GADD45G

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005634 nucleus	IDA PMID:9827804 A family of stress-inducible GADD45-like proteins mediate ac...	ACCEPT	Summary: ACCEPT. The seminal paper by Takekawa and Saito (1998) demonstrated nuclear localization of GADD45G. The crystal structure (PDB:3FFM) confirms nuclear function through homodimerization and interaction with nuclear proteins like PCNA. This is consistent with its role in DNA damage response pathways and cell cycle checkpoint control. Reason: Nuclear localization is well-established for GADD45G based on direct experimental evidence and is consistent with its interactions with nuclear proteins (PCNA, p21, cdc2/cyclin B1) and its role in DNA damage checkpoints. Supporting Evidence: PMID:12716909 CRIF1 localizes exclusively to the nucleus and colocalizes with Gadd45gamma. file:human/GADD45G/GADD45G-deep-research-perplexity.md See deep research file for comprehensive analysis PMID:9827804 A family of stress-inducible GADD45-like proteins mediate activation of the stress-responsive MTK1/MEKK4 MAPKKK.
GO:0005737 cytoplasm	IDA PMID:9827804 A family of stress-inducible GADD45-like proteins mediate ac...	ACCEPT	Summary: ACCEPT. GADD45G shows dual nuclear/cytoplasmic localization. This is consistent with its role in both nuclear DNA damage responses and cytoplasmic MAPK signaling cascades involving MTK1/MEKK4 activation. Reason: Cytoplasmic localization is consistent with GADD45G's role in activating cytoplasmic MTK1/MEKK4 kinase to stimulate p38 and JNK MAPK cascades. The protein functions in both nuclear (DNA damage checkpoint) and cytoplasmic (MAPK signaling) compartments. Supporting Evidence: PMID:9827804 These proteins activated MTK1 kinase activity, both in vivo and in vitro.
GO:0043065 positive regulation of apoptotic process	IDA PMID:9827804 A family of stress-inducible GADD45-like proteins mediate ac...	ACCEPT	Summary: ACCEPT. Core function. Takekawa and Saito (1998) showed that expression of GADD45-like genes induces apoptosis through activation of the p38/JNK pathway via MTK1/MEKK4. This can be partially suppressed by coexpression of a dominant inhibitory MTK1 mutant. Reason: Pro-apoptotic function is a core activity of GADD45G, mediated through activation of the stress-responsive p38 and JNK MAPK pathways via MTK1/MEKK4. This is supported by deep research evidence from the falcon review noting the role in apoptosis/survival decisions. Supporting Evidence: PMID:9827804 Expression of the GADD45-like genes induces p38/JNK activation and apoptosis, which can be partially suppressed by coexpression of a dominant inhibitory MTK1 mutant protein.
GO:0046330 positive regulation of JNK cascade	IDA PMID:9827804 A family of stress-inducible GADD45-like proteins mediate ac...	ACCEPT	Summary: ACCEPT. Core function. GADD45G activates MTK1/MEKK4, which phosphorylates MKK4/MKK7, leading to JNK activation. This pathway mediates stress responses and T helper 1 cell functions. Reason: JNK cascade activation is a well-established core function of GADD45G, acting through MTK1/MEKK4 in response to environmental stresses including UV radiation and chemical mutagens. The deep research falcon review confirms this as a central mechanism. Supporting Evidence: PMID:9827804 We propose that the GADD45-like proteins mediate activation of the p38/JNK pathway, via MTK1/ MEKK4, in response to environmental stresses. PMID:12052864 GADD45 proteins (GADD45alpha, beta, and gamma) were identified as MTK1 activators.
GO:1900745 positive regulation of p38MAPK cascade	IDA PMID:9827804 A family of stress-inducible GADD45-like proteins mediate ac...	ACCEPT	Summary: ACCEPT. Core function. GADD45G binds to and activates MTK1/MEKK4, relieving its autoinhibition and enabling phosphorylation of downstream MKK3/MKK6, which then activate p38 MAPK. Reason: p38 MAPK cascade activation is a core function of GADD45G with multiple physiological roles including stress response, thermogenesis in BAT, and T helper cell differentiation. The mechanism involves relief of MTK1/MEKK4 autoinhibition. Supporting Evidence: PMID:9827804 A human MAPKKK, MTK1 (= MEKK4), mediates activation of both p38 and JNK in response to environmental stresses. PMID:12052864 GADD45 proteins bind a site in MTK1 near the inhibitory domain and relieve autoinhibition. PMID:25071184 GADD45γ regulates the thermogenic capacity of brown adipose tissue.
GO:0120162 positive regulation of cold-induced thermogenesis	ISS PMID:25071184 GADD45γ regulates the thermogenic capacity of brown adipose ...	ACCEPT	Summary: ACCEPT. Well-characterized function. Gantner et al. (2014) showed that Gadd45g knockout mice have defects in UCP1 induction and thermogenic response to cold. GADD45G is rapidly induced by cold/norepinephrine in BAT and activates p38 MAPK, which then activates ERRbeta/gamma to induce UCP1 and oxidative capacity. This ISS annotation from mouse data is well-supported. Reason: Thermogenesis regulation is a specialized physiological function of GADD45G acting through the conserved p38 MAPK pathway. The mouse knockout phenotype provides strong evidence that this function is conserved in mammals. Supporting Evidence: PMID:25071184 Mice lacking Gadd45gamma have defects in Ucp1 induction and the thermogenic response to cold. GADD45gamma works by activating MAPK p38, which is a potent activator of ERRbeta and ERRgamma transcriptional function.
GO:0005515 protein binding	IPI PMID:12052864 Regulation of MTK1/MEKK4 kinase activity by its N-terminal a...	MODIFY	Summary: MODIFY. This paper (Mita et al. 2002) demonstrates that GADD45 proteins bind to and activate MTK1/MEKK4 (MAP3K4) by relieving its N-terminal autoinhibition. The specific interaction should be annotated as mitogen-activated protein kinase kinase kinase binding (GO:0031435). Reason: The interaction with MTK1/MEKK4 (MAP3K4) is a core functional interaction that activates the stress-responsive MAPK pathway. Generic protein binding is uninformative; the more specific MAP3K binding term better captures the functional significance. Proposed replacements: mitogen-activated protein kinase kinase kinase binding Supporting Evidence: PMID:12052864 GADD45 proteins bind a site in MTK1 near the inhibitory domain and relieve autoinhibition.
GO:0005515 protein binding	IPI PMID:12716909 CR6-interacting factor 1 interacts with Gadd45 family protei...	KEEP AS NON CORE	Summary: KEEP_AS_NON_CORE. This paper (Chung et al. 2003) identifies CRIF1 (GADD45GIP1) as a novel interacting partner of GADD45 family proteins. CRIF1 colocalizes with GADD45gamma in the nucleus and has additive inhibitory effects with GADD45 on cdc2/cyclin B1 kinase. The interaction is real but secondary to GADD45G's core function. Reason: The CRIF1 interaction is a validated interaction but represents a modulatory partner rather than a core functional target. CRIF1 enhances GADD45G's cell cycle inhibitory effects. Supporting Evidence: PMID:12716909 CRIF1 binds specifically to the Gadd45 family proteins, as determined by an in vitro glutathione S-transferase pull-down assay and an in vivo mammalian cell two-hybrid assay along with coimmunoprecipitation assays.
GO:0005515 protein binding	IPI PMID:15383276 A protein interaction network links GIT1, an enhancer of hun...	MARK AS OVER ANNOTATED	Summary: MARK_AS_OVER_ANNOTATED. This is a large-scale protein interaction network study linking GIT1 to Huntington's disease. GADD45G appears as a node in the network but this is from high-throughput data without specific validation of GADD45G function in this context. Not informative for GADD45G core function. Supporting Evidence: PMID:15383276 A protein interaction network links GIT1, an enhancer of huntingtin aggregation, to Huntington's disease.
GO:0005515 protein binding	IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in...	MARK AS OVER ANNOTATED	Summary: MARK_AS_OVER_ANNOTATED. Rual et al. (2005) "Towards a proteome-scale map of the human protein-protein interaction network" - this is high-throughput yeast two-hybrid screening. While it may identify real interactions, it does not provide functional context for GADD45G specifically. Generic "protein binding" from HTP data is not useful. Supporting Evidence: PMID:16189514 Towards a proteome-scale map of the human protein-protein interaction network.
GO:0005515 protein binding	IPI PMID:21900206 A directed protein interaction network for investigating int...	MARK AS OVER ANNOTATED	Summary: MARK_AS_OVER_ANNOTATED. "A directed protein interaction network for investigating intracellular signal transduction" - another high-throughput interactome study. Does not provide specific functional insight for GADD45G. Supporting Evidence: PMID:21900206 A directed protein interaction network for investigating intracellular signal transduction.
GO:0005515 protein binding	IPI PMID:21988832 Toward an understanding of the protein interaction network o...	MARK AS OVER ANNOTATED	Summary: MARK_AS_OVER_ANNOTATED. "Toward an understanding of the protein interaction network of the human liver" - proteome-scale interactome study. No specific functional context for GADD45G. Supporting Evidence: PMID:21988832 Toward an understanding of the protein interaction network of the human liver.
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	MARK AS OVER ANNOTATED	Summary: MARK_AS_OVER_ANNOTATED. "A proteome-scale map of the human interactome network" - large-scale interactome mapping. Generic protein binding from HTP data without functional validation specific to GADD45G. Supporting Evidence: PMID:25416956 A proteome-scale map of the human interactome network.
GO:0005515 protein binding	IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari...	MARK AS OVER ANNOTATED	Summary: MARK_AS_OVER_ANNOTATED. "Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations" - population-scale variant analysis. Not directly informative for GADD45G function. 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: MARK_AS_OVER_ANNOTATED. "A reference map of the human binary protein interactome" - HuRI reference interactome. High-throughput data without specific functional context for GADD45G. 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: MARK_AS_OVER_ANNOTATED. "Dual proteome-scale networks reveal cell-specific remodeling of the human interactome" - another proteome-scale interactome study. Generic protein binding annotation is uninformative. Supporting Evidence: PMID:33961781 2021 May 6. Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
GO:0006915 apoptotic process	IEA GO_REF:0000043	MODIFY	Summary: MODIFY. GADD45G promotes apoptosis via p38/JNK activation. The more specific term "positive regulation of apoptotic process" (GO:0043065) is already annotated with IDA evidence. This generic term should be replaced with the more specific one. Proposed replacements: positive regulation of apoptotic process
GO:0030154 cell differentiation	IEA GO_REF:0000043	KEEP AS NON CORE	Summary: KEEP_AS_NON_CORE. GADD45G does have roles in differentiation processes including T helper cell differentiation (Th1 vs Th2), neuronal differentiation, and sex determination. However, these are secondary to its core stress-response function. The term is vague but captures pleiotropic effects.
GO:0043410 positive regulation of MAPK cascade	IEA GO_REF:0000117	MODIFY	Summary: MODIFY. This is correct but too general. GADD45G specifically activates p38 MAPK and JNK pathways via MTK1/MEKK4. More specific terms already exist: GO:0046330 (positive regulation of JNK cascade) and GO:1900745 (positive regulation of p38MAPK cascade). Proposed replacements: positive regulation of JNK cascade
GO:0051726 regulation of cell cycle	IEA GO_REF:0000002	MODIFY	Summary: MODIFY. GADD45G specifically mediates G2/M cell cycle arrest in response to UV and chemical mutagens by inhibiting cdc2/cyclin B1 kinase activity. A more specific term would be "mitotic G2 DNA damage checkpoint signaling" (GO:0007095) or "negative regulation of G2/M transition of mitotic cell cycle". Proposed replacements: mitotic G2 DNA damage checkpoint signaling
GO:0005634 nucleus	IEA GO_REF:0000120	ACCEPT	Summary: ACCEPT. This term is also annotated with IDA evidence from PMID:9827804. The IEA annotation is redundant but correct, confirming nuclear localization from multiple evidence sources. Reason: Nuclear localization is well-established for GADD45G. The IEA provides additional computational support for the IDA-based annotation.
GO:0051726 regulation of cell cycle	IBA GO_REF:0000033	MODIFY	Summary: MODIFY. Same as the IEA annotation above. GADD45G's cell cycle function is specifically at the G2/M checkpoint in response to genotoxic stress. The phylogenetic inference is reasonable but the term is too general. Proposed replacements: mitotic G2 DNA damage checkpoint signaling
GO:0005634 nucleus	IBA GO_REF:0000033	ACCEPT	Summary: ACCEPT. The IBA annotation is consistent with IDA evidence from PMID:9827804 and provides phylogenetic support for conserved nuclear localization across the GADD45 family. Reason: Nuclear localization is conserved across GADD45 family members and is consistent with the protein's interactions with nuclear proteins like PCNA, p21, and cdc2/cyclin B1.
GO:0005737 cytoplasm	IBA GO_REF:0000033	ACCEPT	Summary: ACCEPT. The IBA annotation is consistent with IDA evidence from PMID:9827804 and provides phylogenetic support for conserved cytoplasmic localization across the GADD45 family. Reason: Cytoplasmic localization is conserved across GADD45 family members and is consistent with the protein's role in activating cytoplasmic MTK1/MEKK4 kinase signaling.
GO:0004861 cyclin-dependent protein serine/threonine kinase inhibitor activity	IDA PMID:12716909 CR6-interacting factor 1 interacts with Gadd45 family protei...	NEW	Summary: NEW. GADD45G inhibits cdc2/cyclin B1 kinase activity, contributing to G2/M cell cycle arrest. This molecular function is demonstrated by the additive inhibitory effects of GADD45 proteins with CRIF1 on cdc2/cyclin B1 kinase. Reason: This molecular function term is more informative than the existing regulation of cell cycle annotations and captures the direct biochemical activity of GADD45G in inhibiting CDK1/cyclin B1 kinase. Supporting Evidence: PMID:12716909 Recombinant CRIF1 inhibits the histone H1 kinase activity of immunoprecipitated Cdc2-cyclin B1 and Cdk2-cyclin E, and the inhibitory effects were additive with Gadd45 proteins.
GO:0031435 mitogen-activated protein kinase kinase kinase binding	IDA PMID:12052864 Regulation of MTK1/MEKK4 kinase activity by its N-terminal a...	NEW	Summary: NEW. GADD45G directly binds to MTK1/MEKK4 (MAP3K4) near its autoinhibitory domain, relieving autoinhibition and enabling kinase activation. This is the core molecular function underlying GADD45G's role in stress signaling. Reason: This molecular function term captures the core biochemical activity of GADD45G as an activator of MTK1/MEKK4 kinase. Currently only annotated as generic protein binding, but this specific term is more appropriate. Supporting Evidence: PMID:12052864 GADD45 proteins bind a site in MTK1 near the inhibitory domain and relieve autoinhibition. PMID:9827804 three related proteins, GADD45alpha (= GADD45), GADD45, (= MyD118), and GADD45gamma, were identified that bound to an N-terminal domain of MTK1.
GO:0033554 cellular response to stress	IDA PMID:9827804 A family of stress-inducible GADD45-like proteins mediate ac...	NEW	Summary: NEW. GADD45G is induced by environmental stresses and mediates cellular stress responses through activation of the p38/JNK MAPK pathways. This broad process term captures its central role as a stress sensor. Reason: While more specific terms like positive regulation of p38MAPK cascade are already annotated, this broader process term captures the central role of GADD45G as a stress-inducible protein that mediates cellular stress responses. Supporting Evidence: PMID:9827804 The GADD45-like genes are induced by environmental stresses, including MMS, UV, and gamma irradiation. PMID:9827804 We propose that the GADD45-like proteins mediate activation of the p38/JNK pathway, via MTK1/ MEKK4, in response to environmental stresses.

Gene Description

Existing Annotations Review

Core Functions

GADD45G binds to the N-terminal region of MTK1/MEKK4 (MAP3K4) near its autoinhibitory domain, relieving autoinhibition and allowing MTK1 to interact with and phosphorylate its substrate MKK6. This activation leads to downstream p38 and JNK MAPK pathway activation.

GADD45G inhibits cdc2/cyclin B1 kinase activity through direct binding to cdc2 (not cyclin B1), stabilizing an inactive conformation of the complex without disrupting the complex structure. This leads to G2/M cell cycle arrest in response to DNA damage.

GADD45G activates p38 MAPK signaling through MTK1/MEKK4, which phosphorylates MKK3/MKK6, which then phosphorylate p38. This pathway is critical for stress responses, T helper 1 cell differentiation, brown adipose tissue thermogenesis, and sex determination.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Perplexity

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