GADD45B (Growth arrest and DNA damage-inducible protein GADD45 beta, also known as MyD118) is a stress-inducible protein that mediates activation of stress-responsive MAPK signaling pathways. The protein binds directly to the N-terminal regulatory domain of MTK1/MEKK4 (MAP3K4), relieving autoinhibition and activating its kinase activity. This leads to downstream activation of both p38 MAPK and JNK cascades in response to environmental stresses including UV irradiation, genotoxic agents (MMS), and gamma irradiation. GADD45B also interacts with MKK7 (MAP2K7), where it blocks kinase activity and suppresses JNK-mediated apoptosis. This dual activity - activating MTK1/MEKK4 while inhibiting MKK7 - positions GADD45B as a key modulator of stress responses and cell fate decisions. The gene is transcriptionally regulated by NF-kB, and its expression is elevated in multiple myeloma where it promotes cancer cell survival by blocking MKK7/JNK-mediated apoptosis.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0051726 regulation of cell cycle | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: The GADD45 family is known to regulate cell cycle through interaction with GADD45GIP1/CRIF1 which modulates Cdc2-cyclin B1 and Cdk2-cyclin E activity [PMID:12716909]. IBA evidence from phylogenetic inference is appropriate but this represents a secondary/downstream effect of GADD45B rather than its core molecular function. 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:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: Nuclear localization is confirmed by direct experimental evidence [PMID:9827804]. IBA provides supporting phylogenetic evidence consistent with experimental data. Supporting Evidence: PMID:9827804 Using a yeast two-hybrid method, three related proteins, GADD45alpha (= GADD45), GADD45, (= MyD118), and GADD45gamma, were identified that bound to an N-terminal domain of MTK1 |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: Cytoplasmic localization is confirmed by direct experimental evidence [PMID:9827804]. IBA provides supporting phylogenetic evidence consistent with experimental data. Supporting Evidence: PMID:9827804 These proteins activated MTK1 kinase activity, both in vivo and in vitro |
| GO:0005634 nucleus | IEA GO_REF:0000002 | ACCEPT | Summary: Consistent with IDA-supported annotation from PMID:9827804. InterPro-based inference provides supporting automated evidence for nuclear localization. |
| GO:0006915 apoptotic process | IEA GO_REF:0000043 | MODIFY | Summary: GADD45B has a complex role in apoptosis. It can promote apoptosis via MTK1/MEKK4 activation leading to p38/JNK stress signaling [PMID:9827804], but also acts as an anti-apoptotic factor by inhibiting MKK7/JNK in cancer contexts [PMID:25314077]. The generic term 'apoptotic process' does not capture this complexity. Should be replaced with the more specific term matching the IDA annotation. Proposed replacements: positive regulation of apoptotic process 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 PMID:25314077 GADD45Ξ² promotes the survival of MM cells by inhibiting JNK-mediated apoptosis |
| GO:0030154 cell differentiation | IEA GO_REF:0000043 | MARK AS OVER ANNOTATED | Summary: GADD45B (originally named MyD118 for myeloid differentiation primary response) was identified in myeloid differentiation studies. The keyword-based inference is plausible but lacks direct experimental support for GADD45B specifically being required for differentiation. This may be an over-annotation based on the gene name etymology rather than validated function. |
| GO:0046330 positive regulation of JNK cascade | IEA GO_REF:0000117 | ACCEPT | Summary: This is well-supported by experimental evidence. GADD45B activates MTK1/MEKK4 which in turn activates both p38 and JNK pathways [PMID:9827804]. However, GADD45B also inhibits JNK via MKK7 binding in certain contexts [PMID:25314077], making this context-dependent. The ARBA prediction is valid for the stress-responsive pathway. Supporting Evidence: PMID:9827804 Expression of the GADD45-like genes induces p38/JNK activation and apoptosis |
| GO:0051726 regulation of cell cycle | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Consistent with IBA annotation. InterPro-based inference supports known GADD45 family function in cell cycle regulation via CRIF1 interaction [PMID:12716909]. Supporting Evidence: PMID:12716909 CRIF1 binds specifically to the Gadd45 family proteins |
| GO:1900745 positive regulation of p38MAPK cascade | IEA GO_REF:0000117 | ACCEPT | Summary: This is strongly supported by experimental evidence. GADD45B activates MTK1/MEKK4 which activates MKK6, leading to p38 activation [PMID:9827804, PMID:12052864]. ARBA prediction is accurate. Supporting Evidence: PMID:12052864 GADD45 proteins bind a site in MTK1 near the inhibitory domain and relieve autoinhibition |
| GO:0005515 protein binding | IPI PMID:12052864 Regulation of MTK1/MEKK4 kinase activity by its N-terminal a... | MODIFY | Summary: The vague term 'protein binding' should be replaced with a more specific MF term. This paper shows GADD45B binds MTK1/MEKK4 (a MAPKKK) and activates its kinase activity. MTK1/MEKK4 is a MAPKKK (MAP3K4). Proposed replacements: mitogen-activated protein kinase kinase kinase binding Supporting Evidence: PMID:12052864 By a functional complementation screening with yeast cells, GADD45 proteins (GADD45alpha, beta, and gamma) were identified as MTK1 activators. GADD45 proteins bind a site in MTK1 near the inhibitory domain and relieve autoinhibition |
| GO:0005515 protein binding | IPI PMID:16256071 CIN85 regulates the ability of MEKK4 to activate the p38 MAP... | MODIFY | Summary: This paper shows CIN85 regulates MEKK4 activation by GADD45 proteins. The protein binding annotation is too vague - this involves the MTK1/MEKK4 activation pathway. Proposed replacements: mitogen-activated protein kinase kinase kinase binding Supporting Evidence: PMID:16256071 CIN85 was also shown to regulate the activation of MEKK4 by GADD45 proteins and promote multi-ubiquitination of MEKK4 |
| GO:0005515 protein binding | IPI PMID:25314077 Cancer-selective targeting of the NF-ΞΊB survival pathway wit... | MODIFY | Summary: This paper shows GADD45B binds directly to MKK7 and blocks its catalytic activity. MKK7 is a MAPKK (MAP2K7). Should be annotated to a more specific term. Proposed replacements: mitogen-activated protein kinase kinase binding Supporting Evidence: PMID:25314077 GADD45Ξ² inhibits apoptosis by suppressing JNK signaling. It mediates this function by binding to the JNK kinase MKK7 and blocking its enzymatic activity by engaging the kinase catalytic pocket |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: This is a large-scale binary protein interactome study (HuRI). Generic 'protein binding' from high-throughput studies is not informative without mechanistic context. Reason: High-throughput interactome study. Specific interactions should be curated from focused literature with mechanistic context rather than generic protein binding. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. With approximately 53,000 protein-protein interactions, HuRI has approximately four times as many such interactions as there are high-quality curated interactions from small-scale studies |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: This is BioPlex 3.0, another large-scale protein interactome study. Same rationale as PMID:32296183 - generic protein binding from HT studies is not informative. Reason: High-throughput interactome study. Specific interactions should be curated from focused literature with mechanistic context. Supporting Evidence: PMID:33961781 Through affinity-purification mass spectrometry, we have created two proteome-scale, cell-line-specific interaction networks. The first, BioPlex 3.0, results from affinity purification of 10,128 human proteins-half the proteome-in 293T cells and includes 118,162 interactions among 14,586 proteins |
| GO:0005634 nucleus | IDA PMID:9827804 A family of stress-inducible GADD45-like proteins mediate ac... | ACCEPT | Summary: Direct experimental evidence for nuclear localization. This is a core localization for GADD45B's function in stress response signaling. Supporting Evidence: PMID:9827804 Using a yeast two-hybrid method, three related proteins, GADD45alpha (= GADD45), GADD45, (= MyD118), and GADD45gamma, were identified that bound to an N-terminal domain of MTK1 |
| GO:0005737 cytoplasm | IDA PMID:9827804 A family of stress-inducible GADD45-like proteins mediate ac... | ACCEPT | Summary: Direct experimental evidence for cytoplasmic localization. GADD45B is found in both nucleus and cytoplasm, consistent with its role in signaling between cellular 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: Well-supported by experimental evidence showing expression of GADD45-like genes induces p38/JNK activation and apoptosis. This reflects GADD45B's pro-apoptotic activity through MTK1/MEKK4 activation in response to stress. 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: Well-supported by direct experimental evidence showing GADD45-like proteins mediate activation of the p38/JNK pathway via MTK1/MEKK4. This is a core function. Supporting Evidence: PMID:9827804 Expression of the GADD45-like genes induces p38/JNK activation and apoptosis |
| GO:1900745 positive regulation of p38MAPK cascade | IDA PMID:9827804 A family of stress-inducible GADD45-like proteins mediate ac... | ACCEPT | Summary: Well-supported by direct experimental evidence [PMID:9827804]. Activation of MTK1/MEKK4 by GADD45B leads to p38 MAPK activation. This is a core function. Supporting Evidence: PMID:9827804 The stress-responsive p38 and JNK MAPK pathways regulate cell cycle and apoptosis. A human MAPKKK, MTK1 (= MEKK4), mediates activation of both p38 and JNK in response to environmental stresses |
| GO:0043066 negative regulation of apoptotic process | IDA PMID:25314077 Cancer-selective targeting of the NF-ΞΊB survival pathway wit... | NEW | Summary: GADD45B suppresses JNK-mediated apoptosis by directly binding and inhibiting MKK7. This anti-apoptotic function is context-dependent, particularly relevant in NF-kB-driven cancer cells like multiple myeloma. Supporting Evidence: PMID:25314077 GADD45Ξ² suppresses JNK signaling and apoptosis by blocking MKK7 via direct physical interaction file:human/GADD45B/GADD45B-deep-research-perplexity.md GADD45B has also been identified as a promoter of cell survival through inhibition of JNK activation in multiple contexts |
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Download this section (compressed HTML)Q: How is the switch between GADD45B's pro-apoptotic function (MTK1/MEKK4 activation) and anti-apoptotic function (MKK7 inhibition) regulated in different cellular contexts?
Q: What is the structural basis for GADD45B's selective inhibition of MKK7 versus its activation of MTK1/MEKK4?
Experiment: Solve the structure of GADD45B in complex with MTK1 and separately with MKK7 to understand the molecular basis for its opposing effects on these two kinases.
Type: protein structure
Experiment: Determine the relative binding affinities of GADD45B for MTK1 versus MKK7 and how these are modulated by NF-kB pathway activation.
Type: functional assay
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