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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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 Ξ»1 (IFN-Ξ»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 Ξ»1 (IFN-Ξ»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 PKCΞ΅ 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 PKCΞ΅ promotes oncogenic functions of ATF2 in the nucleus while blocking its apoptotic function at mitochondria. |
| GO:0005737 cytoplasm | IDA PMID:22304920 PKCΞ΅ 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 PKCΞ΅ promotes oncogenic functions of ATF2 in the nucleus while blocking its apoptotic function at mitochondria. |
| GO:0005741 mitochondrial outer membrane | IDA PMID:22304920 PKCΞ΅ 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 PKCΞ΅ 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 PKCΞ΅ 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 PKCΞ΅ 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 PKCΞ΅ 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 PKCΞ΅ 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 PKCΞ΅ 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. |
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