:
PMID:20511396
2010 May 28. In situ proximity ligation detection of c-Jun/AP-1 dimers reveals increased levels of c-Jun/Fra1 complexes in aggressive breast cancer cell lines in vitro and in vivo.
|
|
GO:0005515
protein binding
|
IPI
PMID:22439931 Deconstruction of the SS18-SSX fusion oncoprotein complex: i... |
MARK AS OVER ANNOTATED |
Summary: Protein binding annotation from PMID:22439931. ATF2 interacts with numerous partners including JUN family, FOS family, ATF family, SMAD proteins, and others (UniProt lists >30 interaction partners). However, "protein binding" is uninformative.
Reason: GO:0005515 (protein binding) is too vague to be informative for ATF2. More specific interaction terms such as leucine zipper domain binding (GO:0043522), protein heterodimerization activity (GO:0046982), or specific binding activities should be used instead.
Supporting Evidence:
PMID:22439931
Deconstruction of the SS18-SSX fusion oncoprotein complex: insights into disease etiology and therapeutics.
|
|
GO:0005515
protein binding
|
IPI
PMID:23661758 Networks of bZIP protein-protein interactions diversified ov... |
MARK AS OVER ANNOTATED |
Summary: Protein binding annotation from PMID:23661758. ATF2 interacts with numerous partners including JUN family, FOS family, ATF family, SMAD proteins, and others (UniProt lists >30 interaction partners). However, "protein binding" is uninformative.
Reason: GO:0005515 (protein binding) is too vague to be informative for ATF2. More specific interaction terms such as leucine zipper domain binding (GO:0043522), protein heterodimerization activity (GO:0046982), or specific binding activities should be used instead.
Supporting Evidence:
PMID:23661758
Networks of bZIP protein-protein interactions diversified over a billion years of evolution.
|
|
GO:0005515
protein binding
|
IPI
PMID:24705354 The palmitoyl acyltransferase HIP14 shares a high proportion... |
MARK AS OVER ANNOTATED |
Summary: Protein binding annotation from PMID:24705354. ATF2 interacts with numerous partners including JUN family, FOS family, ATF family, SMAD proteins, and others (UniProt lists >30 interaction partners). However, "protein binding" is uninformative.
Reason: GO:0005515 (protein binding) is too vague to be informative for ATF2. More specific interaction terms such as leucine zipper domain binding (GO:0043522), protein heterodimerization activity (GO:0046982), or specific binding activities should be used instead.
Supporting Evidence:
PMID:24705354
Apr 4. The palmitoyl acyltransferase HIP14 shares a high proportion of interactors with huntingtin: implications for a role in the pathogenesis of Huntington's disease.
|
|
GO:0005515
protein binding
|
IPI
PMID:25416956 A proteome-scale map of the human interactome network. |
MARK AS OVER ANNOTATED |
Summary: Protein binding annotation from PMID:25416956. ATF2 interacts with numerous partners including JUN family, FOS family, ATF family, SMAD proteins, and others (UniProt lists >30 interaction partners). However, "protein binding" is uninformative.
Reason: GO:0005515 (protein binding) is too vague to be informative for ATF2. More specific interaction terms such as leucine zipper domain binding (GO:0043522), protein heterodimerization activity (GO:0046982), or specific binding activities should be used instead.
Supporting Evidence:
PMID:25416956
A proteome-scale map of the human interactome network.
|
|
GO:0005515
protein binding
|
IPI
PMID:25609649 Proteomic analyses reveal distinct chromatin-associated and ... |
MARK AS OVER ANNOTATED |
Summary: Protein binding annotation from PMID:25609649. ATF2 interacts with numerous partners including JUN family, FOS family, ATF family, SMAD proteins, and others (UniProt lists >30 interaction partners). However, "protein binding" is uninformative.
Reason: GO:0005515 (protein binding) is too vague to be informative for ATF2. More specific interaction terms such as leucine zipper domain binding (GO:0043522), protein heterodimerization activity (GO:0046982), or specific binding activities should be used instead.
Supporting Evidence:
PMID:25609649
Proteomic analyses reveal distinct chromatin-associated and soluble transcription factor complexes.
|
|
GO:0005515
protein binding
|
IPI
PMID:26496610 A human interactome in three quantitative dimensions organiz... |
MARK AS OVER ANNOTATED |
Summary: Protein binding annotation from PMID:26496610. ATF2 interacts with numerous partners including JUN family, FOS family, ATF family, SMAD proteins, and others (UniProt lists >30 interaction partners). However, "protein binding" is uninformative.
Reason: GO:0005515 (protein binding) is too vague to be informative for ATF2. More specific interaction terms such as leucine zipper domain binding (GO:0043522), protein heterodimerization activity (GO:0046982), or specific binding activities should be used instead.
Supporting Evidence:
PMID:26496610
Oct 22. A human interactome in three quantitative dimensions organized by stoichiometries and abundances.
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|
GO:0005515
protein binding
|
IPI
PMID:28514442 Architecture of the human interactome defines protein commun... |
MARK AS OVER ANNOTATED |
Summary: Protein binding annotation from PMID:28514442. ATF2 interacts with numerous partners including JUN family, FOS family, ATF family, SMAD proteins, and others (UniProt lists >30 interaction partners). However, "protein binding" is uninformative.
Reason: GO:0005515 (protein binding) is too vague to be informative for ATF2. More specific interaction terms such as leucine zipper domain binding (GO:0043522), protein heterodimerization activity (GO:0046982), or specific binding activities should be used instead.
Supporting Evidence:
PMID:28514442
Architecture of the human interactome defines protein communities and disease networks.
|
|
GO:0005515
protein binding
|
IPI
PMID:31515488 Extensive disruption of protein interactions by genetic vari... |
MARK AS OVER ANNOTATED |
Summary: Protein binding annotation from PMID:31515488. ATF2 interacts with numerous partners including JUN family, FOS family, ATF family, SMAD proteins, and others (UniProt lists >30 interaction partners). However, "protein binding" is uninformative.
Reason: GO:0005515 (protein binding) is too vague to be informative for ATF2. More specific interaction terms such as leucine zipper domain binding (GO:0043522), protein heterodimerization activity (GO:0046982), or specific binding activities should be used instead.
Supporting Evidence:
PMID:31515488
Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations.
|
|
GO:0005515
protein binding
|
IPI
PMID:32296183 A reference map of the human binary protein interactome. |
MARK AS OVER ANNOTATED |
Summary: Protein binding annotation from PMID:32296183. ATF2 interacts with numerous partners including JUN family, FOS family, ATF family, SMAD proteins, and others (UniProt lists >30 interaction partners). However, "protein binding" is uninformative.
Reason: GO:0005515 (protein binding) is too vague to be informative for ATF2. More specific interaction terms such as leucine zipper domain binding (GO:0043522), protein heterodimerization activity (GO:0046982), or specific binding activities should be used instead.
Supporting Evidence:
PMID:32296183
Apr 8. A reference map of the human binary protein interactome.
|
|
GO:0005515
protein binding
|
IPI
PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... |
MARK AS OVER ANNOTATED |
Summary: Protein binding annotation from PMID:33961781. ATF2 interacts with numerous partners including JUN family, FOS family, ATF family, SMAD proteins, and others (UniProt lists >30 interaction partners). However, "protein binding" is uninformative.
Reason: GO:0005515 (protein binding) is too vague to be informative for ATF2. More specific interaction terms such as leucine zipper domain binding (GO:0043522), protein heterodimerization activity (GO:0046982), or specific binding activities should be used instead.
Supporting Evidence:
PMID:33961781
2021 May 6. Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
|
|
GO:0005515
protein binding
|
IPI
PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... |
MARK AS OVER ANNOTATED |
Summary: Protein binding annotation from PMID:35271311. ATF2 interacts with numerous partners including JUN family, FOS family, ATF family, SMAD proteins, and others (UniProt lists >30 interaction partners). However, "protein binding" is uninformative.
Reason: GO:0005515 (protein binding) is too vague to be informative for ATF2. More specific interaction terms such as leucine zipper domain binding (GO:0043522), protein heterodimerization activity (GO:0046982), or specific binding activities should be used instead.
Supporting Evidence:
PMID:35271311
2022 Mar 11. OpenCell: Endogenous tagging for the cartography of human cellular organization.
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|
GO:0005515
protein binding
|
IPI
PMID:40205054 Multimodal cell maps as a foundation for structural and func... |
MARK AS OVER ANNOTATED |
Summary: Protein binding annotation from PMID:40205054. ATF2 interacts with numerous partners including JUN family, FOS family, ATF family, SMAD proteins, and others (UniProt lists >30 interaction partners). However, "protein binding" is uninformative.
Reason: GO:0005515 (protein binding) is too vague to be informative for ATF2. More specific interaction terms such as leucine zipper domain binding (GO:0043522), protein heterodimerization activity (GO:0046982), or specific binding activities should be used instead.
Supporting Evidence:
PMID:40205054
Apr 9. Multimodal cell maps as a foundation for structural and functional genomics.
|
|
GO:0042802
identical protein binding
|
IPI
PMID:16511568 Mutual regulation of c-Jun and ATF2 by transcriptional activ... |
ACCEPT |
Summary: ATF2 forms homodimers through its leucine zipper domain. Supported by PMID:16511568.
Reason: Correct. ATF2 homodimerization is well established. More informative than generic protein binding.
Supporting Evidence:
PMID:16511568
Mutual regulation of c-Jun and ATF2 by transcriptional activation and subcellular localization.
|
|
GO:0042802
identical protein binding
|
IPI
PMID:23661758 Networks of bZIP protein-protein interactions diversified ov... |
ACCEPT |
Summary: ATF2 forms homodimers through its leucine zipper domain. Supported by PMID:23661758.
Reason: Correct. ATF2 homodimerization is well established. More informative than generic protein binding.
Supporting Evidence:
PMID:23661758
Networks of bZIP protein-protein interactions diversified over a billion years of evolution.
|
|
GO:0000165
MAPK cascade
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: ATF2 is a direct substrate and effector of the MAPK cascade. JNK, p38, and ERK phosphorylate ATF2 at Thr-69/Thr-71 to activate its transcriptional activity (PMID:17267404, deep research review).
Reason: Correct. ATF2 is a well-established downstream target/effector in MAPK signaling.
|
|
GO:0000978
RNA polymerase II cis-regulatory region sequence-specific DNA binding
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: ATF2 binds cis-regulatory regions (CRE/AP-1 elements) that control RNA polymerase II transcription. Consistent with its role as a bZIP transcription factor.
Reason: Correct and well supported by experimental evidence.
|
|
GO:0001228
DNA-binding transcription activator activity, RNA polymerase II-specific
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: ATF2 functions as a transcriptional activator at CRE-dependent promoters when phosphorylated (PMID:10821277, PMID:17267404). Also acts as repressor in some contexts (PMID:20116378).
Reason: Correct. ATF2 has well-documented transcription activator function, though it can also repress in some contexts.
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GO:0001701
in utero embryonic development
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: ATF2 knockout mice show developmental defects. This is a pleiotropic downstream phenotypic consequence of ATF2 transcription factor activity, not a core molecular function.
Reason: Pleiotropic developmental phenotype from mouse knockout studies. Not a core function but a downstream consequence of ATF2 transcriptional regulation.
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GO:0001865
NK T cell differentiation
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: Transferred from mouse ortholog data. ATF2 is a broadly expressed transcription factor; effects on NKT cell differentiation likely reflect pleiotropic transcriptional regulation rather than a specific dedicated function.
Reason: Pleiotropic effect. ATF2 is ubiquitously expressed and regulates many genes; this is a downstream phenotypic outcome, not a core function.
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GO:0001889
liver development
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: Transferred from mouse ortholog. Liver development phenotype in ATF2 mutant mice is a pleiotropic consequence of loss of a ubiquitous transcription factor.
Reason: Pleiotropic developmental phenotype, not a core function of ATF2.
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GO:0002244
hematopoietic progenitor cell differentiation
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: Ortholog transfer from mouse. Pleiotropic effect of ATF2 transcriptional regulation on hematopoietic differentiation.
Reason: Pleiotropic downstream effect, not core function.
|
|
GO:0003360
brainstem development
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: Ortholog transfer from mouse. ATF2 is expressed in brain and knockout causes brainstem defects. This is a tissue-specific developmental phenotype.
Reason: Pleiotropic developmental phenotype in mouse.
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|
GO:0003418
growth plate cartilage chondrocyte differentiation
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: Ortholog transfer from mouse. Highly specific developmental phenotype from mouse knockout, reflecting pleiotropic transcriptional effects.
Reason: Overly specific developmental phenotype for a ubiquitous transcription factor. Pleiotropic.
|
|
GO:0003419
growth plate cartilage chondrocyte proliferation
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: Ortholog transfer from mouse. Similar to chondrocyte differentiation, this is a pleiotropic downstream phenotype.
Reason: Pleiotropic developmental phenotype.
|
|
GO:0003682
chromatin binding
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: ATF2 binds chromatin as demonstrated by ChIP experiments showing binding to AARE elements in the CHOP promoter (PMID:17267404). Also has intrinsic HAT activity (PMID:10821277).
Reason: Correct. ATF2 binds chromatin at target gene promoters as shown by ChIP assays.
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GO:0006606
protein import into nucleus
|
IEA
GO_REF:0000107 |
MARK AS OVER ANNOTATED |
Summary: ATF2 shuttles between cytoplasm and nucleus, with nuclear import regulated by heterodimerization with JUN and PKC-epsilon phosphorylation (PMID:22304920). However, this describes the regulation of ATF2 localization rather than ATF2 functioning as a nuclear import factor.
Reason: ATF2 is imported into the nucleus but does not function as a nuclear import factor. This annotation likely reflects the biology of ATF2 being a substrate of nuclear import, not an active participant in the import machinery.
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GO:0006629
lipid metabolic process
|
IEA
GO_REF:0000107 |
MARK AS OVER ANNOTATED |
Summary: Ortholog transfer. Connection to lipid metabolism is indirect at best. ATF2 may regulate some lipid metabolism genes transcriptionally but this is not a core function.
Reason: Tangential. ATF2 is a general transcription factor that may regulate some lipid metabolism genes, but lipid metabolism is not a defining function.
|
|
GO:0006915
apoptotic process
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: ATF2 participates in apoptosis through its mitochondrial localization where it perturbs HK1-VDAC1 complexes and increases mitochondrial membrane permeability (PMID:22304920). It also regulates pro-apoptotic gene transcription.
Reason: ATF2 has a documented role in apoptosis via mitochondrial function and transcriptional regulation of apoptotic genes. However, this is context-dependent (genotoxic stress, specific cancer types), not a core constitutive function.
|
|
GO:0007033
vacuole organization
|
IEA
GO_REF:0000107 |
MARK AS OVER ANNOTATED |
Summary: Ortholog transfer. Very weak connection to ATF2 known biology. No direct evidence for ATF2 involvement in vacuole organization.
Reason: No clear mechanistic link between ATF2 and vacuole organization. Likely an artifact of ortholog transfer from a pleiotropic phenotype.
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|
GO:0007254
JNK cascade
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: ATF2 is a direct downstream target of the JNK cascade. JNK phosphorylates ATF2 at Thr-69/Thr-71 (PMID:17267404, UniProt). ATF2 is a key effector of JNK signaling.
Reason: Correct. ATF2 is a well-established direct substrate and effector of JNK signaling.
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|
GO:0007507
heart development
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: Ortholog transfer from mouse. Developmental phenotype, pleiotropic effect of ubiquitous transcription factor.
Reason: Pleiotropic developmental phenotype.
|
|
GO:0010467
gene expression
|
IEA
GO_REF:0000107 |
MARK AS OVER ANNOTATED |
Summary: ATF2 regulates gene expression as a transcription factor. This is extremely general and redundant with more specific transcription regulation terms.
Reason: Too general. More specific transcription regulation terms are already annotated.
|
|
GO:0016020
membrane
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: ATF2 localizes to the mitochondrial outer membrane under specific conditions (PMID:22304920). However, GO:0016020 (membrane) is extremely non-specific.
Reason: Correct but very general. More specific term GO:0005741 (mitochondrial outer membrane) is also annotated. Acceptable as broad IEA.
|
|
GO:0021742
abducens nucleus development
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: Ortholog transfer from mouse. Highly specific brainstem nucleus developmental phenotype. ATF2 knockout mice show brainstem developmental defects.
Reason: Very specific developmental phenotype from mouse knockout. Pleiotropic.
|
|
GO:0021743
hypoglossal nucleus development
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: Ortholog transfer from mouse. Highly specific brainstem developmental phenotype.
Reason: Very specific developmental phenotype from mouse knockout. Pleiotropic.
|
|
GO:0021754
facial nucleus development
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: Ortholog transfer from mouse. Highly specific brainstem developmental phenotype.
Reason: Very specific developmental phenotype from mouse knockout. Pleiotropic.
|
|
GO:0030509
BMP signaling pathway
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: ATF2 interacts with SMAD3 and SMAD4 (UniProt) and may participate in BMP/TGF-beta signaling crosstalk. However, this is not a core function.
Reason: ATF2 can interact with SMAD proteins and participate in BMP signaling, but this represents a context-dependent signaling crosstalk rather than a core function.
|
|
GO:0034599
cellular response to oxidative stress
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: ATF2 integrates with CREB1-NRF2 signaling to induce glutathione synthesis genes (GCLC, GCLM, GSR, PRDX1) supporting redox homeostasis (Ju et al., 2023, PMID not available in publications). ATF2 is activated by stress-responsive MAPKs.
Reason: Supported by evidence. ATF2 responds to oxidative stress through MAPK activation and regulates antioxidant gene programs.
|
|
GO:0035497
cAMP response element binding
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: Duplicate of IBA annotation for the same term. ATF2 binds CRE elements as a core function.
Reason: Correct. Redundant with IBA annotation but acceptable.
|
|
GO:0035861
site of double-strand break
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: ATF2 localizes to sites of double-strand breaks (IR-induced foci) following ATM-mediated phosphorylation at Ser-490/Ser-498 (PMID:15916964).
Reason: Correct. Experimentally demonstrated by Bhoumik et al. 2005.
|
|
GO:0038066
p38MAPK cascade
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: ATF2 is a direct substrate and effector of p38 MAPK signaling. p38 phosphorylates ATF2 at Thr-69/Thr-71 (UniProt, PMID:9430721).
Reason: Correct. ATF2 is a well-established downstream target of p38 MAPK.
|
|
GO:0042789
mRNA transcription by RNA polymerase II
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: ATF2 activates mRNA transcription by RNA polymerase II at CRE-dependent promoters. Consistent with core function.
Reason: Correct. Core transcriptional function of ATF2.
|
|
GO:0042803
protein homodimerization activity
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: ATF2 forms homodimers through its leucine zipper domain. This is well established (UniProt, PMID:10821277).
Reason: Correct. ATF2 homodimerization is a well-characterized feature of its bZIP domain.
|
|
GO:0043522
leucine zipper domain binding
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: ATF2 contains a leucine zipper domain (residues 380-408, UniProt) used for dimerization with other bZIP proteins including JUN, FOS, and ATF family members.
Reason: Correct. The leucine zipper mediates homo- and heterodimerization, a defining feature of bZIP proteins.
|
|
GO:0043565
sequence-specific DNA binding
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: ATF2 binds specific DNA sequences (CRE and AP-1 elements). More specific terms are also annotated (GO:0035497).
Reason: Correct but general. Acceptable alongside more specific DNA binding terms.
|
|
GO:0045944
positive regulation of transcription by RNA polymerase II
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: ATF2 activates transcription at CRE-dependent promoters when phosphorylated by MAPKs (PMID:17267404, PMID:10821277).
Reason: Correct. ATF2 is a transcriptional activator when phosphorylated.
|
|
GO:0046982
protein heterodimerization activity
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: ATF2 forms heterodimers with JUN, FOS, and other bZIP proteins via its leucine zipper domain. Heterodimerization with JUN is essential for nuclear localization and full transcriptional activity (UniProt, PMID:16511568).
Reason: Correct. Heterodimerization is a core feature of ATF2 biology.
|
|
GO:0050872
white fat cell differentiation
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: Ortholog transfer. Pleiotropic transcriptional effect on adipocyte differentiation, not a core function.
Reason: Pleiotropic downstream effect of transcriptional regulation. Not core.
|
|
GO:0060052
neurofilament cytoskeleton organization
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: Ortholog transfer from mouse. ATF2 may regulate neurofilament genes transcriptionally but this is not a core function.
Reason: Pleiotropic downstream developmental phenotype.
|
|
GO:0060245
detection of cell density
|
IEA
GO_REF:0000107 |
MARK AS OVER ANNOTATED |
Summary: Ortholog transfer. Weak connection to ATF2 core biology. May reflect indirect transcriptional effects.
Reason: No clear direct mechanistic link. Likely indirect consequence of broad transcriptional regulation.
|
|
GO:0072740
cellular response to anisomycin
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: Anisomycin activates JNK and p38 MAPK, which phosphorylate ATF2. This annotation reflects ATF2 activation by a specific MAPK-activating stimulus.
Reason: Correct but very specific stimulus. ATF2 responds to many MAPK-activating stresses; anisomycin is just one example.
|
|
GO:0097049
motor neuron apoptotic process
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: Ortholog transfer from mouse. Highly specific developmental/apoptotic phenotype.
Reason: Very specific phenotype from mouse studies. Pleiotropic.
|
|
GO:0097284
hepatocyte apoptotic process
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: Ortholog transfer. ATF2 has roles in apoptosis generally, but hepatocyte-specific apoptosis is a tissue-specific manifestation.
Reason: Tissue-specific manifestation of a broader apoptotic function.
|
|
GO:0098586
cellular response to virus
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: ATF2 participates in antiviral responses, including through IFN-lambda1 stimulation (PMID:23729669). ATF2/AP-1 transcription complexes regulate immune response genes.
Reason: ATF2 regulates some immune/antiviral genes but this is a context-dependent function, not core.
|
|
GO:1990144
intrinsic apoptotic signaling pathway in response to hypoxia
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: Ortholog transfer. ATF2 has roles in apoptotic signaling, and MAPK activation occurs under hypoxia. This is a specific context for ATF2 apoptotic function.
Reason: Context-specific manifestation of ATF2 apoptotic function.
|
|
GO:1990841
promoter-specific chromatin binding
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: ATF2 binds chromatin at specific promoters as demonstrated by ChIP (PMID:17267404). Consistent with its transcription factor function.
Reason: Correct. Experimentally validated by ChIP studies.
|
|
GO:0005654
nucleoplasm
|
IDA
GO_REF:0000052 |
ACCEPT |
Summary: ATF2 localizes to the nucleoplasm as expected for a transcription factor. Supported by immunofluorescence data.
Reason: Correct. ATF2 is primarily a nuclear/nucleoplasmic protein.
|
|
GO:0004402
histone acetyltransferase activity
|
TAS
Reactome:R-HSA-3318415 |
UNDECIDED |
Summary: ATF2 has reported intrinsic HAT activity toward H2B and H4 (PMID:10821277, Kawasaki et al. 2000, Nature). However, UniProt notes a CAUTION that this activity may be due to contamination. Reactome pathway R-HSA-3318415 describes ATF2 acetylating H2B and H4.
Reason: The HAT activity of ATF2 was reported in Nature (PMID:10821277) and supported by follow-up work (PMID:17267404 showing ATF2-dependent histone acetylation in vivo). However, UniProt flags this with a CAUTION note suggesting possible contamination. The evidence is mixed - the in vitro HAT activity may be genuine but requires further validation.
|
|
GO:0005634
nucleus
|
NAS
PMID:28186491 Combinatorial bZIP dimers display complex DNA-binding specif... |
ACCEPT |
Summary: Nuclear localization of ATF2 demonstrated with NAS evidence from PMID:28186491. Consistent with its role as a transcription factor.
Reason: Correct. ATF2 is primarily nuclear.
Supporting Evidence:
PMID:28186491
Combinatorial bZIP dimers display complex DNA-binding specificity landscapes.
|
|
GO:0006357
regulation of transcription by RNA polymerase II
|
NAS
PMID:28186491 Combinatorial bZIP dimers display complex DNA-binding specif... |
ACCEPT |
Summary: Regulation of transcription by RNA polymerase II from PMID:28186491. Core function of ATF2.
Reason: Correct. Core function.
Supporting Evidence:
PMID:28186491
Combinatorial bZIP dimers display complex DNA-binding specificity landscapes.
|
|
GO:0000122
negative regulation of transcription by RNA polymerase II
|
EXP
PMID:11231009 Identification of mouse Jun dimerization protein 2 as a nove... |
ACCEPT |
Summary: PMID:11231009 identifies JDP2 as a repressor of ATF-2. ATF2 also has documented repressive activity, e.g., repression of thrombomodulin via HDAC4 recruitment (PMID:20116378). This annotation indicates ATF2 participates in negative regulation of transcription.
Reason: Correct. ATF2 can act as both activator and repressor depending on context and binding partners. Both activation and repression are documented functions.
Supporting Evidence:
PMID:11231009
Identification of mouse Jun dimerization protein 2 as a novel repressor of ATF-2.
|
|
GO:0005634
nucleus
|
EXP
PMID:11231009 Identification of mouse Jun dimerization protein 2 as a nove... |
ACCEPT |
Summary: Nuclear localization of ATF2 demonstrated with EXP evidence from PMID:11231009. Consistent with its role as a transcription factor.
Reason: Correct. ATF2 is primarily nuclear.
Supporting Evidence:
PMID:11231009
Identification of mouse Jun dimerization protein 2 as a novel repressor of ATF-2.
|
|
GO:0005634
nucleus
|
NAS
PMID:20102225 Identification of bZIP interaction partners of viral protein... |
ACCEPT |
Summary: Nuclear localization of ATF2 demonstrated with NAS evidence from PMID:20102225. Consistent with its role as a transcription factor.
Reason: Correct. ATF2 is primarily nuclear.
Supporting Evidence:
PMID:20102225
Identification of bZIP interaction partners of viral proteins HBZ, MEQ, BZLF1, and K-bZIP using coiled-coil arrays.
|
|
GO:0005634
nucleus
|
NAS
PMID:23661758 Networks of bZIP protein-protein interactions diversified ov... |
ACCEPT |
Summary: Nuclear localization of ATF2 demonstrated with NAS evidence from PMID:23661758. Consistent with its role as a transcription factor.
Reason: Correct. ATF2 is primarily nuclear.
Supporting Evidence:
PMID:23661758
Networks of bZIP protein-protein interactions diversified over a billion years of evolution.
|
|
GO:0006357
regulation of transcription by RNA polymerase II
|
NAS
PMID:20102225 Identification of bZIP interaction partners of viral protein... |
ACCEPT |
Summary: Regulation of transcription by RNA polymerase II from PMID:20102225. Core function of ATF2.
Reason: Correct. Core function.
Supporting Evidence:
PMID:20102225
Identification of bZIP interaction partners of viral proteins HBZ, MEQ, BZLF1, and K-bZIP using coiled-coil arrays.
|
|
GO:0006357
regulation of transcription by RNA polymerase II
|
NAS
PMID:23661758 Networks of bZIP protein-protein interactions diversified ov... |
ACCEPT |
Summary: Regulation of transcription by RNA polymerase II from PMID:23661758. Core function of ATF2.
Reason: Correct. Core function.
Supporting Evidence:
PMID:23661758
Networks of bZIP protein-protein interactions diversified over a billion years of evolution.
|
|
GO:0045815
transcription initiation-coupled chromatin remodeling
|
IDA
PMID:10821277 ATF-2 has intrinsic histone acetyltransferase activity which... |
UNDECIDED |
Summary: PMID:10821277 reports ATF2 has intrinsic HAT activity that acetylates H2B and H4, modulated by phosphorylation. This connects ATF2 to chromatin remodeling coupled to transcription initiation. However, UniProt cautions this HAT activity may be due to contamination.
Reason: Depends on whether ATF2 HAT activity is genuine. PMID:10821277 reports intrinsic HAT, but UniProt flags potential contamination. PMID:17267404 provides in vivo support showing ATF2-dependent histone acetylation at target promoters. The annotation is plausible but uncertain.
Supporting Evidence:
PMID:10821277
ATF-2 has intrinsic histone acetyltransferase activity which is modulated by phosphorylation.
|
|
GO:0035497
cAMP response element binding
|
IDA
PMID:23729669 Inducible interleukin 32 (IL-32) exerts extensive antiviral ... |
ACCEPT |
Summary: CRE binding demonstrated by direct assay from PMID:23729669. Core molecular function of ATF2.
Reason: Core function. ATF2 was originally identified as CRE-BP1.
Supporting Evidence:
PMID:23729669
Epub 2013 May 31. Inducible interleukin 32 (IL-32) exerts extensive antiviral function via selective stimulation of interferon Ī»1 (IFN-Ī»1).
|
|
GO:0018107
peptidyl-threonine phosphorylation
|
IDA
PMID:17267404 ATF2 is required for amino acid-regulated transcription by o... |
REMOVE |
Summary: MISANNOTATION: ATF2 is a bZIP transcription factor that is extensively PHOSPHORYLATED at Thr-69 and Thr-71 by kinases (p38 MAPK, ERK, CaMK4, JNK). PMID:17267404 describes "phosphorylation of ATF2 on Thr71 precedes histone acetylation" - ATF2 is the SUBSTRATE of phosphorylation, not the enzyme. ATF2 has histone acetyltransferase (HAT) activity (EC 2.3.1.48), not kinase activity. The phosphorylation of ATF2 activates its transcription factor and HAT activities, but ATF2 does not catalyze phosphorylation reactions.
Supporting Evidence:
PMID:17267404
ATF2 is required for amino acid-regulated transcription by orchestrating specific histone acetylation.
|
|
GO:0045944
positive regulation of transcription by RNA polymerase II
|
IDA
PMID:17267404 ATF2 is required for amino acid-regulated transcription by o... |
ACCEPT |
Summary: Positive regulation of transcription by RNA polymerase II from PMID:17267404. ATF2 activates CRE-dependent transcription when phosphorylated.
Reason: Correct. Core transcriptional activator function of ATF2.
Supporting Evidence:
PMID:17267404
ATF2 is required for amino acid-regulated transcription by orchestrating specific histone acetylation.
|
|
GO:1990253
cellular response to leucine starvation
|
IDA
PMID:17267404 ATF2 is required for amino acid-regulated transcription by o... |
KEEP AS NON CORE |
Summary: PMID:17267404 demonstrates ATF2 is essential for CHOP transcriptional induction upon leucine starvation, orchestrating histone acetylation at the AARE. ATF2 is phosphorylated and binds the CHOP promoter in response to amino acid deprivation.
Reason: Correct and experimentally validated. However, this is a specific stimulus context (leucine starvation) for the general stress-responsive transcription function of ATF2.
Supporting Evidence:
PMID:17267404
in cells devoid of ATF2 expression, the induction of CHOP transcription upon amino acid starvation is completely lost
|
|
GO:1990841
promoter-specific chromatin binding
|
IDA
PMID:17267404 ATF2 is required for amino acid-regulated transcription by o... |
ACCEPT |
Summary: PMID:17267404 demonstrates ATF2 binding at the CHOP AARE by ChIP. ATF2 bound to the AARE promotes histone acetylation in vivo.
Reason: Correct. Experimentally demonstrated by ChIP in PMID:17267404.
Supporting Evidence:
PMID:17267404
binding of ATF2 and ATF4 to CHOP AARE are associated with acetylation of histones H4 and H2B in response to amino acid starvation
|
|
GO:0010485
histone H4 acetyltransferase activity
|
IDA
PMID:10821277 ATF-2 has intrinsic histone acetyltransferase activity which... |
UNDECIDED |
Summary: PMID:10821277 reports ATF2 specifically acetylates histones H2B and H4 in vitro. UniProt cautions this may be due to contamination, but PMID:17267404 provides in vivo support for ATF2-dependent H4 acetylation.
Reason: The in vitro HAT activity toward H4 is reported (PMID:10821277) and in vivo H4 acetylation depends on ATF2 (PMID:17267404). However, UniProt expresses caution about contamination. Evidence is suggestive but not definitive.
Supporting Evidence:
PMID:10821277
ATF-2 has intrinsic histone acetyltransferase activity which is modulated by phosphorylation.
|
|
GO:0044013
histone H2B acetyltransferase activity
|
IDA
PMID:10821277 ATF-2 has intrinsic histone acetyltransferase activity which... |
UNDECIDED |
Summary: PMID:10821277 reports ATF2 specifically acetylates H2B in vitro. UniProt flags potential contamination. PMID:17267404 shows ATF2-dependent H2B acetylation in vivo at the CHOP promoter.
Reason: Similar to H4 HAT activity - reported in PMID:10821277, supported in vivo by PMID:17267404, but flagged with caution by UniProt.
Supporting Evidence:
PMID:10821277
ATF-2 has intrinsic histone acetyltransferase activity which is modulated by phosphorylation.
|
|
GO:1902562
H4 histone acetyltransferase complex
|
IDA
PMID:10821277 ATF-2 has intrinsic histone acetyltransferase activity which... |
UNDECIDED |
Summary: This annotation places ATF2 in an H4 histone acetyltransferase complex based on PMID:10821277. Given uncertainty about ATF2 intrinsic HAT activity (UniProt caution), this localization annotation is uncertain.
Reason: Depends on the validity of ATF2 HAT activity. UniProt expresses caution.
Supporting Evidence:
PMID:10821277
ATF-2 has intrinsic histone acetyltransferase activity which is modulated by phosphorylation.
|
|
GO:1990837
sequence-specific double-stranded DNA binding
|
IDA
PMID:28473536 Impact of cytosine methylation on DNA binding specificities ... |
ACCEPT |
Summary: PMID:28473536 studies impact of cytosine methylation on DNA binding of transcription factors including ATF2. ATF2 binds double-stranded DNA in a sequence-specific manner.
Reason: Correct. ATF2 is a sequence-specific dsDNA-binding protein.
Supporting Evidence:
PMID:28473536
Impact of cytosine methylation on DNA binding specificities of human transcription factors.
|
|
GO:0000785
chromatin
|
IDA
PMID:23729669 Inducible interleukin 32 (IL-32) exerts extensive antiviral ... |
ACCEPT |
Summary: PMID:23729669 demonstrates ATF2 binding to chromatin at the IFN-lambda1 promoter in the context of IL-32-induced antiviral response. ChIP evidence.
Reason: Correct. ATF2 chromatin association demonstrated by ChIP.
Supporting Evidence:
PMID:23729669
Epub 2013 May 31. Inducible interleukin 32 (IL-32) exerts extensive antiviral function via selective stimulation of interferon Ī»1 (IFN-Ī»1).
|
|
GO:0001228
DNA-binding transcription activator activity, RNA polymerase II-specific
|
IDA
PMID:16300731 ATF5 increases cisplatin-induced apoptosis through up-regula... |
ACCEPT |
Summary: Transcription activator activity demonstrated from PMID:16300731. ATF2 activates CRE-dependent transcription.
Reason: Correct. Core transcription activator function of ATF2.
Supporting Evidence:
PMID:16300731
ATF5 increases cisplatin-induced apoptosis through up-regulation of cyclin D3 transcription in HeLa cells.
|
|
GO:0000785
chromatin
|
ISA
GO_REF:0000113 |
ACCEPT |
Summary: ATF2 associates with chromatin at target gene promoters as shown by ChIP (PMID:17267404). Consistent with transcription factor function.
Reason: Correct. TFClass-based annotation supported by experimental ChIP data.
|
|
GO:0000981
DNA-binding transcription factor activity, RNA polymerase II-specific
|
ISA
GO_REF:0000113 |
ACCEPT |
Summary: ATF2 is an RNA polymerase II-specific transcription factor. Consistent with IBA and other experimental annotations.
Reason: Correct. Redundant with IBA but acceptable.
|
|
GO:0001228
DNA-binding transcription activator activity, RNA polymerase II-specific
|
IDA
PMID:18671972 IRF2-binding protein-1 is a JDP2 ubiquitin ligase and an inh... |
ACCEPT |
Summary: Transcription activator activity demonstrated from PMID:18671972. ATF2 activates CRE-dependent transcription.
Reason: Correct. Core transcription activator function of ATF2.
Supporting Evidence:
PMID:18671972
Epub 2008 Jul 29. IRF2-binding protein-1 is a JDP2 ubiquitin ligase and an inhibitor of ATF2-dependent transcription.
|
|
GO:0045944
positive regulation of transcription by RNA polymerase II
|
IDA
PMID:18671972 IRF2-binding protein-1 is a JDP2 ubiquitin ligase and an inh... |
ACCEPT |
Summary: Positive regulation of transcription by RNA polymerase II from PMID:18671972. ATF2 activates CRE-dependent transcription when phosphorylated.
Reason: Correct. Core transcriptional activator function of ATF2.
Supporting Evidence:
PMID:18671972
Epub 2008 Jul 29. IRF2-binding protein-1 is a JDP2 ubiquitin ligase and an inhibitor of ATF2-dependent transcription.
|
|
GO:0001228
DNA-binding transcription activator activity, RNA polymerase II-specific
|
IDA
PMID:19861239 cJun modulates Ggamma-globin gene expression via an upstream... |
ACCEPT |
Summary: Transcription activator activity demonstrated from PMID:19861239. ATF2 activates CRE-dependent transcription.
Reason: Correct. Core transcription activator function of ATF2.
Supporting Evidence:
PMID:19861239
Epub 2009 Oct 27. cJun modulates Ggamma-globin gene expression via an upstream cAMP response element.
|
|
GO:0006357
regulation of transcription by RNA polymerase II
|
IDA
PMID:19861239 cJun modulates Ggamma-globin gene expression via an upstream... |
ACCEPT |
Summary: PMID:19861239 shows ATF2 regulates gamma-globin gene transcription through CRE elements. Core function.
Reason: Correct. Core transcription regulation function.
Supporting Evidence:
PMID:19861239
Epub 2009 Oct 27. cJun modulates Ggamma-globin gene expression via an upstream cAMP response element.
|
|
GO:0010628
positive regulation of gene expression
|
IMP
PMID:28977001 MicroRNA-30b controls endothelial cell capillary morphogenes... |
MARK AS OVER ANNOTATED |
Summary: PMID:28977001 describes miR-30b regulation of TGF-beta2 in endothelial cells, with ATF2 as a target. The connection to ATF2 as a positive regulator of gene expression is indirect through miRNA targeting.
Reason: ATF2 is a general transcription factor that positively regulates many genes. This annotation from a miRNA study context is too broad and indirect.
Supporting Evidence:
PMID:28977001
eCollection 2017. MicroRNA-30b controls endothelial cell capillary morphogenesis through regulation of transforming growth factor beta 2.
|
|
GO:0016525
negative regulation of angiogenesis
|
IMP
PMID:28977001 MicroRNA-30b controls endothelial cell capillary morphogenes... |
MARK AS OVER ANNOTATED |
Summary: PMID:28977001 describes miR-30b effects on angiogenesis via TGF-beta2, with ATF2 involvement. The connection of ATF2 to angiogenesis regulation appears indirect.
Reason: Indirect involvement. ATF2 is not primarily an angiogenesis regulator; this likely reflects indirect transcriptional effects in a specific experimental context.
Supporting Evidence:
PMID:28977001
eCollection 2017. MicroRNA-30b controls endothelial cell capillary morphogenesis through regulation of transforming growth factor beta 2.
|
|
GO:0110024
positive regulation of cardiac muscle myoblast proliferation
|
IDA
PMID:22982025 MicroRNA-204 is required for differentiation of human-derive... |
MARK AS OVER ANNOTATED |
Summary: PMID:22982025 describes miR-204 in cardiomyocyte progenitor differentiation, with ATF2 as a target. The annotation of ATF2 as positively regulating cardiac myoblast proliferation appears to be based on ATF2 being a miRNA target rather than a direct cardiac function.
Reason: Indirect. ATF2 is a target of miR-204 in this context. The cardiac proliferation effect is mediated through miRNA regulation of ATF2 levels, not a direct core function of ATF2.
Supporting Evidence:
PMID:22982025
Epub 2012 Sep 7. MicroRNA-204 is required for differentiation of human-derived cardiomyocyte progenitor cells.
|
|
GO:0000987
cis-regulatory region sequence-specific DNA binding
|
IDA
PMID:2196176 Multiple cDNA clones encoding nuclear proteins that bind to ... |
ACCEPT |
Summary: PMID:2196176 cloned CRE-BP1 (ATF2) and showed it binds the tax-dependent enhancer of HTLV-1 containing CRE-like elements. Demonstrates cis-regulatory region sequence-specific DNA binding.
Reason: Correct. Core DNA-binding function of ATF2.
Supporting Evidence:
PMID:2196176
Multiple cDNA clones encoding nuclear proteins that bind to the tax-dependent enhancer of HTLV-1: all contain a leucine zipper structure and basic amino acid domain.
|
|
GO:0045944
positive regulation of transcription by RNA polymerase II
|
IDA
PMID:16300731 ATF5 increases cisplatin-induced apoptosis through up-regula... |
ACCEPT |
Summary: Positive regulation of transcription by RNA polymerase II from PMID:16300731. ATF2 activates CRE-dependent transcription when phosphorylated.
Reason: Correct. Core transcriptional activator function of ATF2.
Supporting Evidence:
PMID:16300731
ATF5 increases cisplatin-induced apoptosis through up-regulation of cyclin D3 transcription in HeLa cells.
|
|
GO:0000977
RNA polymerase II transcription regulatory region sequence-specific DNA binding
|
IMP
PMID:2516827 Transcription factor ATF cDNA clones: an extensive family of... |
ACCEPT |
Summary: PMID:2516827 describes ATF family cDNA clones as leucine zipper proteins that form DNA-binding heterodimers. Demonstrates sequence-specific DNA binding to transcription regulatory regions.
Reason: Correct. Core function demonstrated in early characterization of ATF family.
Supporting Evidence:
PMID:2516827
Transcription factor ATF cDNA clones: an extensive family of leucine zipper proteins able to selectively form DNA-binding heterodimers.
|
|
GO:0005515
protein binding
|
IPI
PMID:15916964 ATM-dependent phosphorylation of ATF2 is required for the DN... |
MARK AS OVER ANNOTATED |
Summary: Protein binding annotation from PMID:15916964. ATF2 interacts with numerous partners including JUN family, FOS family, ATF family, SMAD proteins, and others (UniProt lists >30 interaction partners). However, "protein binding" is uninformative.
Reason: GO:0005515 (protein binding) is too vague to be informative for ATF2. More specific interaction terms such as leucine zipper domain binding (GO:0043522), protein heterodimerization activity (GO:0046982), or specific binding activities should be used instead.
Supporting Evidence:
PMID:15916964
ATM-dependent phosphorylation of ATF2 is required for the DNA damage response.
|
|
GO:0005515
protein binding
|
IPI
PMID:18397884 Regulation of TIP60 by ATF2 modulates ATM activation. |
MARK AS OVER ANNOTATED |
Summary: Protein binding annotation from PMID:18397884. ATF2 interacts with numerous partners including JUN family, FOS family, ATF family, SMAD proteins, and others (UniProt lists >30 interaction partners). However, "protein binding" is uninformative.
Reason: GO:0005515 (protein binding) is too vague to be informative for ATF2. More specific interaction terms such as leucine zipper domain binding (GO:0043522), protein heterodimerization activity (GO:0046982), or specific binding activities should be used instead.
Supporting Evidence:
PMID:18397884
2008 Apr 8. Regulation of TIP60 by ATF2 modulates ATM activation.
|
|
GO:0005634
nucleus
|
IDA
PMID:18397884 Regulation of TIP60 by ATF2 modulates ATM activation. |
ACCEPT |
Summary: Nuclear localization of ATF2 demonstrated with IDA evidence from PMID:18397884. Consistent with its role as a transcription factor.
Reason: Correct. ATF2 is primarily nuclear.
Supporting Evidence:
PMID:18397884
2008 Apr 8. Regulation of TIP60 by ATF2 modulates ATM activation.
|
|
GO:0005634
nucleus
|
IDA
PMID:22304920 PKCĪµ promotes oncogenic functions of ATF2 in the nucleus whi... |
ACCEPT |
Summary: Nuclear localization of ATF2 demonstrated with IDA evidence from PMID:22304920. Consistent with its role as a transcription factor.
Reason: Correct. ATF2 is primarily nuclear.
Supporting Evidence:
PMID:22304920
PKCĪµ promotes oncogenic functions of ATF2 in the nucleus while blocking its apoptotic function at mitochondria.
|
|
GO:0005737
cytoplasm
|
IDA
PMID:22304920 PKCĪµ promotes oncogenic functions of ATF2 in the nucleus whi... |
ACCEPT |
Summary: PMID:22304920 demonstrates ATF2 cytoplasmic localization, particularly under genotoxic stress when PKC-epsilon effect is attenuated. ATF2 nuclear export enables mitochondrial localization.
Reason: Correct. Experimentally demonstrated in Lau et al. 2012 (Cell).
Supporting Evidence:
PMID:22304920
PKCĪµ promotes oncogenic functions of ATF2 in the nucleus while blocking its apoptotic function at mitochondria.
|
|
GO:0005741
mitochondrial outer membrane
|
IDA
PMID:22304920 PKCĪµ promotes oncogenic functions of ATF2 in the nucleus whi... |
ACCEPT |
Summary: PMID:22304920 demonstrates ATF2 localization to the mitochondrial outer membrane under genotoxic stress, where it perturbs HK1-VDAC1 complexes.
Reason: Correct. Experimentally demonstrated in Lau et al. 2012 (Cell).
Supporting Evidence:
PMID:22304920
PKCĪµ promotes oncogenic functions of ATF2 in the nucleus while blocking its apoptotic function at mitochondria.
|
|
GO:0006355
regulation of DNA-templated transcription
|
IMP
PMID:22304920 PKCĪµ promotes oncogenic functions of ATF2 in the nucleus whi... |
ACCEPT |
Summary: PMID:22304920 shows PKC-epsilon promotes ATF2 oncogenic transcriptional functions in the nucleus. ATF2 regulates transcription of target genes.
Reason: Correct. Core function.
Supporting Evidence:
PMID:22304920
PKCĪµ promotes oncogenic functions of ATF2 in the nucleus while blocking its apoptotic function at mitochondria.
|
|
GO:0006974
DNA damage response
|
IMP
PMID:15916964 ATM-dependent phosphorylation of ATF2 is required for the DN... |
ACCEPT |
Summary: PMID:15916964 demonstrates ATM phosphorylates ATF2 at Ser-490/498 following IR, leading to ATF2 colocalization with gamma-H2AX and MRN complex in IRIF. Inhibition of ATF2 impairs DDR including S-phase checkpoint and ATM activation.
Reason: Correct. Well-established non-transcriptional function of ATF2 in DDR.
Supporting Evidence:
PMID:15916964
Inhibition of ATF2 expression decreased recruitment of Mre11 to IRIF, abrogated S phase checkpoint, reduced activation of ATM, Chk1, and Chk2, and impaired radioresistance
|
|
GO:0006974
DNA damage response
|
IDA
PMID:22304920 PKCĪµ promotes oncogenic functions of ATF2 in the nucleus whi... |
ACCEPT |
Summary: PMID:22304920 further characterizes ATF2 role in DNA damage response, showing subcellular localization dynamics during genotoxic stress.
Reason: Correct. Complements PMID:15916964 DDR evidence.
Supporting Evidence:
PMID:22304920
PKCĪµ promotes oncogenic functions of ATF2 in the nucleus while blocking its apoptotic function at mitochondria.
|
|
GO:0031573
mitotic intra-S DNA damage checkpoint signaling
|
IMP
PMID:15916964 ATM-dependent phosphorylation of ATF2 is required for the DN... |
ACCEPT |
Summary: PMID:15916964 demonstrates ATF2 is required for the ionizing radiation-induced S phase checkpoint. ATF2 inhibition abrogated S phase checkpoint signaling.
Reason: Correct. Experimentally demonstrated in PMID:15916964.
Supporting Evidence:
PMID:15916964
Inhibition of ATF2 expression decreased recruitment of Mre11 to IRIF, abrogated S phase checkpoint, reduced activation of ATM, Chk1, and Chk2
|
|
GO:0035861
site of double-strand break
|
IDA
PMID:15916964 ATM-dependent phosphorylation of ATF2 is required for the DN... |
ACCEPT |
Summary: PMID:15916964 demonstrates ATF2 rapid colocalization with gamma-H2AX and MRN components into IR-induced foci (sites of double-strand breaks).
Reason: Correct. Experimentally demonstrated by immunofluorescence in PMID:15916964.
Supporting Evidence:
PMID:15916964
phosphorylation of ATF2 by ATM that results in its rapid colocalization with gamma-H2AX and MRN components into IR-induced foci (IRIF)
|
|
GO:1902110
positive regulation of mitochondrial membrane permeability involved in apoptotic process
|
IMP
PMID:22304920 PKCĪµ promotes oncogenic functions of ATF2 in the nucleus whi... |
KEEP AS NON CORE |
Summary: PMID:22304920 shows ATF2 at mitochondria perturbs HK1-VDAC1 complex, increases mitochondrial permeability, and promotes apoptosis. This is the mechanism of ATF2 tumor suppressor function.
Reason: Correct and experimentally validated. However, this mitochondrial apoptotic function is context-dependent (genotoxic stress, regulated by PKC-epsilon) rather than a constitutive core function.
Supporting Evidence:
PMID:22304920
ATF2 tumor suppressor function is determined by its ability to localize at the mitochondria, where it alters membrane permeability following genotoxic stress
|
|
GO:0005654
nucleoplasm
|
TAS
Reactome:R-HSA-168053 |
ACCEPT |
Summary: Nucleoplasm localization from Reactome pathway Reactome:R-HSA-168053. ATF2 is a nuclear transcription factor.
Reason: Correct. ATF2 is primarily nucleoplasmic.
|
|
GO:0005654
nucleoplasm
|
TAS
Reactome:R-HSA-168440 |
ACCEPT |
Summary: Nucleoplasm localization from Reactome pathway Reactome:R-HSA-168440. ATF2 is a nuclear transcription factor.
Reason: Correct. ATF2 is primarily nucleoplasmic.
|
|
GO:0005654
nucleoplasm
|
TAS
Reactome:R-HSA-3318415 |
ACCEPT |
Summary: Nucleoplasm localization from Reactome pathway Reactome:R-HSA-3318415. ATF2 is a nuclear transcription factor.
Reason: Correct. ATF2 is primarily nucleoplasmic.
|
|
GO:0005654
nucleoplasm
|
TAS
Reactome:R-HSA-6806412 |
ACCEPT |
Summary: Nucleoplasm localization from Reactome pathway Reactome:R-HSA-6806412. ATF2 is a nuclear transcription factor.
Reason: Correct. ATF2 is primarily nucleoplasmic.
|
|
GO:0005654
nucleoplasm
|
TAS
Reactome:R-HSA-8944397 |
ACCEPT |
Summary: Nucleoplasm localization from Reactome pathway Reactome:R-HSA-8944397. ATF2 is a nuclear transcription factor.
Reason: Correct. ATF2 is primarily nucleoplasmic.
|
|
GO:0005654
nucleoplasm
|
TAS
Reactome:R-HSA-9009371 |
ACCEPT |
Summary: Nucleoplasm localization from Reactome pathway Reactome:R-HSA-9009371. ATF2 is a nuclear transcription factor.
Reason: Correct. ATF2 is primarily nucleoplasmic.
|
|
GO:0005654
nucleoplasm
|
TAS
Reactome:R-HSA-9635804 |
ACCEPT |
Summary: Nucleoplasm localization from Reactome pathway Reactome:R-HSA-9635804. ATF2 is a nuclear transcription factor.
Reason: Correct. ATF2 is primarily nucleoplasmic.
|
|
GO:0000981
DNA-binding transcription factor activity, RNA polymerase II-specific
|
IC
PMID:19861239 cJun modulates Ggamma-globin gene expression via an upstream... |
ACCEPT |
Summary: Inferred by curator that ATF2 is a DNA-binding transcription factor for RNA polymerase II based on evidence from PMID:19861239 showing ATF2 binding CRE elements and modulating gamma-globin transcription.
Reason: Correct. Well-supported core function.
Supporting Evidence:
PMID:19861239
Epub 2009 Oct 27. cJun modulates Ggamma-globin gene expression via an upstream cAMP response element.
|
|
GO:0008140
cAMP response element binding protein binding
|
IDA
PMID:19861239 cJun modulates Ggamma-globin gene expression via an upstream... |
ACCEPT |
Summary: PMID:19861239 shows ATF2 interacts with cJun at CRE elements to modulate gamma-globin gene expression. ATF2 binding to CREB response element binding proteins is consistent with its bZIP family membership.
Reason: Correct. ATF2 interacts with CREB family proteins through bZIP-mediated dimerization.
Supporting Evidence:
PMID:19861239
Epub 2009 Oct 27. cJun modulates Ggamma-globin gene expression via an upstream cAMP response element.
|
|
GO:0000978
RNA polymerase II cis-regulatory region sequence-specific DNA binding
|
IDA
PMID:19861239 cJun modulates Ggamma-globin gene expression via an upstream... |
ACCEPT |
Summary: PMID:19861239 demonstrates ATF2 binding to RNA polymerase II cis-regulatory regions (CRE elements in the gamma-globin promoter).
Reason: Correct. Core DNA-binding function.
Supporting Evidence:
PMID:19861239
Epub 2009 Oct 27. cJun modulates Ggamma-globin gene expression via an upstream cAMP response element.
|
|
GO:0005634
nucleus
|
IDA
PMID:19861239 cJun modulates Ggamma-globin gene expression via an upstream... |
ACCEPT |
Summary: Nuclear localization of ATF2 demonstrated with IDA evidence from PMID:19861239. Consistent with its role as a transcription factor.
Reason: Correct. ATF2 is primarily nuclear.
Supporting Evidence:
PMID:19861239
Epub 2009 Oct 27. cJun modulates Ggamma-globin gene expression via an upstream cAMP response element.
|
|
GO:0035497
cAMP response element binding
|
IDA
PMID:19861239 cJun modulates Ggamma-globin gene expression via an upstream... |
ACCEPT |
Summary: CRE binding demonstrated by direct assay from PMID:19861239. Core molecular function of ATF2.
Reason: Core function. ATF2 was originally identified as CRE-BP1.
Supporting Evidence:
PMID:19861239
Epub 2009 Oct 27. cJun modulates Ggamma-globin gene expression via an upstream cAMP response element.
|
|
GO:0061629
RNA polymerase II-specific DNA-binding transcription factor binding
|
IPI
PMID:19861239 cJun modulates Ggamma-globin gene expression via an upstream... |
ACCEPT |
Summary: ATF2 interacts with cJun (an RNA polymerase II-specific DNA-binding transcription factor) at the gamma-globin CRE (PMID:19861239).
Reason: Correct. ATF2 forms heterodimers with JUN family transcription factors.
Supporting Evidence:
PMID:19861239
Epub 2009 Oct 27. cJun modulates Ggamma-globin gene expression via an upstream cAMP response element.
|
|
GO:0005634
nucleus
|
IDA
PMID:21098032 Hyperosmotic stress-induced ATF-2 activation through Polo-li... |
ACCEPT |
Summary: Nuclear localization of ATF2 demonstrated with IDA evidence from PMID:21098032. Consistent with its role as a transcription factor.
Reason: Correct. ATF2 is primarily nuclear.
Supporting Evidence:
PMID:21098032
2010 Nov 22. Hyperosmotic stress-induced ATF-2 activation through Polo-like kinase 3 in human corneal epithelial cells.
|
|
GO:0006970
response to osmotic stress
|
IDA
PMID:21098032 Hyperosmotic stress-induced ATF-2 activation through Polo-li... |
KEEP AS NON CORE |
Summary: PMID:21098032 demonstrates ATF2 activation (Thr-71 phosphorylation) in response to hyperosmotic stress through PLK3 in human corneal epithelial cells.
Reason: Correct. ATF2 responds to osmotic stress via MAPK/PLK3 activation. However, this is one of many stress stimuli that activate ATF2, not a core-defining function.
Supporting Evidence:
PMID:21098032
2010 Nov 22. Hyperosmotic stress-induced ATF-2 activation through Polo-like kinase 3 in human corneal epithelial cells.
|
|
GO:0019901
protein kinase binding
|
IPI
PMID:21098032 Hyperosmotic stress-induced ATF-2 activation through Polo-li... |
ACCEPT |
Summary: PMID:21098032 shows ATF2 interacts with PLK3 (Polo-like kinase 3) which phosphorylates ATF2 at Thr-71. ATF2 also binds JNK (MAPK9, 9 experiments in IntAct), VRK1 (5 experiments), and other kinases.
Reason: Correct. ATF2 is a substrate of multiple protein kinases and must bind them for phosphorylation. More informative than generic protein binding.
Supporting Evidence:
PMID:21098032
2010 Nov 22. Hyperosmotic stress-induced ATF-2 activation through Polo-like kinase 3 in human corneal epithelial cells.
|
|
GO:0005634
nucleus
|
IDA
PMID:8798441 CREB proteins function as positive regulators of the translo... |
ACCEPT |
Summary: Nuclear localization of ATF2 demonstrated with IDA evidence from PMID:8798441. Consistent with its role as a transcription factor.
Reason: Correct. ATF2 is primarily nuclear.
Supporting Evidence:
PMID:8798441
CREB proteins function as positive regulators of the translocated bcl-2 allele in t(14;18) lymphomas.
|
|
GO:0003700
DNA-binding transcription factor activity
|
IDA
PMID:8798441 CREB proteins function as positive regulators of the translo... |
ACCEPT |
Summary: PMID:8798441 shows CREB proteins including ATF2 (CRE-BP1) function as positive regulators of the translocated bcl-2 allele through CRE elements.
Reason: Correct. Core transcription factor function.
Supporting Evidence:
PMID:8798441
CREB proteins function as positive regulators of the translocated bcl-2 allele in t(14;18) lymphomas.
|
|
GO:0005515
protein binding
|
IPI
PMID:9748258 Characterization of functional domains of an embryonic stem ... |
MARK AS OVER ANNOTATED |
Summary: Protein binding annotation from PMID:9748258. ATF2 interacts with numerous partners including JUN family, FOS family, ATF family, SMAD proteins, and others (UniProt lists >30 interaction partners). However, "protein binding" is uninformative.
Reason: GO:0005515 (protein binding) is too vague to be informative for ATF2. More specific interaction terms such as leucine zipper domain binding (GO:0043522), protein heterodimerization activity (GO:0046982), or specific binding activities should be used instead.
Supporting Evidence:
PMID:9748258
Characterization of functional domains of an embryonic stem cell coactivator UTF1 which are conserved and essential for potentiation of ATF-2 activity.
|
|
GO:0005515
protein binding
|
IPI
PMID:8440710 Isolation and characterization of a novel member of the gene... |
MARK AS OVER ANNOTATED |
Summary: Protein binding annotation from PMID:8440710. ATF2 interacts with numerous partners including JUN family, FOS family, ATF family, SMAD proteins, and others (UniProt lists >30 interaction partners). However, "protein binding" is uninformative.
Reason: GO:0005515 (protein binding) is too vague to be informative for ATF2. More specific interaction terms such as leucine zipper domain binding (GO:0043522), protein heterodimerization activity (GO:0046982), or specific binding activities should be used instead.
Supporting Evidence:
PMID:8440710
Isolation and characterization of a novel member of the gene family encoding the cAMP response element-binding protein CRE-BP1.
|
provider: falcon
model: Edison Scientific Literature
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start_time: '2026-03-06T02:46:49.833526'
end_time: '2026-03-06T03:02:04.984324'
duration_seconds: 915.15
template_file: templates/gene_research_go_focused.md
template_variables:
organism: human
gene_id: ATF2
gene_symbol: ATF2
uniprot_accession: P15336
protein_description: 'RecName: Full=Cyclic AMP-dependent transcription factor ATF-2;
Short=cAMP-dependent transcription factor ATF-2; AltName: Full=Activating transcription
factor 2; AltName: Full=Cyclic AMP-responsive element-binding protein 2; Short=CREB-2;
Short=cAMP-responsive element-binding protein 2; AltName: Full=HB16; AltName:
Full=cAMP response element-binding protein CRE-BP1;'
gene_info: Name=ATF2; Synonyms=CREB2, CREBP1;
organism_full: Homo sapiens (Human).
protein_family: Belongs to the bZIP family. ATF subfamily. .
protein_domains: bZIP. (IPR004827); bZIP_sf. (IPR046347); bZIP_transcription_factors.
(IPR051027); TF_CRE-BP1-typ. (IPR016378); Znf_C2H2_sf. (IPR036236)
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citation_count: 21
BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.
DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'ATF2' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information
Please provide a comprehensive research report on the gene ATF2 (gene ID: ATF2, UniProt: P15336) in human.
The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.
We are interested in where in or outside the cell the gene product carries out its function.
We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.
Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.
Question: You are an expert researcher providing comprehensive, well-cited information.
Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies
Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.
BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.
DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'ATF2' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information
Please provide a comprehensive research report on the gene ATF2 (gene ID: ATF2, UniProt: P15336) in human.
The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.
We are interested in where in or outside the cell the gene product carries out its function.
We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.
Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.
The requested target is human activating transcription factor 2 (ATF2), UniProt P15336, a basic leucine zipper (bZIP) transcription factor in the ATF/CREB family. The literature synthesized here consistently discusses ATF2 as a bZIP transcription factor that binds CRE/AP-1ātype DNA elements and is regulated by MAPK and DNA-damage kinases, matching the UniProt description and avoiding conflation with other āATFā family members. (amarah2023emergingrolesof pages 2-3, liu2025activatingtranscriptionfactors pages 2-3)
ATF2 is a phosphorylation-regulated transcription factor that controls gene expression by binding DNA as homo- or heterodimers via its bZIP domain. Partner choice modulates DNA-binding specificity and transcriptional output. (amarah2023emergingrolesof pages 2-3, liu2025activatingtranscriptionfactors pages 2-3)
ATF family bZIP proteins include (i) a basic region for DNA binding and (ii) a leucine zipper for dimerization. Dimerization is a major determinant of which motifs are recognized: ATF homodimers or CREB-family heterodimers preferentially bind CRE consensus motifs, whereas heterodimerization with AP-1 proteins (notably c-JUN) redirects binding toward AP-1 sites. (liu2025activatingtranscriptionfactors pages 2-3)
Consistent with this, ATF2 is described as binding ATF/CRE motifs and functioning as homodimers or heterodimers with AP-1/ATF proteins. (amarah2023emergingrolesof pages 2-3)
A central mechanistic concept for ATF2 is multisite phosphorylation in its transactivation region that tunes transcriptional output downstream of stress/growth-factor signaling (MAPKs). In cancer- and stress-related settings, the most commonly referenced MAPK-regulated activation is at Thr69/Thr71. (amarah2023emergingrolesof pages 2-3)
ATF2 is unusual among transcription factors in that it is also described as participating early in DDR via ATM-dependent phosphorylation at the C-terminus and recruitment to DNA repair foci, suggesting an adaptor/sensor role beyond classical transcriptional regulation. (amarah2023emergingrolesof pages 2-3)
A consolidated set of ATF2 PTMs and upstream kinases (from a 2023 review focused on mechanistic oncology contexts) includes: (amarah2023emergingrolesof pages 2-3)
ATF2 is also placed downstream of oncogenic signaling routes (e.g., RalGDS/Ras/ERK/Src) that activate the transcription factor and feed into proliferation and stress programs. (amarah2023emergingrolesof pages 2-3)
Nuclear localization is primary and expected for a transcription factor. In DNA damage contexts, ATM phosphorylation (Ser490/Ser498) is described to direct ATF2 into DNA repair foci, where it colocalizes with Rad50, Nbs1, and Mre11. (amarah2023emergingrolesof pages 2-3)
ATF2 functions as a node at the intersection of:
In cancer-focused synthesis, ATF2 is linked to transcriptional regulation of multiple genes and programs relevant to proliferation, invasion, EMT, and therapy response, including MMP2/MMP13/MMP3, cyclin A, cyclin D1, aromatase, and COX2 in specific contexts (breast cancer and related models). (amarah2023emergingrolesof pages 4-5, amarah2023emergingrolesof pages 6-7)
A 2023 primary study in human mesenchymal stem cells (MSCs) provides a mechanistic program in which activated ATF2 integrates with CREB1āNRF2 signaling to induce genes involved in glutathione synthesis and redox cycling, including GCLC, GCLM, GSR, and PRDX1, supporting high intracellular glutathione (GSH) and MSC functional properties. (ju2023activatingtranscriptionfactor2 pages 6-10, ju2023activatingtranscriptionfactor2 media 51b94e31)
Ju et al., 2023-02 (Experimental & Molecular Medicine; https://doi.org/10.1038/s12276-023-00943-z) report that ATF2 supports GSH dynamics in human MSCs and that ATF2 silencing impairs MSC proliferation, migration-related phenotypes, and anti-inflammatory capacities, with rescue by exogenous GSH supplementation. Quantitative study details include multiple assay sample sizes (e.g., n=5ā7 for several in vitro readouts; and in vivo cohort sizes n=20 for BALF cellular counts/lung RQ-PCR and n=10 for BALF cytokines), and in vivo dosing of 3Ć10^5 MSCs i.v. (ju2023activatingtranscriptionfactor2 pages 6-10)
A pathway schematic in this paper summarizes AA2G or cAMP signaling ā ATF2/CREB1 ā NRF2 ā GSH gene program (GCLC/GCLM/GSR/PRDX1). (ju2023activatingtranscriptionfactor2 media 51b94e31)
Sun et al., 2023-11 (BMC Cancer; https://doi.org/10.1186/s12885-023-11612-9) provide a mechanistic NSCLC model in which ANKRD49 elevates p-JNK, leading to activation of ATF2 and c-JUN, which interact in the nucleus and bind MMP2/MMP9 promoters (immunoprecipitation and ChIP), thereby promoting migration/invasion. Quantitative descriptors available from the accessible text include n=9 paired fresh NSCLC tissues for qPCR and multiple inhibitor conditions (e.g., 10 ĀµM SP600125 (JNK inhibitor) and 10 ĀµM SB203580 (p38 inhibitor), each 1 h pretreatment) with significance thresholds indicated (P<0.05, P<0.01, **P<0.001) rather than exact p-values. (sun2023ankrd49promotesthe pages 5-9)
Jang et al., 2023-08 (Frontiers in Pharmacology; https://doi.org/10.3389/fphar.2023.1217111) report that sinapic acid directly binds TAK1 and inhibits downstream inflammatory signaling including NF-ĪŗB and MAPK/ATF-2 pathways in Caco-2 epithelial models and DSS colitis in mice. The accessible text provides dosing/time-course detail: sinapic acid 12.5ā50 ĀµM in vitro; TEER measured across 0.5ā24 h after stimulation; and FITC-dextran permeability assessed at 12 and 24 h. (jang2023sinapicacidalleviates pages 2-3)
Cui et al., 2024-11 (Frontiers in Molecular Biosciences; https://doi.org/10.3389/fmolb.2024.1512715) identify ATF2 among ākey genesā associated with chemoradiotherapy response and prognosis in esophageal squamous cell carcinoma and connect high ATF2 expression to EMT pathway upregulation. ATF2 is included in a prognostic nomogram together with TNM stage and two other genes. The accessible excerpt does not include detailed effect sizes/p-values but documents the intended clinical application and mechanistic links (e.g., Rac1āp38āATF2 axis; ATF2 binding GLUT3 promoter in CRC EMT in cited literature). (cui2024identificationofkey pages 9-10)
A 2023 narrative review emphasizes that ATF2 can behave as an oncogene in some contexts and as a tumor suppressor in others (notably ER+ breast cancer), with endocrine therapy resistance mechanisms described. It reports that tamoxifen induces dose-dependent phosphorylation of ATF2 and that phospho-ATF2 is linked to prognosis in tamoxifen-treated ER+ patients (review-level statement without extractable HRs in the provided text). (amarah2023emergingrolesof pages 1-1, amarah2023emergingrolesof pages 6-7)
In MSC therapy-relevant contexts, ATF2 emerges as a determinant of therapeutic potency via redox control; priming strategies (e.g., AA2G) that elevate ATF2 activity are proposed to improve MSC function. (ju2023activatingtranscriptionfactor2 pages 6-10, ju2023activatingtranscriptionfactor2 media 51b94e31)
A 2023 review emphasizes the context dependence (ādual rolesā) of ATF2 as a cancer driver vs suppressor in breast cancer biology, highlighting ambiguity and the need for mechanistic stratification (e.g., by ER status, signaling context, and phosphorylation state). (amarah2023emergingrolesof pages 1-1, amarah2023emergingrolesof pages 6-7)
Several clinically oriented claims (e.g., āpATF2 correlates with OSā in tamoxifen-treated ER+ disease) are present at the review level without the underlying studyās hazard ratios or p-values within the extracted text segments available here. (amarah2023emergingrolesof pages 6-7)
| Category | Key Findings & Mechanisms | Evidence/Citations |
|---|---|---|
| Identity & Domains | Human ATF2 (UniProt P15336) is a bZIP (basic leucine zipper) transcription factor of the ATF/CREB family. It contains a DNA-binding domain and a leucine zipper for dimerization. | (amarah2023emergingrolesof pages 7-8, amarah2023emergingrolesof pages 2-3, liu2025activatingtranscriptionfactors pages 2-3) |
| DNA Binding & Dimerization | Binds to cAMP response elements (CRE: 5'-TGACGTCA-3') and AP-1 sites. Forms homodimers or heterodimers with c-Jun, c-Fos, and CREB. Dimerization partner dictates DNA specificity (e.g., c-Jun heterodimers prefer AP-1 sites). | (amarah2023emergingrolesof pages 4-5, amarah2023emergingrolesof pages 2-3, liu2025activatingtranscriptionfactors pages 2-3) |
| Activation & PTMs | Phosphorylation is critical: ā¢ Thr69/Thr71: Phosphorylated by MAPK/JNK/p38/ERK in response to stress/cytokines/growth factors. ā¢ Ser490/Ser498: Phosphorylated by ATM in response to DNA damage (IR). ā¢ Other sites: Ser62/Thr73 (VRK1), Ser121/Ser340/Ser367 (PKC). |
(amarah2023emergingrolesof pages 7-8, amarah2023emergingrolesof pages 2-3) |
| Subcellular Localization | Primarily nuclear (transcription factor). Under specific conditions (e.g., DNA damage), localizes to DNA repair foci with Rad50/Nbs1/Mre11. Also reported at mitochondria (via Bim/VDAC1 interaction) influencing apoptosis. | (amarah2023emergingrolesof pages 7-8, amarah2023emergingrolesof pages 2-3) |
| Key Downstream Genes | ā¢ Cancer/Metastasis: MMP2, MMP9, MMP13, Cyclin A, Cyclin D1, Aromatase, COX2. ā¢ Antioxidant/Stemness: GCLC, GCLM, GSR, PRDX1 (via CREB1-NRF2 axis in MSCs). |
(amarah2023emergingrolesof pages 4-5, amarah2023emergingrolesof pages 6-7, ju2023activatingtranscriptionfactor2 pages 6-10, sun2023ankrd49promotesthe pages 1-2) |
| 2023-2024 Updates | ā¢ Stem Cells (2023): ATF2 maintains glutathione (GSH) dynamics in MSCs; knockdown impairs therapeutic efficacy in asthma models. ā¢ NSCLC (2023): ANKRD49 promotes metastasis via JNK-ATF2/c-Jun axis binding MMP2/9 promoters. ā¢ ESCC (2024): High ATF2 expression linked to EMT and sorafenib sensitivity; identified as prognostic biomarker. ā¢ Breast Cancer (2023 Review): Dual role as oncogene (proliferation) or tumor suppressor (ER+ breast cancer); phosphorylation by Tamoxifen correlates with resistance. |
(ju2023activatingtranscriptionfactor2 pages 6-10, cui2024identificationofkey pages 9-10, sun2023ankrd49promotesthe pages 1-2, amarah2023emergingrolesof pages 7-8, amarah2023emergingrolesof pages 6-7) |
| Quantitative Data | ā¢ MSC Therapy: ATF2 knockdown reduced MSC chemotaxis (n=7) and anti-inflammatory effect (n=6). ā¢ Survival: High p-ATF2 correlates with poorer OS in Tamoxifen-treated patients (qualitative association reported). ā¢ Biomarker: Included in 4-gene prognostic nomogram for ESCC. |
(ju2023activatingtranscriptionfactor2 pages 6-10, amarah2023emergingrolesof pages 6-7, cui2024identificationofkey pages 9-10) |
Table: This table synthesizes current functional data for human ATF2 (UniProt P15336), detailing molecular mechanisms, downstream targets, and recent findings from 2023-2024 literature.
A pathway schematic from Ju et al. (2023) depicts the ATF2/CREB1āNRF2 axis controlling glutathione synthesis and redox genes (GCLC/GCLM/GSR/PRDX1), supporting ATF2ās role in redox homeostasis and MSC potency. (ju2023activatingtranscriptionfactor2 media 51b94e31)
References
(amarah2023emergingrolesof pages 2-3): Ahmed Amarah, Ahmed Adel Elsabagh, Amr Ouda, Omar Karen, Khaled Ferih, Ibrahim Elmakaty, and Mohammed Imad Malki. Emerging roles of activating transcription factor 2 in the development of breast cancer: a comprehensive review. Precision Clinical Medicine, Oct 2023. URL: https://doi.org/10.1093/pcmedi/pbad028, doi:10.1093/pcmedi/pbad028. This article has 8 citations.
(liu2025activatingtranscriptionfactors pages 2-3): Yue-Chen Liu, Jia-Wei Zhao, Xiong-Tao Yue, Qi-Jie Chen, Shan-Jie Rong, Shi-Wei Liu, Fei Sun, Chun-Liang Yang, and Cong-Yi Wang. Activating transcription factors: orchestrators of macrophage biology in pathological settings (review). International Journal of Molecular Medicine, 57:1-28, Dec 2025. URL: https://doi.org/10.3892/ijmm.2025.5720, doi:10.3892/ijmm.2025.5720. This article has 0 citations and is from a peer-reviewed journal.
(amarah2023emergingrolesof pages 7-8): Ahmed Amarah, Ahmed Adel Elsabagh, Amr Ouda, Omar Karen, Khaled Ferih, Ibrahim Elmakaty, and Mohammed Imad Malki. Emerging roles of activating transcription factor 2 in the development of breast cancer: a comprehensive review. Precision Clinical Medicine, Oct 2023. URL: https://doi.org/10.1093/pcmedi/pbad028, doi:10.1093/pcmedi/pbad028. This article has 8 citations.
(amarah2023emergingrolesof pages 3-4): Ahmed Amarah, Ahmed Adel Elsabagh, Amr Ouda, Omar Karen, Khaled Ferih, Ibrahim Elmakaty, and Mohammed Imad Malki. Emerging roles of activating transcription factor 2 in the development of breast cancer: a comprehensive review. Precision Clinical Medicine, Oct 2023. URL: https://doi.org/10.1093/pcmedi/pbad028, doi:10.1093/pcmedi/pbad028. This article has 8 citations.
(amarah2023emergingrolesof pages 4-5): Ahmed Amarah, Ahmed Adel Elsabagh, Amr Ouda, Omar Karen, Khaled Ferih, Ibrahim Elmakaty, and Mohammed Imad Malki. Emerging roles of activating transcription factor 2 in the development of breast cancer: a comprehensive review. Precision Clinical Medicine, Oct 2023. URL: https://doi.org/10.1093/pcmedi/pbad028, doi:10.1093/pcmedi/pbad028. This article has 8 citations.
(amarah2023emergingrolesof pages 6-7): Ahmed Amarah, Ahmed Adel Elsabagh, Amr Ouda, Omar Karen, Khaled Ferih, Ibrahim Elmakaty, and Mohammed Imad Malki. Emerging roles of activating transcription factor 2 in the development of breast cancer: a comprehensive review. Precision Clinical Medicine, Oct 2023. URL: https://doi.org/10.1093/pcmedi/pbad028, doi:10.1093/pcmedi/pbad028. This article has 8 citations.
(ju2023activatingtranscriptionfactor2 pages 6-10): Hyein Ju, HongDuck Yun, YongHwan Kim, Yun Ji Nam, Seungun Lee, Jinwon Lee, Seon Min Jeong, Jinbeom Heo, Hyungu Kwon, You Sook Cho, Gowun Jeong, Chae-Min Ryu, and Dong-Myung Shin. Activating transcription factor-2 supports the antioxidant capacity and ability of human mesenchymal stem cells to prevent asthmatic airway inflammation. Experimental & Molecular Medicine, Feb 2023. URL: https://doi.org/10.1038/s12276-023-00943-z, doi:10.1038/s12276-023-00943-z. This article has 22 citations and is from a peer-reviewed journal.
(ju2023activatingtranscriptionfactor2 media 51b94e31): Hyein Ju, HongDuck Yun, YongHwan Kim, Yun Ji Nam, Seungun Lee, Jinwon Lee, Seon Min Jeong, Jinbeom Heo, Hyungu Kwon, You Sook Cho, Gowun Jeong, Chae-Min Ryu, and Dong-Myung Shin. Activating transcription factor-2 supports the antioxidant capacity and ability of human mesenchymal stem cells to prevent asthmatic airway inflammation. Experimental & Molecular Medicine, Feb 2023. URL: https://doi.org/10.1038/s12276-023-00943-z, doi:10.1038/s12276-023-00943-z. This article has 22 citations and is from a peer-reviewed journal.
(sun2023ankrd49promotesthe pages 5-9): Jia Sun, Jin-rui Hu, Chao-feng Liu, Yuan Li, Wei Wang, Rong Fu, Min Guo, Hai-long Wang, and Min Pang. Ankrd49 promotes the metastasis of nsclc via activating jnk-atf2/c-jun-mmp-2/9 axis. BMC Cancer, Nov 2023. URL: https://doi.org/10.1186/s12885-023-11612-9, doi:10.1186/s12885-023-11612-9. This article has 14 citations and is from a peer-reviewed journal.
(jang2023sinapicacidalleviates pages 2-3): Sehyeon Jang, San Kim, Bo Ram So, Younghoon Kim, Chang-Kil Kim, Jeong Jae Lee, and Sung Keun Jung. Sinapic acid alleviates inflammatory bowel disease (ibd) through localization of tight junction proteins by direct binding to tak1 and improves intestinal microbiota. Frontiers in Pharmacology, Aug 2023. URL: https://doi.org/10.3389/fphar.2023.1217111, doi:10.3389/fphar.2023.1217111. This article has 26 citations.
(cui2024identificationofkey pages 9-10): Yingying Cui, Jing Wen, Jianhua Fu, and Changsen Leng. Identification of key genes to predict response to chemoradiotherapy and prognosis in esophageal squamous cell carcinoma. Frontiers in Molecular Biosciences, Nov 2024. URL: https://doi.org/10.3389/fmolb.2024.1512715, doi:10.3389/fmolb.2024.1512715. This article has 2 citations.
(amarah2023emergingrolesof pages 1-1): Ahmed Amarah, Ahmed Adel Elsabagh, Amr Ouda, Omar Karen, Khaled Ferih, Ibrahim Elmakaty, and Mohammed Imad Malki. Emerging roles of activating transcription factor 2 in the development of breast cancer: a comprehensive review. Precision Clinical Medicine, Oct 2023. URL: https://doi.org/10.1093/pcmedi/pbad028, doi:10.1093/pcmedi/pbad028. This article has 8 citations.
(amarah2023emergingrolesof pages 5-6): Ahmed Amarah, Ahmed Adel Elsabagh, Amr Ouda, Omar Karen, Khaled Ferih, Ibrahim Elmakaty, and Mohammed Imad Malki. Emerging roles of activating transcription factor 2 in the development of breast cancer: a comprehensive review. Precision Clinical Medicine, Oct 2023. URL: https://doi.org/10.1093/pcmedi/pbad028, doi:10.1093/pcmedi/pbad028. This article has 8 citations.
(sun2023ankrd49promotesthe pages 1-2): Jia Sun, Jin-rui Hu, Chao-feng Liu, Yuan Li, Wei Wang, Rong Fu, Min Guo, Hai-long Wang, and Min Pang. Ankrd49 promotes the metastasis of nsclc via activating jnk-atf2/c-jun-mmp-2/9 axis. BMC Cancer, Nov 2023. URL: https://doi.org/10.1186/s12885-023-11612-9, doi:10.1186/s12885-023-11612-9. This article has 14 citations and is from a peer-reviewed journal.
id: P15336
gene_symbol: ATF2
product_type: PROTEIN
status: DRAFT
taxon:
id: NCBITaxon:9606
label: Homo sapiens
description: ATF2 (Activating Transcription Factor 2, also known as CRE-BP1 or CREB2)
is a phosphorylation-regulated bZIP transcription factor of the ATF/CREB subfamily.
It binds CRE (5'-TGACGTCA-3') and AP-1 (5'-TGACTCA-3') DNA elements as homodimers
or heterodimers with JUN family members and other bZIP proteins. Its transcriptional
activity is activated by MAPK-mediated phosphorylation at Thr-69/Thr-71 downstream
of stress, cytokine, and growth factor signaling (JNK, p38, ERK). ATF2 possesses
intrinsic histone acetyltransferase (HAT) activity toward histones H2B and H4, though
the physiological significance of this activity has been debated. Beyond transcription,
ATF2 participates in the DNA damage response through ATM-dependent phosphorylation
at Ser-490/Ser-498, which recruits it to IR-induced foci independently of its DNA-binding
domain. ATF2 subcellular localization is regulated by PKC-epsilon; under genotoxic
stress, ATF2 can translocate to the mitochondrial outer membrane where it perturbs
HK1-VDAC1 complexes to promote apoptosis. ATF2 regulates genes involved in stress
response, cell proliferation, DNA repair, and redox homeostasis.
existing_annotations:
- term:
id: GO:0000981
label: DNA-binding transcription factor activity, RNA polymerase II-specific
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: ATF2 is a well-established bZIP transcription factor that binds CRE and
AP-1 elements to regulate RNA polymerase II-dependent transcription. This is
a core function supported by extensive evidence (PMID:2529117, PMID:10821277,
PMID:17267404).
action: ACCEPT
reason: Core molecular function of ATF2 as a sequence-specific DNA-binding transcription
factor. IBA annotation is well supported phylogenetically and by extensive experimental
literature.
- term:
id: GO:0006357
label: regulation of transcription by RNA polymerase II
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: ATF2 regulates transcription by RNA polymerase II through binding CRE/AP-1
elements as homo- or heterodimers with JUN family proteins. This is a core biological
process (PMID:17267404, PMID:10821277).
action: ACCEPT
reason: Core biological process for ATF2. Well established by multiple experimental
studies.
- term:
id: GO:0035497
label: cAMP response element binding
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: ATF2 (also known as CRE-BP1) was originally identified by its ability
to bind CRE elements (5-prime-TGACGTCA-3-prime). This is a defining feature
of the protein (PMID:2529117, PMID:19861239).
action: ACCEPT
reason: Core molecular function. ATF2 was named CRE-BP1 precisely because of its
CRE-binding activity. IBA is at the right level of specificity.
- term:
id: GO:0003677
label: DNA binding
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: ATF2 is a bZIP transcription factor with well-documented DNA binding
activity to CRE and AP-1 elements. This IEA is correct but more general than
the IBA for cAMP response element binding (GO:0035497).
action: ACCEPT
reason: Correct but general. More specific terms (GO:0035497 cAMP response element
binding) are also annotated. Acceptable as a broader IEA.
- term:
id: GO:0003700
label: DNA-binding transcription factor activity
evidence_type: IEA
original_reference_id: GO_REF:0000002
review:
summary: ATF2 is a DNA-binding transcription factor. IEA from InterPro mapping.
More specific IBA term (GO:0000981) is also annotated.
action: ACCEPT
reason: Correct but less specific than GO:0000981. Acceptable as broader IEA.
- term:
id: GO:0005634
label: nucleus
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: ATF2 is primarily nuclear as expected for a transcription factor. UniProt
confirms nuclear localization (PMID:15105425, PMID:22304920). Also demonstrated
by IDA evidence.
action: ACCEPT
reason: Correct. ATF2 is primarily localized to the nucleus, consistent with its
role as a transcription factor.
- term:
id: GO:0005737
label: cytoplasm
evidence_type: IEA
original_reference_id: GO_REF:0000044
review:
summary: ATF2 can localize to the cytoplasm under stress conditions and in disease
states. PKC-epsilon directs ATF2 nuclear localization; genotoxic stress enables
nuclear export and mitochondrial localization (PMID:22304920).
action: ACCEPT
reason: Correct. UniProt and experimental evidence confirm cytoplasmic localization
under specific conditions.
- term:
id: GO:0005741
label: mitochondrial outer membrane
evidence_type: IEA
original_reference_id: GO_REF:0000044
review:
summary: ATF2 localizes to the mitochondrial outer membrane under genotoxic stress,
where it perturbs HK1-VDAC1 complexes and promotes apoptosis (PMID:22304920).
action: ACCEPT
reason: Correct. Lau et al. 2012 in Cell demonstrated ATF2 mitochondrial outer
membrane localization and its functional consequence.
- term:
id: GO:0006355
label: regulation of DNA-templated transcription
evidence_type: IEA
original_reference_id: GO_REF:0000002
review:
summary: ATF2 regulates DNA-templated transcription. IEA from InterPro. More specific
term GO:0006357 (regulation of transcription by RNAPII) also annotated.
action: ACCEPT
reason: Correct but general. Acceptable as broader IEA alongside more specific
terms.
- term:
id: GO:0006974
label: DNA damage response
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: ATF2 participates in DNA damage response through ATM-dependent phosphorylation
at Ser-490/Ser-498, recruiting to IR-induced foci and activating the intra-S
checkpoint (PMID:15916964).
action: ACCEPT
reason: Correct. ATF2 role in DDR is well established by experimental evidence
from Bhoumik et al. 2005.
- term:
id: GO:0008270
label: zinc ion binding
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: ATF2 has a C2H2-type zinc finger domain at residues 25-49 (UniProt FT
record). Zinc ion binding is expected from this domain.
action: ACCEPT
reason: Correct. ATF2 contains a well-annotated C2H2-type zinc finger domain that
requires zinc ion coordination.
- term:
id: GO:0046872
label: metal ion binding
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: ATF2 binds metal ions through its C2H2-type zinc finger domain. This
is a parent term of zinc ion binding.
action: ACCEPT
reason: Correct but very general parent of GO:0008270. Acceptable as IEA.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:10327051
review:
summary: Protein binding annotation from PMID:10327051. ATF2 interacts with numerous
partners including JUN family, FOS family, ATF family, SMAD proteins, and others
(UniProt lists >30 interaction partners). However, "protein binding" is uninformative.
action: MARK_AS_OVER_ANNOTATED
supported_by:
- reference_id: PMID:10327051
supporting_text: The N-terminal transactivation domain of ATF2 is a target for
the co-operative activation of the c-jun promoter by p300 and 12S E1A.
reason: GO:0005515 (protein binding) is too vague to be informative for ATF2.
More specific interaction terms such as leucine zipper domain binding (GO:0043522),
protein heterodimerization activity (GO:0046982), or specific binding activities
should be used instead.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:15105425
review:
summary: Protein binding annotation from PMID:15105425. ATF2 interacts with numerous
partners including JUN family, FOS family, ATF family, SMAD proteins, and others
(UniProt lists >30 interaction partners). However, "protein binding" is uninformative.
action: MARK_AS_OVER_ANNOTATED
supported_by:
- reference_id: PMID:15105425
supporting_text: 2004 Apr 21. Human vaccinia-related kinase 1 (VRK1) activates
the ATF2 transcriptional activity by novel phosphorylation on Thr-73 and Ser-62
and cooperates with JNK.
reason: GO:0005515 (protein binding) is too vague to be informative for ATF2.
More specific interaction terms such as leucine zipper domain binding (GO:0043522),
protein heterodimerization activity (GO:0046982), or specific binding activities
should be used instead.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:16511568
review:
summary: Protein binding annotation from PMID:16511568. ATF2 interacts with numerous
partners including JUN family, FOS family, ATF family, SMAD proteins, and others
(UniProt lists >30 interaction partners). However, "protein binding" is uninformative.
action: MARK_AS_OVER_ANNOTATED
supported_by:
- reference_id: PMID:16511568
supporting_text: Mutual regulation of c-Jun and ATF2 by transcriptional activation
and subcellular localization.
reason: GO:0005515 (protein binding) is too vague to be informative for ATF2.
More specific interaction terms such as leucine zipper domain binding (GO:0043522),
protein heterodimerization activity (GO:0046982), or specific binding activities
should be used instead.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:20102225
review:
summary: Protein binding annotation from PMID:20102225. ATF2 interacts with numerous
partners including JUN family, FOS family, ATF family, SMAD proteins, and others
(UniProt lists >30 interaction partners). However, "protein binding" is uninformative.
action: MARK_AS_OVER_ANNOTATED
supported_by:
- reference_id: PMID:20102225
supporting_text: Identification of bZIP interaction partners of viral proteins
HBZ, MEQ, BZLF1, and K-bZIP using coiled-coil arrays.
reason: GO:0005515 (protein binding) is too vague to be informative for ATF2.
More specific interaction terms such as leucine zipper domain binding (GO:0043522),
protein heterodimerization activity (GO:0046982), or specific binding activities
should be used instead.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:20116378
review:
summary: Protein binding annotation from PMID:20116378. ATF2 interacts with numerous
partners including JUN family, FOS family, ATF family, SMAD proteins, and others
(UniProt lists >30 interaction partners). However, "protein binding" is uninformative.
action: MARK_AS_OVER_ANNOTATED
supported_by:
- reference_id: PMID:20116378
supporting_text: 2010 Jan 30. JNK-ATF-2 inhibits thrombomodulin (TM) expression
by recruiting histone deacetylase4 (HDAC4) and forming a transcriptional repression
complex in the TM promoter.
reason: GO:0005515 (protein binding) is too vague to be informative for ATF2.
More specific interaction terms such as leucine zipper domain binding (GO:0043522),
protein heterodimerization activity (GO:0046982), or specific binding activities
should be used instead.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:20195357
review:
summary: Protein binding annotation from PMID:20195357. ATF2 interacts with numerous
partners including JUN family, FOS family, ATF family, SMAD proteins, and others
(UniProt lists >30 interaction partners). However, "protein binding" is uninformative.
action: MARK_AS_OVER_ANNOTATED
supported_by:
- reference_id: PMID:20195357
supporting_text: A comprehensive resource of interacting protein regions for
refining human transcription factor networks.
reason: GO:0005515 (protein binding) is too vague to be informative for ATF2.
More specific interaction terms such as leucine zipper domain binding (GO:0043522),
protein heterodimerization activity (GO:0046982), or specific binding activities
should be used instead.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:20211142
review:
summary: Protein binding annotation from PMID:20211142. ATF2 interacts with numerous
partners including JUN family, FOS family, ATF family, SMAD proteins, and others
(UniProt lists >30 interaction partners). However, "protein binding" is uninformative.
action: MARK_AS_OVER_ANNOTATED
supported_by:
- reference_id: PMID:20211142
supporting_text: An atlas of combinatorial transcriptional regulation in mouse
and man.
reason: GO:0005515 (protein binding) is too vague to be informative for ATF2.
More specific interaction terms such as leucine zipper domain binding (GO:0043522),
protein heterodimerization activity (GO:0046982), or specific binding activities
should be used instead.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:20511396
review:
summary: Protein binding annotation from PMID:20511396. ATF2 interacts with numerous
partners including JUN family, FOS family, ATF family, SMAD proteins, and others
(UniProt lists >30 interaction partners). However, "protein binding" is uninformative.
action: MARK_AS_OVER_ANNOTATED
supported_by:
- reference_id: PMID:20511396
supporting_text: 2010 May 28. In situ proximity ligation detection of c-Jun/AP-1
dimers reveals increased levels of c-Jun/Fra1 complexes in aggressive breast
cancer cell lines in vitro and in vivo.
reason: GO:0005515 (protein binding) is too vague to be informative for ATF2.
More specific interaction terms such as leucine zipper domain binding (GO:0043522),
protein heterodimerization activity (GO:0046982), or specific binding activities
should be used instead.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:22439931
review:
summary: Protein binding annotation from PMID:22439931. ATF2 interacts with numerous
partners including JUN family, FOS family, ATF family, SMAD proteins, and others
(UniProt lists >30 interaction partners). However, "protein binding" is uninformative.
action: MARK_AS_OVER_ANNOTATED
supported_by:
- reference_id: PMID:22439931
supporting_text: 'Deconstruction of the SS18-SSX fusion oncoprotein complex:
insights into disease etiology and therapeutics.'
reason: GO:0005515 (protein binding) is too vague to be informative for ATF2.
More specific interaction terms such as leucine zipper domain binding (GO:0043522),
protein heterodimerization activity (GO:0046982), or specific binding activities
should be used instead.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:23661758
review:
summary: Protein binding annotation from PMID:23661758. ATF2 interacts with numerous
partners including JUN family, FOS family, ATF family, SMAD proteins, and others
(UniProt lists >30 interaction partners). However, "protein binding" is uninformative.
action: MARK_AS_OVER_ANNOTATED
supported_by:
- reference_id: PMID:23661758
supporting_text: Networks of bZIP protein-protein interactions diversified over
a billion years of evolution.
reason: GO:0005515 (protein binding) is too vague to be informative for ATF2.
More specific interaction terms such as leucine zipper domain binding (GO:0043522),
protein heterodimerization activity (GO:0046982), or specific binding activities
should be used instead.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:24705354
review:
summary: Protein binding annotation from PMID:24705354. ATF2 interacts with numerous
partners including JUN family, FOS family, ATF family, SMAD proteins, and others
(UniProt lists >30 interaction partners). However, "protein binding" is uninformative.
action: MARK_AS_OVER_ANNOTATED
supported_by:
- reference_id: PMID:24705354
supporting_text: 'Apr 4. The palmitoyl acyltransferase HIP14 shares a high proportion
of interactors with huntingtin: implications for a role in the pathogenesis
of Huntington''s disease.'
reason: GO:0005515 (protein binding) is too vague to be informative for ATF2.
More specific interaction terms such as leucine zipper domain binding (GO:0043522),
protein heterodimerization activity (GO:0046982), or specific binding activities
should be used instead.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:25416956
review:
summary: Protein binding annotation from PMID:25416956. ATF2 interacts with numerous
partners including JUN family, FOS family, ATF family, SMAD proteins, and others
(UniProt lists >30 interaction partners). However, "protein binding" is uninformative.
action: MARK_AS_OVER_ANNOTATED
supported_by:
- reference_id: PMID:25416956
supporting_text: A proteome-scale map of the human interactome network.
reason: GO:0005515 (protein binding) is too vague to be informative for ATF2.
More specific interaction terms such as leucine zipper domain binding (GO:0043522),
protein heterodimerization activity (GO:0046982), or specific binding activities
should be used instead.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:25609649
review:
summary: Protein binding annotation from PMID:25609649. ATF2 interacts with numerous
partners including JUN family, FOS family, ATF family, SMAD proteins, and others
(UniProt lists >30 interaction partners). However, "protein binding" is uninformative.
action: MARK_AS_OVER_ANNOTATED
supported_by:
- reference_id: PMID:25609649
supporting_text: Proteomic analyses reveal distinct chromatin-associated and
soluble transcription factor complexes.
reason: GO:0005515 (protein binding) is too vague to be informative for ATF2.
More specific interaction terms such as leucine zipper domain binding (GO:0043522),
protein heterodimerization activity (GO:0046982), or specific binding activities
should be used instead.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:26496610
review:
summary: Protein binding annotation from PMID:26496610. ATF2 interacts with numerous
partners including JUN family, FOS family, ATF family, SMAD proteins, and others
(UniProt lists >30 interaction partners). However, "protein binding" is uninformative.
action: MARK_AS_OVER_ANNOTATED
supported_by:
- reference_id: PMID:26496610
supporting_text: Oct 22. A human interactome in three quantitative dimensions
organized by stoichiometries and abundances.
reason: GO:0005515 (protein binding) is too vague to be informative for ATF2.
More specific interaction terms such as leucine zipper domain binding (GO:0043522),
protein heterodimerization activity (GO:0046982), or specific binding activities
should be used instead.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:28514442
review:
summary: Protein binding annotation from PMID:28514442. ATF2 interacts with numerous
partners including JUN family, FOS family, ATF family, SMAD proteins, and others
(UniProt lists >30 interaction partners). However, "protein binding" is uninformative.
action: MARK_AS_OVER_ANNOTATED
supported_by:
- reference_id: PMID:28514442
supporting_text: Architecture of the human interactome defines protein communities
and disease networks.
reason: GO:0005515 (protein binding) is too vague to be informative for ATF2.
More specific interaction terms such as leucine zipper domain binding (GO:0043522),
protein heterodimerization activity (GO:0046982), or specific binding activities
should be used instead.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:31515488
review:
summary: Protein binding annotation from PMID:31515488. ATF2 interacts with numerous
partners including JUN family, FOS family, ATF family, SMAD proteins, and others
(UniProt lists >30 interaction partners). However, "protein binding" is uninformative.
action: MARK_AS_OVER_ANNOTATED
supported_by:
- reference_id: PMID:31515488
supporting_text: Extensive disruption of protein interactions by genetic variants
across the allele frequency spectrum in human populations.
reason: GO:0005515 (protein binding) is too vague to be informative for ATF2.
More specific interaction terms such as leucine zipper domain binding (GO:0043522),
protein heterodimerization activity (GO:0046982), or specific binding activities
should be used instead.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:32296183
review:
summary: Protein binding annotation from PMID:32296183. ATF2 interacts with numerous
partners including JUN family, FOS family, ATF family, SMAD proteins, and others
(UniProt lists >30 interaction partners). However, "protein binding" is uninformative.
action: MARK_AS_OVER_ANNOTATED
supported_by:
- reference_id: PMID:32296183
supporting_text: Apr 8. A reference map of the human binary protein interactome.
reason: GO:0005515 (protein binding) is too vague to be informative for ATF2.
More specific interaction terms such as leucine zipper domain binding (GO:0043522),
protein heterodimerization activity (GO:0046982), or specific binding activities
should be used instead.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:33961781
review:
summary: Protein binding annotation from PMID:33961781. ATF2 interacts with numerous
partners including JUN family, FOS family, ATF family, SMAD proteins, and others
(UniProt lists >30 interaction partners). However, "protein binding" is uninformative.
action: MARK_AS_OVER_ANNOTATED
supported_by:
- reference_id: PMID:33961781
supporting_text: 2021 May 6. Dual proteome-scale networks reveal cell-specific
remodeling of the human interactome.
reason: GO:0005515 (protein binding) is too vague to be informative for ATF2.
More specific interaction terms such as leucine zipper domain binding (GO:0043522),
protein heterodimerization activity (GO:0046982), or specific binding activities
should be used instead.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:35271311
review:
summary: Protein binding annotation from PMID:35271311. ATF2 interacts with numerous
partners including JUN family, FOS family, ATF family, SMAD proteins, and others
(UniProt lists >30 interaction partners). However, "protein binding" is uninformative.
action: MARK_AS_OVER_ANNOTATED
supported_by:
- reference_id: PMID:35271311
supporting_text: '2022 Mar 11. OpenCell: Endogenous tagging for the cartography
of human cellular organization.'
reason: GO:0005515 (protein binding) is too vague to be informative for ATF2.
More specific interaction terms such as leucine zipper domain binding (GO:0043522),
protein heterodimerization activity (GO:0046982), or specific binding activities
should be used instead.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:40205054
review:
summary: Protein binding annotation from PMID:40205054. ATF2 interacts with numerous
partners including JUN family, FOS family, ATF family, SMAD proteins, and others
(UniProt lists >30 interaction partners). However, "protein binding" is uninformative.
action: MARK_AS_OVER_ANNOTATED
supported_by:
- reference_id: PMID:40205054
supporting_text: Apr 9. Multimodal cell maps as a foundation for structural
and functional genomics.
reason: GO:0005515 (protein binding) is too vague to be informative for ATF2.
More specific interaction terms such as leucine zipper domain binding (GO:0043522),
protein heterodimerization activity (GO:0046982), or specific binding activities
should be used instead.
- term:
id: GO:0042802
label: identical protein binding
evidence_type: IPI
original_reference_id: PMID:16511568
review:
summary: ATF2 forms homodimers through its leucine zipper domain. Supported by
PMID:16511568.
action: ACCEPT
supported_by:
- reference_id: PMID:16511568
supporting_text: Mutual regulation of c-Jun and ATF2 by transcriptional activation
and subcellular localization.
reason: Correct. ATF2 homodimerization is well established. More informative than
generic protein binding.
- term:
id: GO:0042802
label: identical protein binding
evidence_type: IPI
original_reference_id: PMID:23661758
review:
summary: ATF2 forms homodimers through its leucine zipper domain. Supported by
PMID:23661758.
action: ACCEPT
supported_by:
- reference_id: PMID:23661758
supporting_text: Networks of bZIP protein-protein interactions diversified over
a billion years of evolution.
reason: Correct. ATF2 homodimerization is well established. More informative than
generic protein binding.
- term:
id: GO:0000165
label: MAPK cascade
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: ATF2 is a direct substrate and effector of the MAPK cascade. JNK, p38,
and ERK phosphorylate ATF2 at Thr-69/Thr-71 to activate its transcriptional
activity (PMID:17267404, deep research review).
action: ACCEPT
reason: Correct. ATF2 is a well-established downstream target/effector in MAPK
signaling.
- term:
id: GO:0000978
label: RNA polymerase II cis-regulatory region sequence-specific DNA binding
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: ATF2 binds cis-regulatory regions (CRE/AP-1 elements) that control RNA
polymerase II transcription. Consistent with its role as a bZIP transcription
factor.
action: ACCEPT
reason: Correct and well supported by experimental evidence.
- term:
id: GO:0001228
label: DNA-binding transcription activator activity, RNA polymerase II-specific
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: ATF2 functions as a transcriptional activator at CRE-dependent promoters
when phosphorylated (PMID:10821277, PMID:17267404). Also acts as repressor in
some contexts (PMID:20116378).
action: ACCEPT
reason: Correct. ATF2 has well-documented transcription activator function, though
it can also repress in some contexts.
- term:
id: GO:0001701
label: in utero embryonic development
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: ATF2 knockout mice show developmental defects. This is a pleiotropic
downstream phenotypic consequence of ATF2 transcription factor activity, not
a core molecular function.
action: KEEP_AS_NON_CORE
reason: Pleiotropic developmental phenotype from mouse knockout studies. Not a
core function but a downstream consequence of ATF2 transcriptional regulation.
- term:
id: GO:0001865
label: NK T cell differentiation
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Transferred from mouse ortholog data. ATF2 is a broadly expressed transcription
factor; effects on NKT cell differentiation likely reflect pleiotropic transcriptional
regulation rather than a specific dedicated function.
action: KEEP_AS_NON_CORE
reason: Pleiotropic effect. ATF2 is ubiquitously expressed and regulates many
genes; this is a downstream phenotypic outcome, not a core function.
- term:
id: GO:0001889
label: liver development
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Transferred from mouse ortholog. Liver development phenotype in ATF2
mutant mice is a pleiotropic consequence of loss of a ubiquitous transcription
factor.
action: KEEP_AS_NON_CORE
reason: Pleiotropic developmental phenotype, not a core function of ATF2.
- term:
id: GO:0002244
label: hematopoietic progenitor cell differentiation
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Ortholog transfer from mouse. Pleiotropic effect of ATF2 transcriptional
regulation on hematopoietic differentiation.
action: KEEP_AS_NON_CORE
reason: Pleiotropic downstream effect, not core function.
- term:
id: GO:0003360
label: brainstem development
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Ortholog transfer from mouse. ATF2 is expressed in brain and knockout
causes brainstem defects. This is a tissue-specific developmental phenotype.
action: KEEP_AS_NON_CORE
reason: Pleiotropic developmental phenotype in mouse.
- term:
id: GO:0003418
label: growth plate cartilage chondrocyte differentiation
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Ortholog transfer from mouse. Highly specific developmental phenotype
from mouse knockout, reflecting pleiotropic transcriptional effects.
action: KEEP_AS_NON_CORE
reason: Overly specific developmental phenotype for a ubiquitous transcription
factor. Pleiotropic.
- term:
id: GO:0003419
label: growth plate cartilage chondrocyte proliferation
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Ortholog transfer from mouse. Similar to chondrocyte differentiation,
this is a pleiotropic downstream phenotype.
action: KEEP_AS_NON_CORE
reason: Pleiotropic developmental phenotype.
- term:
id: GO:0003682
label: chromatin binding
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: ATF2 binds chromatin as demonstrated by ChIP experiments showing binding
to AARE elements in the CHOP promoter (PMID:17267404). Also has intrinsic HAT
activity (PMID:10821277).
action: ACCEPT
reason: Correct. ATF2 binds chromatin at target gene promoters as shown by ChIP
assays.
- term:
id: GO:0006606
label: protein import into nucleus
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: ATF2 shuttles between cytoplasm and nucleus, with nuclear import regulated
by heterodimerization with JUN and PKC-epsilon phosphorylation (PMID:22304920).
However, this describes the regulation of ATF2 localization rather than ATF2
functioning as a nuclear import factor.
action: MARK_AS_OVER_ANNOTATED
reason: ATF2 is imported into the nucleus but does not function as a nuclear import
factor. This annotation likely reflects the biology of ATF2 being a substrate
of nuclear import, not an active participant in the import machinery.
- term:
id: GO:0006629
label: lipid metabolic process
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Ortholog transfer. Connection to lipid metabolism is indirect at best.
ATF2 may regulate some lipid metabolism genes transcriptionally but this is
not a core function.
action: MARK_AS_OVER_ANNOTATED
reason: Tangential. ATF2 is a general transcription factor that may regulate some
lipid metabolism genes, but lipid metabolism is not a defining function.
- term:
id: GO:0006915
label: apoptotic process
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: ATF2 participates in apoptosis through its mitochondrial localization
where it perturbs HK1-VDAC1 complexes and increases mitochondrial membrane permeability
(PMID:22304920). It also regulates pro-apoptotic gene transcription.
action: KEEP_AS_NON_CORE
reason: ATF2 has a documented role in apoptosis via mitochondrial function and
transcriptional regulation of apoptotic genes. However, this is context-dependent
(genotoxic stress, specific cancer types), not a core constitutive function.
- term:
id: GO:0007033
label: vacuole organization
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Ortholog transfer. Very weak connection to ATF2 known biology. No direct
evidence for ATF2 involvement in vacuole organization.
action: MARK_AS_OVER_ANNOTATED
reason: No clear mechanistic link between ATF2 and vacuole organization. Likely
an artifact of ortholog transfer from a pleiotropic phenotype.
- term:
id: GO:0007254
label: JNK cascade
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: ATF2 is a direct downstream target of the JNK cascade. JNK phosphorylates
ATF2 at Thr-69/Thr-71 (PMID:17267404, UniProt). ATF2 is a key effector of JNK
signaling.
action: ACCEPT
reason: Correct. ATF2 is a well-established direct substrate and effector of JNK
signaling.
- term:
id: GO:0007507
label: heart development
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Ortholog transfer from mouse. Developmental phenotype, pleiotropic effect
of ubiquitous transcription factor.
action: KEEP_AS_NON_CORE
reason: Pleiotropic developmental phenotype.
- term:
id: GO:0010467
label: gene expression
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: ATF2 regulates gene expression as a transcription factor. This is extremely
general and redundant with more specific transcription regulation terms.
action: MARK_AS_OVER_ANNOTATED
reason: Too general. More specific transcription regulation terms are already
annotated.
- term:
id: GO:0016020
label: membrane
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: ATF2 localizes to the mitochondrial outer membrane under specific conditions
(PMID:22304920). However, GO:0016020 (membrane) is extremely non-specific.
action: ACCEPT
reason: Correct but very general. More specific term GO:0005741 (mitochondrial
outer membrane) is also annotated. Acceptable as broad IEA.
- term:
id: GO:0021742
label: abducens nucleus development
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Ortholog transfer from mouse. Highly specific brainstem nucleus developmental
phenotype. ATF2 knockout mice show brainstem developmental defects.
action: KEEP_AS_NON_CORE
reason: Very specific developmental phenotype from mouse knockout. Pleiotropic.
- term:
id: GO:0021743
label: hypoglossal nucleus development
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Ortholog transfer from mouse. Highly specific brainstem developmental
phenotype.
action: KEEP_AS_NON_CORE
reason: Very specific developmental phenotype from mouse knockout. Pleiotropic.
- term:
id: GO:0021754
label: facial nucleus development
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Ortholog transfer from mouse. Highly specific brainstem developmental
phenotype.
action: KEEP_AS_NON_CORE
reason: Very specific developmental phenotype from mouse knockout. Pleiotropic.
- term:
id: GO:0030509
label: BMP signaling pathway
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: ATF2 interacts with SMAD3 and SMAD4 (UniProt) and may participate in
BMP/TGF-beta signaling crosstalk. However, this is not a core function.
action: KEEP_AS_NON_CORE
reason: ATF2 can interact with SMAD proteins and participate in BMP signaling,
but this represents a context-dependent signaling crosstalk rather than a core
function.
- term:
id: GO:0034599
label: cellular response to oxidative stress
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: ATF2 integrates with CREB1-NRF2 signaling to induce glutathione synthesis
genes (GCLC, GCLM, GSR, PRDX1) supporting redox homeostasis (Ju et al., 2023,
PMID not available in publications). ATF2 is activated by stress-responsive
MAPKs.
action: ACCEPT
reason: Supported by evidence. ATF2 responds to oxidative stress through MAPK
activation and regulates antioxidant gene programs.
- term:
id: GO:0035497
label: cAMP response element binding
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Duplicate of IBA annotation for the same term. ATF2 binds CRE elements
as a core function.
action: ACCEPT
reason: Correct. Redundant with IBA annotation but acceptable.
- term:
id: GO:0035861
label: site of double-strand break
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: ATF2 localizes to sites of double-strand breaks (IR-induced foci) following
ATM-mediated phosphorylation at Ser-490/Ser-498 (PMID:15916964).
action: ACCEPT
reason: Correct. Experimentally demonstrated by Bhoumik et al. 2005.
- term:
id: GO:0038066
label: p38MAPK cascade
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: ATF2 is a direct substrate and effector of p38 MAPK signaling. p38 phosphorylates
ATF2 at Thr-69/Thr-71 (UniProt, PMID:9430721).
action: ACCEPT
reason: Correct. ATF2 is a well-established downstream target of p38 MAPK.
- term:
id: GO:0042789
label: mRNA transcription by RNA polymerase II
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: ATF2 activates mRNA transcription by RNA polymerase II at CRE-dependent
promoters. Consistent with core function.
action: ACCEPT
reason: Correct. Core transcriptional function of ATF2.
- term:
id: GO:0042803
label: protein homodimerization activity
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: ATF2 forms homodimers through its leucine zipper domain. This is well
established (UniProt, PMID:10821277).
action: ACCEPT
reason: Correct. ATF2 homodimerization is a well-characterized feature of its
bZIP domain.
- term:
id: GO:0043522
label: leucine zipper domain binding
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: ATF2 contains a leucine zipper domain (residues 380-408, UniProt) used
for dimerization with other bZIP proteins including JUN, FOS, and ATF family
members.
action: ACCEPT
reason: Correct. The leucine zipper mediates homo- and heterodimerization, a defining
feature of bZIP proteins.
- term:
id: GO:0043565
label: sequence-specific DNA binding
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: ATF2 binds specific DNA sequences (CRE and AP-1 elements). More specific
terms are also annotated (GO:0035497).
action: ACCEPT
reason: Correct but general. Acceptable alongside more specific DNA binding terms.
- term:
id: GO:0045944
label: positive regulation of transcription by RNA polymerase II
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: ATF2 activates transcription at CRE-dependent promoters when phosphorylated
by MAPKs (PMID:17267404, PMID:10821277).
action: ACCEPT
reason: Correct. ATF2 is a transcriptional activator when phosphorylated.
- term:
id: GO:0046982
label: protein heterodimerization activity
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: ATF2 forms heterodimers with JUN, FOS, and other bZIP proteins via its
leucine zipper domain. Heterodimerization with JUN is essential for nuclear
localization and full transcriptional activity (UniProt, PMID:16511568).
action: ACCEPT
reason: Correct. Heterodimerization is a core feature of ATF2 biology.
- term:
id: GO:0050872
label: white fat cell differentiation
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Ortholog transfer. Pleiotropic transcriptional effect on adipocyte differentiation,
not a core function.
action: KEEP_AS_NON_CORE
reason: Pleiotropic downstream effect of transcriptional regulation. Not core.
- term:
id: GO:0060052
label: neurofilament cytoskeleton organization
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Ortholog transfer from mouse. ATF2 may regulate neurofilament genes transcriptionally
but this is not a core function.
action: KEEP_AS_NON_CORE
reason: Pleiotropic downstream developmental phenotype.
- term:
id: GO:0060245
label: detection of cell density
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Ortholog transfer. Weak connection to ATF2 core biology. May reflect
indirect transcriptional effects.
action: MARK_AS_OVER_ANNOTATED
reason: No clear direct mechanistic link. Likely indirect consequence of broad
transcriptional regulation.
- term:
id: GO:0072740
label: cellular response to anisomycin
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Anisomycin activates JNK and p38 MAPK, which phosphorylate ATF2. This
annotation reflects ATF2 activation by a specific MAPK-activating stimulus.
action: KEEP_AS_NON_CORE
reason: Correct but very specific stimulus. ATF2 responds to many MAPK-activating
stresses; anisomycin is just one example.
- term:
id: GO:0097049
label: motor neuron apoptotic process
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Ortholog transfer from mouse. Highly specific developmental/apoptotic
phenotype.
action: KEEP_AS_NON_CORE
reason: Very specific phenotype from mouse studies. Pleiotropic.
- term:
id: GO:0097284
label: hepatocyte apoptotic process
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Ortholog transfer. ATF2 has roles in apoptosis generally, but hepatocyte-specific
apoptosis is a tissue-specific manifestation.
action: KEEP_AS_NON_CORE
reason: Tissue-specific manifestation of a broader apoptotic function.
- term:
id: GO:0098586
label: cellular response to virus
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: ATF2 participates in antiviral responses, including through IFN-lambda1
stimulation (PMID:23729669). ATF2/AP-1 transcription complexes regulate immune
response genes.
action: KEEP_AS_NON_CORE
reason: ATF2 regulates some immune/antiviral genes but this is a context-dependent
function, not core.
- term:
id: GO:1990144
label: intrinsic apoptotic signaling pathway in response to hypoxia
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Ortholog transfer. ATF2 has roles in apoptotic signaling, and MAPK activation
occurs under hypoxia. This is a specific context for ATF2 apoptotic function.
action: KEEP_AS_NON_CORE
reason: Context-specific manifestation of ATF2 apoptotic function.
- term:
id: GO:1990841
label: promoter-specific chromatin binding
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: ATF2 binds chromatin at specific promoters as demonstrated by ChIP (PMID:17267404).
Consistent with its transcription factor function.
action: ACCEPT
reason: Correct. Experimentally validated by ChIP studies.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: IDA
original_reference_id: GO_REF:0000052
review:
summary: ATF2 localizes to the nucleoplasm as expected for a transcription factor.
Supported by immunofluorescence data.
action: ACCEPT
reason: Correct. ATF2 is primarily a nuclear/nucleoplasmic protein.
- term:
id: GO:0004402
label: histone acetyltransferase activity
evidence_type: TAS
original_reference_id: Reactome:R-HSA-3318415
review:
summary: ATF2 has reported intrinsic HAT activity toward H2B and H4 (PMID:10821277,
Kawasaki et al. 2000, Nature). However, UniProt notes a CAUTION that this activity
may be due to contamination. Reactome pathway R-HSA-3318415 describes ATF2 acetylating
H2B and H4.
action: UNDECIDED
reason: The HAT activity of ATF2 was reported in Nature (PMID:10821277) and supported
by follow-up work (PMID:17267404 showing ATF2-dependent histone acetylation
in vivo). However, UniProt flags this with a CAUTION note suggesting possible
contamination. The evidence is mixed - the in vitro HAT activity may be genuine
but requires further validation.
- term:
id: GO:0005634
label: nucleus
evidence_type: NAS
original_reference_id: PMID:28186491
review:
summary: Nuclear localization of ATF2 demonstrated with NAS evidence from PMID:28186491.
Consistent with its role as a transcription factor.
action: ACCEPT
supported_by:
- reference_id: PMID:28186491
supporting_text: Combinatorial bZIP dimers display complex DNA-binding specificity
landscapes.
reason: Correct. ATF2 is primarily nuclear.
- term:
id: GO:0006357
label: regulation of transcription by RNA polymerase II
evidence_type: NAS
original_reference_id: PMID:28186491
review:
summary: Regulation of transcription by RNA polymerase II from PMID:28186491.
Core function of ATF2.
action: ACCEPT
supported_by:
- reference_id: PMID:28186491
supporting_text: Combinatorial bZIP dimers display complex DNA-binding specificity
landscapes.
reason: Correct. Core function.
- term:
id: GO:0000122
label: negative regulation of transcription by RNA polymerase II
evidence_type: EXP
original_reference_id: PMID:11231009
review:
summary: PMID:11231009 identifies JDP2 as a repressor of ATF-2. ATF2 also has
documented repressive activity, e.g., repression of thrombomodulin via HDAC4
recruitment (PMID:20116378). This annotation indicates ATF2 participates in
negative regulation of transcription.
action: ACCEPT
supported_by:
- reference_id: PMID:11231009
supporting_text: Identification of mouse Jun dimerization protein 2 as a novel
repressor of ATF-2.
reason: Correct. ATF2 can act as both activator and repressor depending on context
and binding partners. Both activation and repression are documented functions.
- term:
id: GO:0005634
label: nucleus
evidence_type: EXP
original_reference_id: PMID:11231009
review:
summary: Nuclear localization of ATF2 demonstrated with EXP evidence from PMID:11231009.
Consistent with its role as a transcription factor.
action: ACCEPT
supported_by:
- reference_id: PMID:11231009
supporting_text: Identification of mouse Jun dimerization protein 2 as a novel
repressor of ATF-2.
reason: Correct. ATF2 is primarily nuclear.
- term:
id: GO:0005634
label: nucleus
evidence_type: NAS
original_reference_id: PMID:20102225
review:
summary: Nuclear localization of ATF2 demonstrated with NAS evidence from PMID:20102225.
Consistent with its role as a transcription factor.
action: ACCEPT
supported_by:
- reference_id: PMID:20102225
supporting_text: Identification of bZIP interaction partners of viral proteins
HBZ, MEQ, BZLF1, and K-bZIP using coiled-coil arrays.
reason: Correct. ATF2 is primarily nuclear.
- term:
id: GO:0005634
label: nucleus
evidence_type: NAS
original_reference_id: PMID:23661758
review:
summary: Nuclear localization of ATF2 demonstrated with NAS evidence from PMID:23661758.
Consistent with its role as a transcription factor.
action: ACCEPT
supported_by:
- reference_id: PMID:23661758
supporting_text: Networks of bZIP protein-protein interactions diversified over
a billion years of evolution.
reason: Correct. ATF2 is primarily nuclear.
- term:
id: GO:0006357
label: regulation of transcription by RNA polymerase II
evidence_type: NAS
original_reference_id: PMID:20102225
review:
summary: Regulation of transcription by RNA polymerase II from PMID:20102225.
Core function of ATF2.
action: ACCEPT
supported_by:
- reference_id: PMID:20102225
supporting_text: Identification of bZIP interaction partners of viral proteins
HBZ, MEQ, BZLF1, and K-bZIP using coiled-coil arrays.
reason: Correct. Core function.
- term:
id: GO:0006357
label: regulation of transcription by RNA polymerase II
evidence_type: NAS
original_reference_id: PMID:23661758
review:
summary: Regulation of transcription by RNA polymerase II from PMID:23661758.
Core function of ATF2.
action: ACCEPT
supported_by:
- reference_id: PMID:23661758
supporting_text: Networks of bZIP protein-protein interactions diversified over
a billion years of evolution.
reason: Correct. Core function.
- term:
id: GO:0045815
label: transcription initiation-coupled chromatin remodeling
evidence_type: IDA
original_reference_id: PMID:10821277
review:
summary: PMID:10821277 reports ATF2 has intrinsic HAT activity that acetylates
H2B and H4, modulated by phosphorylation. This connects ATF2 to chromatin remodeling
coupled to transcription initiation. However, UniProt cautions this HAT activity
may be due to contamination.
action: UNDECIDED
supported_by:
- reference_id: PMID:10821277
supporting_text: ATF-2 has intrinsic histone acetyltransferase activity which
is modulated by phosphorylation.
reason: Depends on whether ATF2 HAT activity is genuine. PMID:10821277 reports
intrinsic HAT, but UniProt flags potential contamination. PMID:17267404 provides
in vivo support showing ATF2-dependent histone acetylation at target promoters.
The annotation is plausible but uncertain.
- term:
id: GO:0035497
label: cAMP response element binding
evidence_type: IDA
original_reference_id: PMID:23729669
review:
summary: CRE binding demonstrated by direct assay from PMID:23729669. Core molecular
function of ATF2.
action: ACCEPT
supported_by:
- reference_id: PMID:23729669
supporting_text: Epub 2013 May 31. Inducible interleukin 32 (IL-32) exerts extensive
antiviral function via selective stimulation of interferon Ī»1 (IFN-Ī»1).
reason: Core function. ATF2 was originally identified as CRE-BP1.
- term:
id: GO:0018107
label: peptidyl-threonine phosphorylation
evidence_type: IDA
original_reference_id: PMID:17267404
review:
summary: 'MISANNOTATION: ATF2 is a bZIP transcription factor that is extensively
PHOSPHORYLATED at Thr-69 and Thr-71 by kinases (p38 MAPK, ERK, CaMK4, JNK).
PMID:17267404 describes "phosphorylation of ATF2 on Thr71 precedes histone acetylation"
- ATF2 is the SUBSTRATE of phosphorylation, not the enzyme. ATF2 has histone
acetyltransferase (HAT) activity (EC 2.3.1.48), not kinase activity. The phosphorylation
of ATF2 activates its transcription factor and HAT activities, but ATF2 does
not catalyze phosphorylation reactions.'
action: REMOVE
supported_by:
- reference_id: PMID:17267404
supporting_text: ATF2 is required for amino acid-regulated transcription by
orchestrating specific histone acetylation.
- term:
id: GO:0045944
label: positive regulation of transcription by RNA polymerase II
evidence_type: IDA
original_reference_id: PMID:17267404
review:
summary: Positive regulation of transcription by RNA polymerase II from PMID:17267404.
ATF2 activates CRE-dependent transcription when phosphorylated.
action: ACCEPT
supported_by:
- reference_id: PMID:17267404
supporting_text: ATF2 is required for amino acid-regulated transcription by
orchestrating specific histone acetylation.
reason: Correct. Core transcriptional activator function of ATF2.
- term:
id: GO:1990253
label: cellular response to leucine starvation
evidence_type: IDA
original_reference_id: PMID:17267404
review:
summary: PMID:17267404 demonstrates ATF2 is essential for CHOP transcriptional
induction upon leucine starvation, orchestrating histone acetylation at the
AARE. ATF2 is phosphorylated and binds the CHOP promoter in response to amino
acid deprivation.
action: KEEP_AS_NON_CORE
supported_by:
- reference_id: PMID:17267404
supporting_text: in cells devoid of ATF2 expression, the induction of CHOP transcription
upon amino acid starvation is completely lost
reason: Correct and experimentally validated. However, this is a specific stimulus
context (leucine starvation) for the general stress-responsive transcription
function of ATF2.
- term:
id: GO:1990841
label: promoter-specific chromatin binding
evidence_type: IDA
original_reference_id: PMID:17267404
review:
summary: PMID:17267404 demonstrates ATF2 binding at the CHOP AARE by ChIP. ATF2
bound to the AARE promotes histone acetylation in vivo.
action: ACCEPT
supported_by:
- reference_id: PMID:17267404
supporting_text: binding of ATF2 and ATF4 to CHOP AARE are associated with acetylation
of histones H4 and H2B in response to amino acid starvation
reason: Correct. Experimentally demonstrated by ChIP in PMID:17267404.
- term:
id: GO:0010485
label: histone H4 acetyltransferase activity
evidence_type: IDA
original_reference_id: PMID:10821277
review:
summary: PMID:10821277 reports ATF2 specifically acetylates histones H2B and H4
in vitro. UniProt cautions this may be due to contamination, but PMID:17267404
provides in vivo support for ATF2-dependent H4 acetylation.
action: UNDECIDED
supported_by:
- reference_id: PMID:10821277
supporting_text: ATF-2 has intrinsic histone acetyltransferase activity which
is modulated by phosphorylation.
reason: The in vitro HAT activity toward H4 is reported (PMID:10821277) and in
vivo H4 acetylation depends on ATF2 (PMID:17267404). However, UniProt expresses
caution about contamination. Evidence is suggestive but not definitive.
- term:
id: GO:0044013
label: histone H2B acetyltransferase activity
evidence_type: IDA
original_reference_id: PMID:10821277
review:
summary: PMID:10821277 reports ATF2 specifically acetylates H2B in vitro. UniProt
flags potential contamination. PMID:17267404 shows ATF2-dependent H2B acetylation
in vivo at the CHOP promoter.
action: UNDECIDED
supported_by:
- reference_id: PMID:10821277
supporting_text: ATF-2 has intrinsic histone acetyltransferase activity which
is modulated by phosphorylation.
reason: Similar to H4 HAT activity - reported in PMID:10821277, supported in vivo
by PMID:17267404, but flagged with caution by UniProt.
- term:
id: GO:1902562
label: H4 histone acetyltransferase complex
evidence_type: IDA
original_reference_id: PMID:10821277
review:
summary: This annotation places ATF2 in an H4 histone acetyltransferase complex
based on PMID:10821277. Given uncertainty about ATF2 intrinsic HAT activity
(UniProt caution), this localization annotation is uncertain.
action: UNDECIDED
supported_by:
- reference_id: PMID:10821277
supporting_text: ATF-2 has intrinsic histone acetyltransferase activity which
is modulated by phosphorylation.
reason: Depends on the validity of ATF2 HAT activity. UniProt expresses caution.
- term:
id: GO:1990837
label: sequence-specific double-stranded DNA binding
evidence_type: IDA
original_reference_id: PMID:28473536
review:
summary: PMID:28473536 studies impact of cytosine methylation on DNA binding of
transcription factors including ATF2. ATF2 binds double-stranded DNA in a sequence-specific
manner.
action: ACCEPT
supported_by:
- reference_id: PMID:28473536
supporting_text: Impact of cytosine methylation on DNA binding specificities
of human transcription factors.
reason: Correct. ATF2 is a sequence-specific dsDNA-binding protein.
- term:
id: GO:0000785
label: chromatin
evidence_type: IDA
original_reference_id: PMID:23729669
review:
summary: PMID:23729669 demonstrates ATF2 binding to chromatin at the IFN-lambda1
promoter in the context of IL-32-induced antiviral response. ChIP evidence.
action: ACCEPT
supported_by:
- reference_id: PMID:23729669
supporting_text: Epub 2013 May 31. Inducible interleukin 32 (IL-32) exerts extensive
antiviral function via selective stimulation of interferon Ī»1 (IFN-Ī»1).
reason: Correct. ATF2 chromatin association demonstrated by ChIP.
- term:
id: GO:0001228
label: DNA-binding transcription activator activity, RNA polymerase II-specific
evidence_type: IDA
original_reference_id: PMID:16300731
review:
summary: Transcription activator activity demonstrated from PMID:16300731. ATF2
activates CRE-dependent transcription.
action: ACCEPT
supported_by:
- reference_id: PMID:16300731
supporting_text: ATF5 increases cisplatin-induced apoptosis through up-regulation
of cyclin D3 transcription in HeLa cells.
reason: Correct. Core transcription activator function of ATF2.
- term:
id: GO:0000785
label: chromatin
evidence_type: ISA
original_reference_id: GO_REF:0000113
review:
summary: ATF2 associates with chromatin at target gene promoters as shown by ChIP
(PMID:17267404). Consistent with transcription factor function.
action: ACCEPT
reason: Correct. TFClass-based annotation supported by experimental ChIP data.
- term:
id: GO:0000981
label: DNA-binding transcription factor activity, RNA polymerase II-specific
evidence_type: ISA
original_reference_id: GO_REF:0000113
review:
summary: ATF2 is an RNA polymerase II-specific transcription factor. Consistent
with IBA and other experimental annotations.
action: ACCEPT
reason: Correct. Redundant with IBA but acceptable.
- term:
id: GO:0001228
label: DNA-binding transcription activator activity, RNA polymerase II-specific
evidence_type: IDA
original_reference_id: PMID:18671972
review:
summary: Transcription activator activity demonstrated from PMID:18671972. ATF2
activates CRE-dependent transcription.
action: ACCEPT
supported_by:
- reference_id: PMID:18671972
supporting_text: Epub 2008 Jul 29. IRF2-binding protein-1 is a JDP2 ubiquitin
ligase and an inhibitor of ATF2-dependent transcription.
reason: Correct. Core transcription activator function of ATF2.
- term:
id: GO:0045944
label: positive regulation of transcription by RNA polymerase II
evidence_type: IDA
original_reference_id: PMID:18671972
review:
summary: Positive regulation of transcription by RNA polymerase II from PMID:18671972.
ATF2 activates CRE-dependent transcription when phosphorylated.
action: ACCEPT
supported_by:
- reference_id: PMID:18671972
supporting_text: Epub 2008 Jul 29. IRF2-binding protein-1 is a JDP2 ubiquitin
ligase and an inhibitor of ATF2-dependent transcription.
reason: Correct. Core transcriptional activator function of ATF2.
- term:
id: GO:0001228
label: DNA-binding transcription activator activity, RNA polymerase II-specific
evidence_type: IDA
original_reference_id: PMID:19861239
review:
summary: Transcription activator activity demonstrated from PMID:19861239. ATF2
activates CRE-dependent transcription.
action: ACCEPT
supported_by:
- reference_id: PMID:19861239
supporting_text: Epub 2009 Oct 27. cJun modulates Ggamma-globin gene expression
via an upstream cAMP response element.
reason: Correct. Core transcription activator function of ATF2.
- term:
id: GO:0006357
label: regulation of transcription by RNA polymerase II
evidence_type: IDA
original_reference_id: PMID:19861239
review:
summary: PMID:19861239 shows ATF2 regulates gamma-globin gene transcription through
CRE elements. Core function.
action: ACCEPT
supported_by:
- reference_id: PMID:19861239
supporting_text: Epub 2009 Oct 27. cJun modulates Ggamma-globin gene expression
via an upstream cAMP response element.
reason: Correct. Core transcription regulation function.
- term:
id: GO:0010628
label: positive regulation of gene expression
evidence_type: IMP
original_reference_id: PMID:28977001
review:
summary: PMID:28977001 describes miR-30b regulation of TGF-beta2 in endothelial
cells, with ATF2 as a target. The connection to ATF2 as a positive regulator
of gene expression is indirect through miRNA targeting.
action: MARK_AS_OVER_ANNOTATED
supported_by:
- reference_id: PMID:28977001
supporting_text: eCollection 2017. MicroRNA-30b controls endothelial cell capillary
morphogenesis through regulation of transforming growth factor beta 2.
reason: ATF2 is a general transcription factor that positively regulates many
genes. This annotation from a miRNA study context is too broad and indirect.
- term:
id: GO:0016525
label: negative regulation of angiogenesis
evidence_type: IMP
original_reference_id: PMID:28977001
review:
summary: PMID:28977001 describes miR-30b effects on angiogenesis via TGF-beta2,
with ATF2 involvement. The connection of ATF2 to angiogenesis regulation appears
indirect.
action: MARK_AS_OVER_ANNOTATED
supported_by:
- reference_id: PMID:28977001
supporting_text: eCollection 2017. MicroRNA-30b controls endothelial cell capillary
morphogenesis through regulation of transforming growth factor beta 2.
reason: Indirect involvement. ATF2 is not primarily an angiogenesis regulator;
this likely reflects indirect transcriptional effects in a specific experimental
context.
- term:
id: GO:0110024
label: positive regulation of cardiac muscle myoblast proliferation
evidence_type: IDA
original_reference_id: PMID:22982025
review:
summary: PMID:22982025 describes miR-204 in cardiomyocyte progenitor differentiation,
with ATF2 as a target. The annotation of ATF2 as positively regulating cardiac
myoblast proliferation appears to be based on ATF2 being a miRNA target rather
than a direct cardiac function.
action: MARK_AS_OVER_ANNOTATED
supported_by:
- reference_id: PMID:22982025
supporting_text: Epub 2012 Sep 7. MicroRNA-204 is required for differentiation
of human-derived cardiomyocyte progenitor cells.
reason: Indirect. ATF2 is a target of miR-204 in this context. The cardiac proliferation
effect is mediated through miRNA regulation of ATF2 levels, not a direct core
function of ATF2.
- term:
id: GO:0000987
label: cis-regulatory region sequence-specific DNA binding
evidence_type: IDA
original_reference_id: PMID:2196176
review:
summary: PMID:2196176 cloned CRE-BP1 (ATF2) and showed it binds the tax-dependent
enhancer of HTLV-1 containing CRE-like elements. Demonstrates cis-regulatory
region sequence-specific DNA binding.
action: ACCEPT
supported_by:
- reference_id: PMID:2196176
supporting_text: 'Multiple cDNA clones encoding nuclear proteins that bind to
the tax-dependent enhancer of HTLV-1: all contain a leucine zipper structure
and basic amino acid domain.'
reason: Correct. Core DNA-binding function of ATF2.
- term:
id: GO:0045944
label: positive regulation of transcription by RNA polymerase II
evidence_type: IDA
original_reference_id: PMID:16300731
review:
summary: Positive regulation of transcription by RNA polymerase II from PMID:16300731.
ATF2 activates CRE-dependent transcription when phosphorylated.
action: ACCEPT
supported_by:
- reference_id: PMID:16300731
supporting_text: ATF5 increases cisplatin-induced apoptosis through up-regulation
of cyclin D3 transcription in HeLa cells.
reason: Correct. Core transcriptional activator function of ATF2.
- term:
id: GO:0000977
label: RNA polymerase II transcription regulatory region sequence-specific DNA
binding
evidence_type: IMP
original_reference_id: PMID:2516827
review:
summary: PMID:2516827 describes ATF family cDNA clones as leucine zipper proteins
that form DNA-binding heterodimers. Demonstrates sequence-specific DNA binding
to transcription regulatory regions.
action: ACCEPT
supported_by:
- reference_id: PMID:2516827
supporting_text: 'Transcription factor ATF cDNA clones: an extensive family
of leucine zipper proteins able to selectively form DNA-binding heterodimers.'
reason: Correct. Core function demonstrated in early characterization of ATF family.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:15916964
review:
summary: Protein binding annotation from PMID:15916964. ATF2 interacts with numerous
partners including JUN family, FOS family, ATF family, SMAD proteins, and others
(UniProt lists >30 interaction partners). However, "protein binding" is uninformative.
action: MARK_AS_OVER_ANNOTATED
supported_by:
- reference_id: PMID:15916964
supporting_text: ATM-dependent phosphorylation of ATF2 is required for the DNA
damage response.
reason: GO:0005515 (protein binding) is too vague to be informative for ATF2.
More specific interaction terms such as leucine zipper domain binding (GO:0043522),
protein heterodimerization activity (GO:0046982), or specific binding activities
should be used instead.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:18397884
review:
summary: Protein binding annotation from PMID:18397884. ATF2 interacts with numerous
partners including JUN family, FOS family, ATF family, SMAD proteins, and others
(UniProt lists >30 interaction partners). However, "protein binding" is uninformative.
action: MARK_AS_OVER_ANNOTATED
supported_by:
- reference_id: PMID:18397884
supporting_text: 2008 Apr 8. Regulation of TIP60 by ATF2 modulates ATM activation.
reason: GO:0005515 (protein binding) is too vague to be informative for ATF2.
More specific interaction terms such as leucine zipper domain binding (GO:0043522),
protein heterodimerization activity (GO:0046982), or specific binding activities
should be used instead.
- term:
id: GO:0005634
label: nucleus
evidence_type: IDA
original_reference_id: PMID:18397884
review:
summary: Nuclear localization of ATF2 demonstrated with IDA evidence from PMID:18397884.
Consistent with its role as a transcription factor.
action: ACCEPT
supported_by:
- reference_id: PMID:18397884
supporting_text: 2008 Apr 8. Regulation of TIP60 by ATF2 modulates ATM activation.
reason: Correct. ATF2 is primarily nuclear.
- term:
id: GO:0005634
label: nucleus
evidence_type: IDA
original_reference_id: PMID:22304920
review:
summary: Nuclear localization of ATF2 demonstrated with IDA evidence from PMID:22304920.
Consistent with its role as a transcription factor.
action: ACCEPT
supported_by:
- reference_id: PMID:22304920
supporting_text: PKCĪµ promotes oncogenic functions of ATF2 in the nucleus while
blocking its apoptotic function at mitochondria.
reason: Correct. ATF2 is primarily nuclear.
- term:
id: GO:0005737
label: cytoplasm
evidence_type: IDA
original_reference_id: PMID:22304920
review:
summary: PMID:22304920 demonstrates ATF2 cytoplasmic localization, particularly
under genotoxic stress when PKC-epsilon effect is attenuated. ATF2 nuclear export
enables mitochondrial localization.
action: ACCEPT
supported_by:
- reference_id: PMID:22304920
supporting_text: PKCĪµ promotes oncogenic functions of ATF2 in the nucleus while
blocking its apoptotic function at mitochondria.
reason: Correct. Experimentally demonstrated in Lau et al. 2012 (Cell).
- term:
id: GO:0005741
label: mitochondrial outer membrane
evidence_type: IDA
original_reference_id: PMID:22304920
review:
summary: PMID:22304920 demonstrates ATF2 localization to the mitochondrial outer
membrane under genotoxic stress, where it perturbs HK1-VDAC1 complexes.
action: ACCEPT
supported_by:
- reference_id: PMID:22304920
supporting_text: PKCĪµ promotes oncogenic functions of ATF2 in the nucleus while
blocking its apoptotic function at mitochondria.
reason: Correct. Experimentally demonstrated in Lau et al. 2012 (Cell).
- term:
id: GO:0006355
label: regulation of DNA-templated transcription
evidence_type: IMP
original_reference_id: PMID:22304920
review:
summary: PMID:22304920 shows PKC-epsilon promotes ATF2 oncogenic transcriptional
functions in the nucleus. ATF2 regulates transcription of target genes.
action: ACCEPT
supported_by:
- reference_id: PMID:22304920
supporting_text: PKCĪµ promotes oncogenic functions of ATF2 in the nucleus while
blocking its apoptotic function at mitochondria.
reason: Correct. Core function.
- term:
id: GO:0006974
label: DNA damage response
evidence_type: IMP
original_reference_id: PMID:15916964
review:
summary: PMID:15916964 demonstrates ATM phosphorylates ATF2 at Ser-490/498 following
IR, leading to ATF2 colocalization with gamma-H2AX and MRN complex in IRIF.
Inhibition of ATF2 impairs DDR including S-phase checkpoint and ATM activation.
action: ACCEPT
supported_by:
- reference_id: PMID:15916964
supporting_text: Inhibition of ATF2 expression decreased recruitment of Mre11
to IRIF, abrogated S phase checkpoint, reduced activation of ATM, Chk1, and
Chk2, and impaired radioresistance
reason: Correct. Well-established non-transcriptional function of ATF2 in DDR.
- term:
id: GO:0006974
label: DNA damage response
evidence_type: IDA
original_reference_id: PMID:22304920
review:
summary: PMID:22304920 further characterizes ATF2 role in DNA damage response,
showing subcellular localization dynamics during genotoxic stress.
action: ACCEPT
supported_by:
- reference_id: PMID:22304920
supporting_text: PKCĪµ promotes oncogenic functions of ATF2 in the nucleus while
blocking its apoptotic function at mitochondria.
reason: Correct. Complements PMID:15916964 DDR evidence.
- term:
id: GO:0031573
label: mitotic intra-S DNA damage checkpoint signaling
evidence_type: IMP
original_reference_id: PMID:15916964
review:
summary: PMID:15916964 demonstrates ATF2 is required for the ionizing radiation-induced
S phase checkpoint. ATF2 inhibition abrogated S phase checkpoint signaling.
action: ACCEPT
supported_by:
- reference_id: PMID:15916964
supporting_text: Inhibition of ATF2 expression decreased recruitment of Mre11
to IRIF, abrogated S phase checkpoint, reduced activation of ATM, Chk1, and
Chk2
reason: Correct. Experimentally demonstrated in PMID:15916964.
- term:
id: GO:0035861
label: site of double-strand break
evidence_type: IDA
original_reference_id: PMID:15916964
review:
summary: PMID:15916964 demonstrates ATF2 rapid colocalization with gamma-H2AX
and MRN components into IR-induced foci (sites of double-strand breaks).
action: ACCEPT
supported_by:
- reference_id: PMID:15916964
supporting_text: phosphorylation of ATF2 by ATM that results in its rapid colocalization
with gamma-H2AX and MRN components into IR-induced foci (IRIF)
reason: Correct. Experimentally demonstrated by immunofluorescence in PMID:15916964.
- term:
id: GO:1902110
label: positive regulation of mitochondrial membrane permeability involved in
apoptotic process
evidence_type: IMP
original_reference_id: PMID:22304920
review:
summary: PMID:22304920 shows ATF2 at mitochondria perturbs HK1-VDAC1 complex,
increases mitochondrial permeability, and promotes apoptosis. This is the mechanism
of ATF2 tumor suppressor function.
action: KEEP_AS_NON_CORE
supported_by:
- reference_id: PMID:22304920
supporting_text: ATF2 tumor suppressor function is determined by its ability
to localize at the mitochondria, where it alters membrane permeability following
genotoxic stress
reason: Correct and experimentally validated. However, this mitochondrial apoptotic
function is context-dependent (genotoxic stress, regulated by PKC-epsilon) rather
than a constitutive core function.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-168053
review:
summary: Nucleoplasm localization from Reactome pathway Reactome:R-HSA-168053.
ATF2 is a nuclear transcription factor.
action: ACCEPT
reason: Correct. ATF2 is primarily nucleoplasmic.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-168440
review:
summary: Nucleoplasm localization from Reactome pathway Reactome:R-HSA-168440.
ATF2 is a nuclear transcription factor.
action: ACCEPT
reason: Correct. ATF2 is primarily nucleoplasmic.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-3318415
review:
summary: Nucleoplasm localization from Reactome pathway Reactome:R-HSA-3318415.
ATF2 is a nuclear transcription factor.
action: ACCEPT
reason: Correct. ATF2 is primarily nucleoplasmic.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6806412
review:
summary: Nucleoplasm localization from Reactome pathway Reactome:R-HSA-6806412.
ATF2 is a nuclear transcription factor.
action: ACCEPT
reason: Correct. ATF2 is primarily nucleoplasmic.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8944397
review:
summary: Nucleoplasm localization from Reactome pathway Reactome:R-HSA-8944397.
ATF2 is a nuclear transcription factor.
action: ACCEPT
reason: Correct. ATF2 is primarily nucleoplasmic.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9009371
review:
summary: Nucleoplasm localization from Reactome pathway Reactome:R-HSA-9009371.
ATF2 is a nuclear transcription factor.
action: ACCEPT
reason: Correct. ATF2 is primarily nucleoplasmic.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9635804
review:
summary: Nucleoplasm localization from Reactome pathway Reactome:R-HSA-9635804.
ATF2 is a nuclear transcription factor.
action: ACCEPT
reason: Correct. ATF2 is primarily nucleoplasmic.
- term:
id: GO:0000981
label: DNA-binding transcription factor activity, RNA polymerase II-specific
evidence_type: IC
original_reference_id: PMID:19861239
review:
summary: Inferred by curator that ATF2 is a DNA-binding transcription factor for
RNA polymerase II based on evidence from PMID:19861239 showing ATF2 binding
CRE elements and modulating gamma-globin transcription.
action: ACCEPT
supported_by:
- reference_id: PMID:19861239
supporting_text: Epub 2009 Oct 27. cJun modulates Ggamma-globin gene expression
via an upstream cAMP response element.
reason: Correct. Well-supported core function.
- term:
id: GO:0008140
label: cAMP response element binding protein binding
evidence_type: IDA
original_reference_id: PMID:19861239
review:
summary: PMID:19861239 shows ATF2 interacts with cJun at CRE elements to modulate
gamma-globin gene expression. ATF2 binding to CREB response element binding
proteins is consistent with its bZIP family membership.
action: ACCEPT
supported_by:
- reference_id: PMID:19861239
supporting_text: Epub 2009 Oct 27. cJun modulates Ggamma-globin gene expression
via an upstream cAMP response element.
reason: Correct. ATF2 interacts with CREB family proteins through bZIP-mediated
dimerization.
- term:
id: GO:0000978
label: RNA polymerase II cis-regulatory region sequence-specific DNA binding
evidence_type: IDA
original_reference_id: PMID:19861239
review:
summary: PMID:19861239 demonstrates ATF2 binding to RNA polymerase II cis-regulatory
regions (CRE elements in the gamma-globin promoter).
action: ACCEPT
supported_by:
- reference_id: PMID:19861239
supporting_text: Epub 2009 Oct 27. cJun modulates Ggamma-globin gene expression
via an upstream cAMP response element.
reason: Correct. Core DNA-binding function.
- term:
id: GO:0005634
label: nucleus
evidence_type: IDA
original_reference_id: PMID:19861239
review:
summary: Nuclear localization of ATF2 demonstrated with IDA evidence from PMID:19861239.
Consistent with its role as a transcription factor.
action: ACCEPT
supported_by:
- reference_id: PMID:19861239
supporting_text: Epub 2009 Oct 27. cJun modulates Ggamma-globin gene expression
via an upstream cAMP response element.
reason: Correct. ATF2 is primarily nuclear.
- term:
id: GO:0035497
label: cAMP response element binding
evidence_type: IDA
original_reference_id: PMID:19861239
review:
summary: CRE binding demonstrated by direct assay from PMID:19861239. Core molecular
function of ATF2.
action: ACCEPT
supported_by:
- reference_id: PMID:19861239
supporting_text: Epub 2009 Oct 27. cJun modulates Ggamma-globin gene expression
via an upstream cAMP response element.
reason: Core function. ATF2 was originally identified as CRE-BP1.
- term:
id: GO:0061629
label: RNA polymerase II-specific DNA-binding transcription factor binding
evidence_type: IPI
original_reference_id: PMID:19861239
review:
summary: ATF2 interacts with cJun (an RNA polymerase II-specific DNA-binding transcription
factor) at the gamma-globin CRE (PMID:19861239).
action: ACCEPT
supported_by:
- reference_id: PMID:19861239
supporting_text: Epub 2009 Oct 27. cJun modulates Ggamma-globin gene expression
via an upstream cAMP response element.
reason: Correct. ATF2 forms heterodimers with JUN family transcription factors.
- term:
id: GO:0005634
label: nucleus
evidence_type: IDA
original_reference_id: PMID:21098032
review:
summary: Nuclear localization of ATF2 demonstrated with IDA evidence from PMID:21098032.
Consistent with its role as a transcription factor.
action: ACCEPT
supported_by:
- reference_id: PMID:21098032
supporting_text: 2010 Nov 22. Hyperosmotic stress-induced ATF-2 activation through
Polo-like kinase 3 in human corneal epithelial cells.
reason: Correct. ATF2 is primarily nuclear.
- term:
id: GO:0006970
label: response to osmotic stress
evidence_type: IDA
original_reference_id: PMID:21098032
review:
summary: PMID:21098032 demonstrates ATF2 activation (Thr-71 phosphorylation) in
response to hyperosmotic stress through PLK3 in human corneal epithelial cells.
action: KEEP_AS_NON_CORE
supported_by:
- reference_id: PMID:21098032
supporting_text: 2010 Nov 22. Hyperosmotic stress-induced ATF-2 activation through
Polo-like kinase 3 in human corneal epithelial cells.
reason: Correct. ATF2 responds to osmotic stress via MAPK/PLK3 activation. However,
this is one of many stress stimuli that activate ATF2, not a core-defining function.
- term:
id: GO:0019901
label: protein kinase binding
evidence_type: IPI
original_reference_id: PMID:21098032
review:
summary: PMID:21098032 shows ATF2 interacts with PLK3 (Polo-like kinase 3) which
phosphorylates ATF2 at Thr-71. ATF2 also binds JNK (MAPK9, 9 experiments in
IntAct), VRK1 (5 experiments), and other kinases.
action: ACCEPT
supported_by:
- reference_id: PMID:21098032
supporting_text: 2010 Nov 22. Hyperosmotic stress-induced ATF-2 activation through
Polo-like kinase 3 in human corneal epithelial cells.
reason: Correct. ATF2 is a substrate of multiple protein kinases and must bind
them for phosphorylation. More informative than generic protein binding.
- term:
id: GO:0005634
label: nucleus
evidence_type: IDA
original_reference_id: PMID:8798441
review:
summary: Nuclear localization of ATF2 demonstrated with IDA evidence from PMID:8798441.
Consistent with its role as a transcription factor.
action: ACCEPT
supported_by:
- reference_id: PMID:8798441
supporting_text: CREB proteins function as positive regulators of the translocated
bcl-2 allele in t(14;18) lymphomas.
reason: Correct. ATF2 is primarily nuclear.
- term:
id: GO:0003700
label: DNA-binding transcription factor activity
evidence_type: IDA
original_reference_id: PMID:8798441
review:
summary: PMID:8798441 shows CREB proteins including ATF2 (CRE-BP1) function as
positive regulators of the translocated bcl-2 allele through CRE elements.
action: ACCEPT
supported_by:
- reference_id: PMID:8798441
supporting_text: CREB proteins function as positive regulators of the translocated
bcl-2 allele in t(14;18) lymphomas.
reason: Correct. Core transcription factor function.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:9748258
review:
summary: Protein binding annotation from PMID:9748258. ATF2 interacts with numerous
partners including JUN family, FOS family, ATF family, SMAD proteins, and others
(UniProt lists >30 interaction partners). However, "protein binding" is uninformative.
action: MARK_AS_OVER_ANNOTATED
supported_by:
- reference_id: PMID:9748258
supporting_text: Characterization of functional domains of an embryonic stem
cell coactivator UTF1 which are conserved and essential for potentiation of
ATF-2 activity.
reason: GO:0005515 (protein binding) is too vague to be informative for ATF2.
More specific interaction terms such as leucine zipper domain binding (GO:0043522),
protein heterodimerization activity (GO:0046982), or specific binding activities
should be used instead.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:8440710
review:
summary: Protein binding annotation from PMID:8440710. ATF2 interacts with numerous
partners including JUN family, FOS family, ATF family, SMAD proteins, and others
(UniProt lists >30 interaction partners). However, "protein binding" is uninformative.
action: MARK_AS_OVER_ANNOTATED
supported_by:
- reference_id: PMID:8440710
supporting_text: Isolation and characterization of a novel member of the gene
family encoding the cAMP response element-binding protein CRE-BP1.
reason: GO:0005515 (protein binding) is too vague to be informative for ATF2.
More specific interaction terms such as leucine zipper domain binding (GO:0043522),
protein heterodimerization activity (GO:0046982), or specific binding activities
should be used instead.
references:
- id: GO_REF:0000002
title: Gene Ontology annotation through association of InterPro records with GO
terms
findings: []
- id: GO_REF:0000033
title: Annotation inferences using phylogenetic trees
findings: []
- id: GO_REF:0000043
title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
findings: []
- id: GO_REF:0000044
title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
vocabulary mapping, accompanied by conservative changes to GO terms applied by
UniProt
findings: []
- id: GO_REF:0000052
title: Gene Ontology annotation based on curation of immunofluorescence data
findings: []
- id: GO_REF:0000107
title: Automatic transfer of experimentally verified manual GO annotation data to
orthologs using Ensembl Compara
findings: []
- id: GO_REF:0000113
title: Gene Ontology annotation of human sequence-specific DNA binding transcription
factors (DbTFs) based on the TFClass database
findings: []
- id: GO_REF:0000120
title: Combined Automated Annotation using Multiple IEA Methods
findings: []
- id: PMID:10327051
title: The N-terminal transactivation domain of ATF2 is a target for the co-operative
activation of the c-jun promoter by p300 and 12S E1A.
findings: []
- id: PMID:10821277
title: ATF-2 has intrinsic histone acetyltransferase activity which is modulated
by phosphorylation.
findings:
- statement: ATF2 has intrinsic histone acetyltransferase activity that specifically
acetylates H2B and H4 in vitro, modulated by phosphorylation at Thr-69/Thr-71
- id: PMID:11231009
title: Identification of mouse Jun dimerization protein 2 as a novel repressor of
ATF-2.
findings: []
- id: PMID:15105425
title: Human vaccinia-related kinase 1 (VRK1) activates the ATF2 transcriptional
activity by novel phosphorylation on Thr-73 and Ser-62 and cooperates with JNK.
findings: []
- id: PMID:15916964
title: ATM-dependent phosphorylation of ATF2 is required for the DNA damage response.
findings:
- statement: ATM phosphorylates ATF2 at Ser-490/498 following IR, resulting in colocalization
with gamma-H2AX and MRN complex at IRIF. ATF2 is required for S-phase checkpoint
and recruitment of Mre11 to foci.
- id: PMID:16300731
title: ATF5 increases cisplatin-induced apoptosis through up-regulation of cyclin
D3 transcription in HeLa cells.
findings: []
- id: PMID:16511568
title: Mutual regulation of c-Jun and ATF2 by transcriptional activation and subcellular
localization.
findings: []
- id: PMID:17267404
title: ATF2 is required for amino acid-regulated transcription by orchestrating
specific histone acetylation.
findings:
- statement: ATF2 is essential for amino acid starvation-induced CHOP transcription,
orchestrating histone H4 and H2B acetylation at the AARE through promoter-specific
chromatin binding.
- id: PMID:18397884
title: Regulation of TIP60 by ATF2 modulates ATM activation.
findings:
- statement: ATF2 regulation of TIP60 modulates ATM activation. ATF2 promotes CUL3-mediated
degradation of KAT5, attenuating ATM acetylation.
- id: PMID:18671972
title: IRF2-binding protein-1 is a JDP2 ubiquitin ligase and an inhibitor of ATF2-dependent
transcription.
findings: []
- id: PMID:19861239
title: cJun modulates Ggamma-globin gene expression via an upstream cAMP response
element.
findings:
- statement: ATF2 (with cJun) modulates gamma-globin gene expression via upstream
CRE element, demonstrating CRE-binding and transcriptional activator activity.
- id: PMID:20102225
title: Identification of bZIP interaction partners of viral proteins HBZ, MEQ, BZLF1,
and K-bZIP using coiled-coil arrays.
findings: []
- id: PMID:20116378
title: JNK-ATF-2 inhibits thrombomodulin (TM) expression by recruiting histone deacetylase4
(HDAC4) and forming a transcriptional repression complex in the TM promoter.
findings: []
- id: PMID:20195357
title: A comprehensive resource of interacting protein regions for refining human
transcription factor networks.
findings: []
- id: PMID:20211142
title: An atlas of combinatorial transcriptional regulation in mouse and man.
findings: []
- id: PMID:20511396
title: In situ proximity ligation detection of c-Jun/AP-1 dimers reveals increased
levels of c-Jun/Fra1 complexes in aggressive breast cancer cell lines in vitro
and in vivo.
findings: []
- id: PMID:21098032
title: Hyperosmotic stress-induced ATF-2 activation through Polo-like kinase 3 in
human corneal epithelial cells.
findings: []
- id: PMID:2196176
title: 'Multiple cDNA clones encoding nuclear proteins that bind to the tax-dependent
enhancer of HTLV-1: all contain a leucine zipper structure and basic amino acid
domain.'
findings:
- statement: ATF2 clones bind to the tax-dependent enhancer of HTLV-1; all contain
leucine zipper structure and basic amino acid domain.
- id: PMID:22304920
title: PKCĪµ promotes oncogenic functions of ATF2 in the nucleus while blocking its
apoptotic function at mitochondria.
findings:
- statement: PKC-epsilon directs ATF2 nuclear localization. Under genotoxic stress,
ATF2 exports to mitochondrial outer membrane where it perturbs HK1-VDAC1 complex,
promotes apoptosis. Dual oncogenic (nuclear) and tumor suppressor (mitochondrial)
functions.
- id: PMID:22439931
title: 'Deconstruction of the SS18-SSX fusion oncoprotein complex: insights into
disease etiology and therapeutics.'
findings: []
- id: PMID:22982025
title: MicroRNA-204 is required for differentiation of human-derived cardiomyocyte
progenitor cells.
findings: []
- id: PMID:23661758
title: Networks of bZIP protein-protein interactions diversified over a billion
years of evolution.
findings: []
- id: PMID:23729669
title: Inducible interleukin 32 (IL-32) exerts extensive antiviral function via
selective stimulation of interferon Ī»1 (IFN-Ī»1).
findings: []
- id: PMID:24705354
title: 'The palmitoyl acyltransferase HIP14 shares a high proportion of interactors
with huntingtin: implications for a role in the pathogenesis of Huntington''s
disease.'
findings: []
- id: PMID:2516827
title: 'Transcription factor ATF cDNA clones: an extensive family of leucine zipper
proteins able to selectively form DNA-binding heterodimers.'
findings: []
- id: PMID:25416956
title: A proteome-scale map of the human interactome network.
findings: []
- id: PMID:25609649
title: Proteomic analyses reveal distinct chromatin-associated and soluble transcription
factor complexes.
findings: []
- id: PMID:26496610
title: A human interactome in three quantitative dimensions organized by stoichiometries
and abundances.
findings: []
- id: PMID:28186491
title: Combinatorial bZIP dimers display complex DNA-binding specificity landscapes.
findings: []
- id: PMID:28473536
title: Impact of cytosine methylation on DNA binding specificities of human transcription
factors.
findings: []
- id: PMID:28514442
title: Architecture of the human interactome defines protein communities and disease
networks.
findings: []
- id: PMID:28977001
title: MicroRNA-30b controls endothelial cell capillary morphogenesis through regulation
of transforming growth factor beta 2.
findings: []
- id: PMID:31515488
title: Extensive disruption of protein interactions by genetic variants across the
allele frequency spectrum in human populations.
findings: []
- id: PMID:32296183
title: A reference map of the human binary protein interactome.
findings: []
- id: PMID:33961781
title: Dual proteome-scale networks reveal cell-specific remodeling of the human
interactome.
findings: []
- id: PMID:35271311
title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
findings: []
- id: PMID:40205054
title: Multimodal cell maps as a foundation for structural and functional genomics.
findings: []
- id: PMID:8440710
title: Isolation and characterization of a novel member of the gene family encoding
the cAMP response element-binding protein CRE-BP1.
findings: []
- id: PMID:8798441
title: CREB proteins function as positive regulators of the translocated bcl-2 allele
in t(14;18) lymphomas.
findings: []
- id: PMID:9748258
title: Characterization of functional domains of an embryonic stem cell coactivator
UTF1 which are conserved and essential for potentiation of ATF-2 activity.
findings: []
- id: Reactome:R-HSA-168053
title: Phosphorylated MAPKs phosphorylate ATF-2
findings: []
- id: Reactome:R-HSA-168440
title: 'Formation of Activated Protein 1 (AP-1) complex. ATF2/c-JUN heterodimer. '
findings: []
- id: Reactome:R-HSA-3318415
title: ATF2 acetylates histone H2B, H4
findings: []
- id: Reactome:R-HSA-6806412
title: TP53 and AP-1 bind the MSH2 promoter
findings: []
- id: Reactome:R-HSA-8944397
title: p-T69,T71-ATF2 binds PTEN gene promoter
findings: []
- id: Reactome:R-HSA-9009371
title: Binding of AP1 transcriptional activator complexes to CCND1 promoter
findings: []
- id: Reactome:R-HSA-9635804
title: ATF4 and phospho-ATF2 bind the DDIT3 promoter
findings: []
core_functions:
- description: >-
Sequence-specific DNA-binding transcription factor that binds CRE
(5-prime-TGACGTCA-3-prime) and AP-1 (5-prime-TGACTCA-3-prime) elements as
homo- or heterodimers with JUN family and other bZIP proteins, activating
transcription by RNA polymerase II. Direct substrate and effector of MAPK
cascade signaling (JNK, p38, ERK); phosphorylation at Thr-69/Thr-71 by
these kinases activates transcriptional activity in response to stress,
cytokines, and growth factors. Also participates in the DNA damage response
through ATM-dependent phosphorylation at Ser-490/Ser-498, recruiting to
IR-induced foci and promoting S-phase checkpoint signaling. Primarily
localized to the nucleus; under genotoxic stress, can translocate to the
mitochondrial outer membrane where it promotes apoptosis by perturbing
HK1-VDAC1 complexes.
molecular_function:
id: GO:0000981
label: DNA-binding transcription factor activity, RNA polymerase II-specific
directly_involved_in:
- id: GO:0000165
label: MAPK cascade
- id: GO:0006974
label: DNA damage response
locations:
- id: GO:0005634
label: nucleus
- id: GO:0005741
label: mitochondrial outer membrane
supported_by:
- reference_id: PMID:2529117
- reference_id: PMID:10821277
- reference_id: PMID:17267404
- reference_id: PMID:9430721
- reference_id: PMID:15916964
- reference_id: PMID:18397884
- reference_id: PMID:22304920
- description: >-
Binds cAMP response elements (CRE) in target gene promoters as a defining
molecular function. Originally named CRE-BP1 for this activity.
molecular_function:
id: GO:0035497
label: cAMP response element binding
locations:
- id: GO:0005634
label: nucleus
supported_by:
- reference_id: PMID:2529117
- reference_id: PMID:19861239
- reference_id: PMID:23729669