MAP2K4 (MKK4, SEK1, JNKK1, MEK4) is a dual-specificity protein kinase of the STE group that, together with MKK7, forms the MAP kinase kinase tier of the JNK stress-activated MAPK cascade, and in addition contributes to activation of p38 MAPKs. It is activated by phosphorylation of Ser257 and Thr261 in its activation loop by many MAP3Ks, including MEKK1 (MAP3K1), TAK1 (MAP3K7), ASK1 (MAP3K5) and the mixed-lineage kinases, which dock onto its C-terminal DVD site. Activated MKK4 docks onto its substrates through an intrinsically disordered N-terminal D-site that binds JNK1-3 and p38alpha/beta with comparable affinity, and phosphorylates the threonine and tyrosine of the MAPK activation-loop motif, with a marked preference for the tyrosine (Tyr185) of the JNK Thr-Pro-Tyr motif; MKK7 prefers the threonine, so the two kinases cooperate for full JNK activation. MKK4 does not activate ERK. It is a soluble protein found in the cytoplasm and nucleus and is activated by UV and ionizing radiation, heat shock, hyperosmolarity, oxidative stress and inflammatory cytokines, relaying these signals through JNK and p38 to transcriptional programmes controlling stress adaptation, apoptosis and proliferation. MAP2K4 is recurrently inactivated in some epithelial cancers, and its N terminus is cleaved by anthrax lethal factor.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000165 MAPK cascade | IBA GO_REF:0000033 | ACCEPT | Summary: IBA propagation of MAPK cascade from the PAINT MAP2K node PTN000684494 (includes MKK3/MKK6/MKK7 and yeast/fly/worm MAP2Ks). MKK4 is a bona fide MAP2K tier kinase that activates JNK and p38 MAPKs. Reason: MKK4 is the MAP2K tier of the stress-activated MAPK cascades and sits squarely within the clade that inherited this function; there is no evidence of divergence. The IBA is correct, though JNK cascade (GO:0007254) is the more informative process term, which is present separately. Supporting Evidence: PMID:7716521 A dual-specificity kinase that activates JNK, named JNKK, was identified that functions between MEKK and JNK. PMID:7839144 Two human MAP kinase kinases (MKK3 and MKK4) were cloned that phosphorylate and activate p38 MAP kinase. |
| GO:0000165 MAPK cascade | IEA GO_REF:0000107 | ACCEPT | Summary: IEA transfer of MAPK cascade from mouse Map2k4 (P47809) via Ensembl Compara. Reason: Correct; mouse Map2k4 has experimental MAPK cascade annotations and the human ortholog has the same function. General term; JNK cascade is the specific process. Supporting Evidence: file:human/MAP2K4/MAP2K4-uniprot.txt With MAP2K7/MKK7, is the one of the |
| GO:0004672 protein kinase activity | IEA GO_REF:0000002 | MODIFY | Summary: InterPro-derived protein kinase activity (Ser/Thr kinase active site signature). Reason: Correct but uninformative for a MAP2K. MKK4 phosphorylates the Thr and Tyr of MAPK activation loops; MAP kinase kinase activity (GO:0004708) is the informative replacement, as in the MAP2K3 and MAP2K6 reviews. Proposed replacements: MAP kinase kinase activity Supporting Evidence: file:human/MAP2K4/MAP2K4-uniprot.txt With MAP2K7/MKK7, is the one of the PMID:7716521 JNKK activated the JNKs but did not activate the ERKs and was unresponsive to Raf-1 in transfected HeLa cells. |
| GO:0004672 protein kinase activity | TAS PMID:7716521 Identification of a dual specificity kinase that activates t... | MODIFY | Summary: TAS protein kinase activity from the original JNKK identification paper (Lin et al. 1995), which described MKK4/JNKK as a dual-specificity kinase activating JNKs and p38. Reason: The paper defines this kinase specifically as a JNK kinase (JNKK) that activates JNKs (and p38) but not ERKs. JUN kinase kinase activity (GO:0008545, is_a MAP kinase kinase activity) is the precise, informative MF. Proposed replacements: JUN kinase kinase activity Supporting Evidence: PMID:7716521 A dual-specificity kinase that activates JNK, named JNKK, was identified that functions between MEKK and JNK. PMID:7716521 JNKK activated the JNKs but did not activate the ERKs and was unresponsive to Raf-1 in transfected HeLa cells. |
| GO:0004708 MAP kinase kinase activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA MAP kinase kinase activity from PAINT node PTN000684494 (MAP2K family), with experimental grounding in many members (MKK3, MKK6, MKK7, Ste7, Pbs2, etc.). Reason: This is the core molecular function of MKK4, supported directly by biochemical data showing MKK4 phosphorylates and activates JNK and p38 MAPKs. Supporting Evidence: PMID:7716521 A dual-specificity kinase that activates JNK, named JNKK, was identified that functions between MEKK and JNK. PMID:7839144 Two human MAP kinase kinases (MKK3 and MKK4) were cloned that phosphorylate and activate p38 MAP kinase. PMID:12788955 inhibited both MKK4/JNK binding and MKK4-mediated phosphorylation of JNK1 |
| GO:0004708 MAP kinase kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: IEA MAP kinase kinase activity (ARBA/EC 2.7.12.2 combined methods). Reason: Correct core molecular function (EC 2.7.12.2). Supporting Evidence: file:human/MAP2K4/MAP2K4-uniprot.txt With MAP2K7/MKK7, is the one of the PMID:7839144 Two human MAP kinase kinases (MKK3 and MKK4) were cloned that phosphorylate and activate p38 MAP kinase. |
| GO:0004713 protein tyrosine kinase activity | IEA GO_REF:0000116 | MODIFY | Summary: Rhea-derived protein tyrosine kinase activity (RHEA:10596) from the generic EC 2.7.12.2 reaction set. Reason: MKK4 phosphorylates a tyrosine (preferentially JNK Tyr185, and the p38 TGY tyrosine) but only as part of the dual-specificity MAPK activation-loop reaction; it is not a general tyrosine kinase. MAP kinase kinase activity (GO:0004708) describes the reaction informatively, as for MAP2K3/MAP2K6. Proposed replacements: MAP kinase kinase activity Supporting Evidence: file:human/MAP2K4/MAP2K4-uniprot.txt Tyr residue and MAP2K7/MKK7 for the Thr residue. Reactome:R-HSA-168162 MKK4 shows a striking preference for the tyrosine residue (Tyr-185) |
| GO:0005515 protein binding | IPI PMID:15299019 Human tribbles, a protein family controlling mitogen-activat... | REMOVE | Summary: MKK4-TRIB1 interaction reported in the human tribbles paper (Kiss-Toth et al. 2004); abstract only in cache. Reason: Bare protein binding is uninformative. TRIB1 is a pseudokinase; the paper reports that MAPKKs interact with tribbles and that tribbles regulate MAPKK activity and levels, which is a function of TRIB1 rather than a defined molecular activity of MKK4. No informative MF for MKK4 can be derived, so the annotation is removed; this does not imply the interaction is false. Supporting Evidence: PMID:15299019 MAPK kinases interact with Trbs and regulate their steady state levels. |
| GO:0005515 protein binding | IPI PMID:16533805 Interacting JNK-docking sites in MKK7 promote binding and ac... | MODIFY | Summary: MKK4-JNK1 binding: the MKK4 D-site (residues 36-49) binds JNK1 and competes with MKK7 for the same docking region on JNK1 (Ho et al. 2006, MKK7 docking paper). Reason: Bare protein binding is uninformative. JNK1 (MAPK8) is a direct substrate that MKK4 docks onto through its N-terminal D-site before phosphorylating the TPY motif. Mitogen-activated protein kinase binding (GO:0051019) is the informative replacement, consistent with the MAP2K3/MAP2K6 reviews. Proposed replacements: mitogen-activated protein kinase binding Supporting Evidence: PMID:16533805 Previously, we used this approach to show that the D-sites of JIP-1 and MKK4 compete for interaction with JNK PMID:16533805 Optimal activation of JNK requires the activity of both MKK4 and MKK7; although both MEKs are capable of dual phosphorylation of JNK at the activation loop residues Thr and Tyr, MKK4 prefers the Tyr and MKK7 prefers the Thr |
| GO:0005515 protein binding | IPI PMID:21900206 A directed protein interaction network for investigating int... | MODIFY | Summary: MKK4-JNK2 (MAPK9) interaction from a large-scale yeast two-hybrid directed signalling network. Reason: Bare protein binding is uninformative. JNK2 is a direct MKK4 substrate bound through the D-site (PMID:12788955), and the interaction is reproduced in independent studies (IntAct NbExp=3). Mitogen-activated protein kinase binding (GO:0051019) is the informative replacement. Proposed replacements: mitogen-activated protein kinase binding Supporting Evidence: PMID:21900206 we searched for protein interaction partners of more than 450 signaling-related proteins by means of automated yeast two-hybrid interaction mating PMID:12788955 This docking site was both necessary and sufficient for the high affinity binding of the MAPKs JNK1, JNK2, JNK3, p38 alpha, and p38 beta to MKK4. file:human/MAP2K4/MAP2K4-uniprot.txt P45985; P45984: MAPK9; NbExp=3; IntAct=EBI-447868, EBI-713568; |
| GO:0005515 protein binding | IPI PMID:32707033 Kinase Interaction Network Expands Functional and Disease Ro... | MODIFY | Summary: MKK4-JNK1 association detected in a mass-spectrometry kinase interaction network. Reason: Bare protein binding is uninformative. JNK1 is a direct MKK4 substrate docked through the D-site. Mitogen-activated protein kinase binding (GO:0051019) is the informative replacement, as in the MAP2K3/MAP2K6 reviews for the same high-throughput dataset. Proposed replacements: mitogen-activated protein kinase binding Supporting Evidence: PMID:32707033 Here, we present a comprehensive mass-spectrometry-based analysis of a human kinase interaction network covering more than 300 kinases. PMID:12788955 This docking site was both necessary and sufficient for the high affinity binding of the MAPKs JNK1, JNK2, JNK3, p38 alpha, and p38 beta to MKK4. file:human/MAP2K4/MAP2K4-uniprot.txt P45985; P45983: MAPK8; NbExp=4; IntAct=EBI-447868, EBI-286483; |
| GO:0005515 protein binding | IPI PMID:34439869 Enthalpy-Entropy Compensation in the Promiscuous Interaction... | MODIFY | Summary: NMR/ITC study of the disordered MKK4 regulatory domain (residues 12-86) binding JNK1 and p38alpha with comparable affinities via folding-upon-binding. Reason: Bare protein binding is uninformative. The partners JNK1 and p38alpha are the two classes of MAPK substrate recruited by the MKK4 docking site. Mitogen-activated protein kinase binding (GO:0051019) is the informative replacement; the same paper already supports a GO:0051019 EXP annotation. Proposed replacements: mitogen-activated protein kinase binding Supporting Evidence: PMID:34439869 the promiscuous interaction of the disordered regulatory domain of MKK4 with p38Ξ± and JNK1 is facilitated by folding-upon-binding into two different conformations PMID:34439869 One exception is MKK4 that contains an 86-amino acid disordered domain with a docking site motif that can recruit both the JNK and p38 kinases. |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | MODIFY | Summary: MKK4-JNK1 co-purification in the OpenCell endogenous-tagging IP-MS resource. Reason: Bare protein binding is uninformative. JNK1 is a direct MKK4 substrate; mitogen-activated protein kinase binding (GO:0051019) is the informative replacement. Proposed replacements: mitogen-activated protein kinase binding Supporting Evidence: PMID:35271311 We combined genome engineering, confocal live-cell imaging, mass spectrometry and data science to systematically map the localization and interactions of human proteins. file:human/MAP2K4/MAP2K4-uniprot.txt P45985; P45983: MAPK8; NbExp=4; IntAct=EBI-447868, EBI-286483; |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | MODIFY | Summary: MKK4-JNK2 co-purification in the OpenCell endogenous-tagging IP-MS resource. Reason: Bare protein binding is uninformative. JNK2 is a direct MKK4 substrate; mitogen-activated protein kinase binding (GO:0051019) is the informative replacement. Proposed replacements: mitogen-activated protein kinase binding Supporting Evidence: PMID:35271311 We combined genome engineering, confocal live-cell imaging, mass spectrometry and data science to systematically map the localization and interactions of human proteins. file:human/MAP2K4/MAP2K4-uniprot.txt P45985; P45984: MAPK9; NbExp=3; IntAct=EBI-447868, EBI-713568; |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | MODIFY | Summary: MKK4-JNK1 interaction in the multimodal U2OS cell map (AP-MS plus imaging). Reason: Bare protein binding is uninformative. JNK1 is a direct MKK4 substrate; mitogen-activated protein kinase binding (GO:0051019) is the informative replacement. Proposed replacements: mitogen-activated protein kinase binding Supporting Evidence: PMID:40205054 Here we construct a global map of human subcellular architecture through joint measurement of biophysical interactions and immunofluorescence images for over 5,100 proteins in U2OS osteosarcoma cells. file:human/MAP2K4/MAP2K4-uniprot.txt P45985; P45983: MAPK8; NbExp=4; IntAct=EBI-447868, EBI-286483; |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | MODIFY | Summary: MKK4-JNK2 interaction in the multimodal U2OS cell map (AP-MS plus imaging). Reason: Bare protein binding is uninformative. JNK2 is a direct MKK4 substrate; mitogen-activated protein kinase binding (GO:0051019) is the informative replacement. Proposed replacements: mitogen-activated protein kinase binding Supporting Evidence: PMID:40205054 Here we construct a global map of human subcellular architecture through joint measurement of biophysical interactions and immunofluorescence images for over 5,100 proteins in U2OS osteosarcoma cells. file:human/MAP2K4/MAP2K4-uniprot.txt P45985; P45984: MAPK9; NbExp=3; IntAct=EBI-447868, EBI-713568; |
| GO:0005515 protein binding | IPI PMID:9808624 JNKK1 organizes a MAP kinase module through specific and seq... | MODIFY | Summary: MKK4/JNKK1 binds its upstream activator MEKK1 (MAP3K1) through its amino-terminal extension; MEKK1 preferentially phosphorylates JNKK1 and JNK competes with MEKK1 for JNKK1 binding. Reason: Bare protein binding is uninformative. MEKK1 is a canonical upstream MAP3K of MKK4, and the paper shows specific binding required for MEKK1-mediated activation. Mitogen-activated protein kinase kinase kinase binding (GO:0031435) is the informative replacement, as used for ASK1 in the MAP2K3 review. Proposed replacements: mitogen-activated protein kinase kinase kinase binding Supporting Evidence: PMID:9808624 The specificity of JNK activation is determined by the MAPKK JNKK1, which interacts with the MAPKKK MEKK1 and JNK through its amino-terminal extension. PMID:9808624 As JNK and MEKK1 compete for binding to JNKK1 and activation of JNKK1 prevents its binding to MEKK1 |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-derived ATP binding (protein kinase domain / ATP-binding site signature). Reason: MKK4 is an active ATP-dependent protein kinase with a canonical ATP-binding site (residues 108-116, K131). Supporting Evidence: file:human/MAP2K4/MAP2K4-uniprot.txt /ligand="ATP" |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: Nucleus from UniProt subcellular location (by similarity). Reason: MKK4 is a soluble kinase reported in both cytoplasm and nucleus; nuclear presence is consistent with the literature summarised in the deep-research report, although the evidence is less direct than for cytosol. Supporting Evidence: file:human/MAP2K4/MAP2K4-uniprot.txt -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. Nucleus {ECO:0000250}. file:human/MAP2K4/MAP2K4-deep-research-falcon.md Its working localization is best annotated as **cytoplasmic and nuclear, dynamic and cell-context dependent**. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Cytoplasm from UniProt subcellular location (by similarity). Reason: MKK4 is a soluble cytoplasmic kinase that phosphorylates cytoplasmic JNK/p38. Supporting Evidence: file:human/MAP2K4/MAP2K4-uniprot.txt -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. Nucleus {ECO:0000250}. file:human/MAP2K4/MAP2K4-deep-research-falcon.md Its working localization is best annotated as **cytoplasmic and nuclear, dynamic and cell-context dependent**. |
| GO:0005829 cytosol | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA-predicted cytosol. Reason: Consistent with Reactome placing MKK4 activation and MKK4-catalysed JNK phosphorylation in the cytosol. Supporting Evidence: Reactome:R-HSA-168162 Activated human JNK kinases (MKK4 and MKK7) phosphorylate Thr183 and Tyr185 residues in the characteristic Thr-Pro-Tyr phosphoacceptor loop of each JNK. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-168162 | ACCEPT | Summary: Reactome places MKK4/MKK7 phosphorylation of JNKs in the cytosol. Reason: MKK4 is a soluble cytosolic kinase; consistent with UniProt and other sources. Supporting Evidence: Reactome:R-HSA-168162 Activated human JNK kinases (MKK4 and MKK7) phosphorylate Thr183 and Tyr185 residues in the characteristic Thr-Pro-Tyr phosphoacceptor loop of each JNK. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2730896 | ACCEPT | Summary: Reactome places MEKK1-mediated phosphorylation of MKK4 (Ser257/Thr261) in the cytosol. Reason: Cytosolic location of MKK4 during its activation is consistent with other sources. Supporting Evidence: Reactome:R-HSA-2730896 Activated MEKK1 then phosphorylates and activates SAPK/Erk kinase (SEK1), also known as MKK4 or Jun kinase kinase (JNKK) on serine and threonine residues at positions 257 and 261, respectively. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-450337 | ACCEPT | Summary: Reactome places TAK1-mediated phosphorylation of MKK4/MKK7 in the cytosol. Reason: Cytosolic location of MKK4 during its activation is consistent with other sources. Supporting Evidence: Reactome:R-HSA-450337 In human, phosphorylation of MKK4 (MAP2K4) and MKK7 (MAP2K7) by TAK1 occurs at the typical Ser-Xaa-Ala-Xaa-Thr motif in their activation loops. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5211391 | ACCEPT | Summary: Reactome: anthrax lethal factor cleaves MAP2K4 in the target-cell cytosol. Reason: The reaction documents cytosolic MKK4 as the target of lethal-factor cleavage; the location assertion is correct. Supporting Evidence: Reactome:R-HSA-5211391 in the target cell cytosol, cleaves MAP2K4 (MEK4, mitogen activated protein kinase kinase 4) |
| GO:0007165 signal transduction | TAS PMID:7716521 Identification of a dual specificity kinase that activates t... | MODIFY | Summary: TAS signal transduction from the JNKK identification paper. Reason: Correct but too general. The paper places JNKK between MEKK and JNK, i.e. in the JNK cascade (GO:0007254), the informative process term (analogous to the p38MAPK cascade replacement in the MAP2K3/MAP2K6 reviews). Proposed replacements: JNK cascade Supporting Evidence: PMID:7716521 A dual-specificity kinase that activates JNK, named JNKK, was identified that functions between MEKK and JNK. |
| GO:0007166 cell surface receptor signaling pathway | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: ARBA-predicted cell surface receptor signaling pathway. Reason: MKK4 acts in intracellular MAPK cascades downstream of many inputs (stresses, cytokine receptors, TCR), but it is not a component of any specific cell-surface receptor pathway; the broad receptor-signalling term adds little and over-states a receptor-proximal role. The specific process is the JNK / stress-activated MAPK cascade. Supporting Evidence: file:human/MAP2K4/MAP2K4-uniprot.txt Activated in response to a variety of cellular |
| GO:0007254 JNK cascade | TAS PMID:7716521 Identification of a dual specificity kinase that activates t... | ACCEPT | Summary: TAS JNK cascade from Lin et al. 1995, which identified JNKK as the kinase between MEKK and JNK. Reason: Core process: MKK4 directly phosphorylates and activates JNK1-3. Supporting Evidence: PMID:7716521 A dual-specificity kinase that activates JNK, named JNKK, was identified that functions between MEKK and JNK. PMID:7716521 JNKK activated the JNKs but did not activate the ERKs and was unresponsive to Raf-1 in transfected HeLa cells. |
| GO:0007254 JNK cascade | TAS Reactome:R-HSA-450321 | ACCEPT | Summary: Reactome: TAK1-mediated JNK activation through MKK4/MKK7. Reason: Core process; MKK4 is one of the two MAP2Ks that directly activate JNK. Supporting Evidence: Reactome:R-HSA-450321 Activation of JNKs is mediated by activated TAK1 which phosphorylates two dual specificity enzymes MKK4 (MAPK kinase 4) and MKK7(MAPK kinase 7). Reactome:R-HSA-450337 JNK and p38 MAPK activities were decreased by around 80% and 20%, respectively, following deletion of the mkk4 gene. |
| GO:0007528 neuromuscular junction development | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA neuromuscular junction development transferred from mouse Map2k4 (P47809) by Ensembl orthology. Reason: MKK4 is a general stress/cytokine MAP2K; a role in neuromuscular junction development is at most an indirect consequence of JNK signalling. The mouse source annotation (not cached here) was not reviewed; nothing in the evidence available to this review establishes MKK4 as a developmental component of NMJ formation. Not a core process. Supporting Evidence: file:human/MAP2K4/MAP2K4-uniprot.txt With MAP2K7/MKK7, is the one of the |
| GO:0008545 JUN kinase kinase activity | TAS Reactome:R-HSA-168162 | ACCEPT | Summary: Reactome: MKK4/MKK7 phosphorylate human JNKs on Thr183/Tyr185, MKK4 preferring Tyr185. Reason: Core, specific MF. MKK4 directly phosphorylates JNK1-3, with preference for the tyrosine of the TPY motif; biochemically supported by docking and kinase assays. Supporting Evidence: Reactome:R-HSA-168162 Activated human JNK kinases (MKK4 and MKK7) phosphorylate Thr183 and Tyr185 residues in the characteristic Thr-Pro-Tyr phosphoacceptor loop of each JNK. Reactome:R-HSA-168162 MKK4 shows a striking preference for the tyrosine residue (Tyr-185) PMID:12788955 inhibited both MKK4/JNK binding and MKK4-mediated phosphorylation of JNK1 file:human/MAP2K4/MAP2K4-uniprot.txt Tyr residue and MAP2K7/MKK7 for the Thr residue. |
| GO:0033554 cellular response to stress | IEA GO_REF:0000117 | MODIFY | Summary: ARBA-predicted cellular response to stress. Reason: Correct in spirit: MKK4 is activated by UV, irradiation, heat shock, hyperosmolarity, peroxide and cytokines. The informative process for its participation is the stress-activated MAPK cascade (GO:0051403), which MKK4 executes by activating JNK and p38. Proposed replacements: stress-activated MAPK cascade Supporting Evidence: file:human/MAP2K4/MAP2K4-uniprot.txt Activated in response to a variety of cellular file:human/MAP2K4/MAP2K4-uniprot.txt Essential component of the stress-activated protein kinase/c-Jun N-terminal |
| GO:0034390 smooth muscle cell apoptotic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA smooth muscle cell apoptotic process transferred from mouse Map2k4 by Ensembl orthology. Reason: MKK4-JNK signalling contributes to stress-induced apoptosis in several cell types, but this is a cell-type-specific downstream outcome rather than a core function. Supporting Evidence: file:human/MAP2K4/MAP2K4-uniprot.txt involved in mitochondrial death signaling pathway, including the |
| GO:0036481 intrinsic apoptotic signaling pathway in response to hydrogen peroxide | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA intrinsic apoptotic signaling in response to hydrogen peroxide transferred from mouse Map2k4 by Ensembl orthology. Reason: Peroxide activates MKK4 and the MKK4-JNK pathway participates in mitochondrial apoptotic signalling; plausible but context-specific and downstream of the core kinase function. Supporting Evidence: file:human/MAP2K4/MAP2K4-uniprot.txt hyperosmolarity, T-cell receptor stimulation, peroxide and inflammatory file:human/MAP2K4/MAP2K4-uniprot.txt involved in mitochondrial death signaling pathway, including the |
| GO:0038095 Fc-epsilon receptor signaling pathway | TAS Reactome:R-HSA-2454202 | KEEP AS NON CORE | Summary: Reactome FCERI signalling pathway (FCERI-mediated MAPK activation includes MKK4/MKK7-JNK). Reason: MKK4 participates in JNK activation downstream of FCERI in mast cells as one of many receptor inputs; valid pathway membership but not a core function. Supporting Evidence: Reactome:R-HSA-2454202 These pathways lead to activation of the ERK, JNK and p38 MAP kinases, histamine release and cytokine production. |
| GO:0038127 ERBB signaling pathway | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA ERBB signaling pathway from mouse Map2k4 (IDA in a neuregulin/ARIA muscle AChR-induction study). Reason: Neuregulin-ErbB signalling in muscle activates JNK, and MKK4 can relay this; this is one of many receptor contexts for MKK4 and is not core. Supporting Evidence: file:human/MAP2K4/MAP2K4-uniprot.txt With MAP2K7/MKK7, is the one of the |
| GO:0048273 mitogen-activated protein kinase p38 binding | EXP PMID:29276882 Deciphering the Dynamic Interaction Profile of an Intrinsica... | ACCEPT | Summary: EXP (DisProt): NMR exchange spectroscopy of the complex between p38alpha and the intrinsically disordered MKK4 regulatory domain. Reason: Direct biophysical evidence that the MKK4 docking region binds p38alpha, its substrate; informative, specific binding term consistent with MKK4 acting as a p38 activator. Supporting Evidence: PMID:29276882 We apply the approach to the dynamic signaling complex formed between the mitogen-activated protein kinase (MAPK) p38Ξ± and the intrinsically disordered regulatory domain of the MAPK kinase MKK4. |
| GO:0051019 mitogen-activated protein kinase binding | EXP PMID:34439869 Enthalpy-Entropy Compensation in the Promiscuous Interaction... | ACCEPT | Summary: EXP (DisProt): NMR/ITC show the MKK4 disordered regulatory domain binds JNK1 and p38alpha with comparable affinities. Reason: Direct evidence of substrate-MAPK docking by the MKK4 D-site; informative binding term supporting the core MAPKK function. Supporting Evidence: PMID:34439869 the promiscuous interaction of the disordered regulatory domain of MKK4 with p38Ξ± and JNK1 is facilitated by folding-upon-binding into two different conformations PMID:12788955 This docking site was both necessary and sufficient for the high affinity binding of the MAPKs JNK1, JNK2, JNK3, p38 alpha, and p38 beta to MKK4. |
| GO:0071260 cellular response to mechanical stimulus | IEP PMID:19593445 Expression of the Bcl-2 protein BAD promotes prostate cancer... | UNDECIDED | Summary: IEP cellular response to mechanical stimulus citing PMID:19593445, a study of BAD expression in prostate cancer growth. Reason: The cached full text of PMID:19593445 (BAD in prostate cancer xenografts) contains no mention of MKK4/MAP2K4 or of mechanical stimulation; the same PMID supports IEP mechanical-stimulus annotations on FAS, GADD45A, MAP3K1 and TNFRSF1A, suggesting a batch mis-citation of a different (e.g. mechanical-stretch expression) study. Because the intended source cannot be identified, the curator decision is not overruled; the annotation cannot be verified from the cited paper. Even if valid, an IEP response term would be non-core. Supporting Evidence: PMID:19593445 Analysis of the effect of BAD on prostate cancer xenografts has shown that increased BAD expression enhances tumor growth |
| GO:0090398 cellular senescence | TAS Reactome:R-HSA-2559583 | KEEP AS NON CORE | Summary: Reactome cellular senescence (oxidative-stress-induced senescence includes MKK3/MKK4/MKK6-p38 activation). Reason: MKK4 contributes to stress-MAPK signalling that feeds into oxidative-stress-induced senescence; a downstream, context-dependent outcome rather than a core function. Supporting Evidence: Reactome:R-HSA-2559583 Oxidative stress, which may or may not be caused by oncogenic RAS signaling, can also trigger senescence. |
| GO:0106310 protein serine kinase activity | IEA GO_REF:0000116 | MODIFY | Summary: Rhea-derived protein serine kinase activity (RHEA:17989) from the generic EC 2.7.12.2 reaction set. Reason: No serine substrate of MKK4 is established; the physiological reaction is Thr/Tyr phosphorylation of MAPK activation loops. MAP kinase kinase activity (GO:0004708) is the accurate replacement, as in the MAP2K3 review. Proposed replacements: MAP kinase kinase activity Supporting Evidence: file:human/MAP2K4/MAP2K4-uniprot.txt Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + file:human/MAP2K4/MAP2K4-uniprot.txt With MAP2K7/MKK7, is the one of the |
| GO:0038066 p38MAPK cascade | IDA PMID:7839144 Independent human MAP-kinase signal transduction pathways de... | NEW | Summary: MKK4 phosphorylates and activates p38 MAPKs in addition to JNKs; it is the only MAP2K that feeds both the JNK and p38 cascades. Reason: MKK4 performs a catalytic step of the p38 cascade (dual phosphorylation of the p38 TGY motif), so the participation test is met. Comparator check: the other p38-activating MAP2Ks, MKK3 and MKK6, carry GO:0038066 (see MAP2K3/MAP2K6 reviews), so absence for MKK4 reflects a gap rather than a convention. MKK4 contributes less to p38 than to JNK activation in cells (~20% vs ~80% loss on deletion), but the contribution is direct. Supporting Evidence: PMID:7839144 Two human MAP kinase kinases (MKK3 and MKK4) were cloned that phosphorylate and activate p38 MAP kinase. PMID:7716521 JNKK also activated another MAPK, p38 (Mpk2; the mammalian homolog of HOG1 from yeast), whose activity is regulated similarly to that of the JNKs. file:human/MAP2K4/MAP2K4-uniprot.txt exclusively activates JNKs, MAP2K4/MKK4 additionally activates the p38 Reactome:R-HSA-450337 JNK and p38 MAPK activities were decreased by around 80% and 20%, respectively, following deletion of the mkk4 gene. |
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Download this section (compressed HTML)Q: What is the source publication for the IEP "cellular response to mechanical stimulus" annotation currently attributed to PMID:19593445 (a BAD/prostate cancer paper that does not mention MKK4), and does MKK4 respond to mechanical stimuli?
Q: Under which physiological stimuli and in which cell types does MKK4 make a non-redundant contribution to p38 activation relative to MKK3 and MKK6?
Q: Is MKK4 activity in the nucleus functionally significant, or is its nuclear pool a reservoir with JNK/p38 phosphorylation occurring mainly in the cytosol?
Experiment: Acute MKK4 depletion (degron) versus kinase-inactive knock-in in human cells, combined with MKK7 loss, to quantify MKK4-specific JNK Tyr185 and p38 TGY phosphorylation across stresses (UV, osmotic, oxidative, cytokine).
Experiment: Compartment-restricted MKK4 (NES/NLS-tagged) rescue in MKK4-null cells to determine where MKK4 must reside to activate JNK and p38.
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