MAP2K7 (MKK7, JNKK2, MEK7) is a dual-specificity protein kinase of the STE group that, together with MKK4, forms the MAP kinase kinase tier of the JNK stress-activated MAPK cascade. It is activated by phosphorylation of Ser271 and Thr275 in its activation loop by MAP3Ks such as MEKK1, TAK1, ASK1, DLK and the mixed-lineage kinases, which dock onto its C-terminal DVD site. Activated MKK7 binds JNK1-3 through three low-affinity docking sites in its disordered N-terminal region and phosphorylates the JNK Thr-Pro-Tyr activation motif, with a strong preference for the threonine (Thr183); threonine phosphorylation alone raises JNK activity, and MKK4, which prefers the tyrosine, cooperates for full activation. Unlike MKK4, MKK7 is highly selective for JNK and does not activate p38 or (canonically) ERK MAPKs. MKK7 is activated by environmental stresses (UV, heat, osmotic shock) and is the MAP2K that is essential for JNK activation by the pro-inflammatory cytokines TNF and IL-1. It is a soluble cytoplasmic and nuclear protein that is assembled with MAP3Ks and JNK on scaffolds such as JIP1, and its activity is restrained by binding partners including GADD45beta and c-FLIPL. In human neurons MKK7 has also been reported to relay ApoE signalling from DLK to ERK1/2.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000287 magnesium ion binding | IDA PMID:9535930 Human mitogen-activated protein kinase kinase 7 (MKK7) is a ... | KEEP AS NON CORE | Summary: Magnesium ion binding attributed to the MKK7 cloning paper (Foltz et al. 1998), which characterised MKK7 as a JNK-activating kinase; Mg2+ is the cofactor of the kinase reaction. Reason: MKK7, like all protein kinases, uses Mg2+-ATP as co-substrate (UniProt COFACTOR Mg2+). The cached abstract does not describe a metal-binding experiment, but kinase assays inherently require Mg2+ and the curator saw the full text. Cofactor binding is correct but is not an informative description of MKK7 function. Supporting Evidence: file:human/MAP2K7/MAP2K7-uniprot.txt Name=Mg(2+); Xref=ChEBI:CHEBI:18420; PMID:9535930 MKK7 phosphorylated and activated JNK1 but failed to activate p38 MAPK in co-expression studies. |
| GO:0000287 magnesium ion binding | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA machine-learning assignment of magnesium ion binding. Reason: Consistent with the Mg2+ cofactor requirement of protein kinases (UniProt COFACTOR); correct but not informative about MKK7's specific function. Supporting Evidence: file:human/MAP2K7/MAP2K7-uniprot.txt Name=Mg(2+); Xref=ChEBI:CHEBI:18420; |
| 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. MKK7 phosphorylates the activation-loop Thr (and Tyr) of JNK MAPKs; MAP kinase kinase activity (GO:0004708) is the informative replacement at the level supported by an automated method, as done in the MAP2K3/MAP2K4 reviews. JUN kinase kinase activity (GO:0008545) is carried separately by IBA/ISS/TAS rows. Proposed replacements: MAP kinase kinase activity Supporting Evidence: PMID:9207092 In vitro protein kinase assays demonstrate that MKK7 phosphorylates and activates JNK, but not the p38 or extracellular signal-regulated kinase groups of MAP kinase. PMID:11390361 JNK is phosphorylated preferentially on Tyr by MKK4 and on Thr by MKK7. |
| GO:0004708 MAP kinase kinase activity | IDA PMID:9535930 Human mitogen-activated protein kinase kinase 7 (MKK7) is a ... | ACCEPT | Summary: Foltz et al. (1998) cloned human MKK7 and showed that it phosphorylated and activated JNK1 but not p38. Reason: Direct experimental support for MAP kinase kinase activity of human MKK7. The more specific JUN kinase kinase activity (GO:0008545) is also present via other rows and is used as the core MF. Supporting Evidence: PMID:9535930 MKK7 phosphorylated and activated JNK1 but failed to activate p38 MAPK in co-expression studies. PMID:9207092 In vitro protein kinase assays demonstrate that MKK7 phosphorylates and activates JNK, but not the p38 or extracellular signal-regulated kinase groups of MAP kinase. |
| GO:0004708 MAP kinase kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Combined IEA (ARBA / EC 2.7.12.2) MAP kinase kinase activity. Reason: Correct: MKK7 is EC 2.7.12.2 and a bona fide MAP2K that phosphorylates JNK1-3. Supporting Evidence: PMID:9207092 In vitro protein kinase assays demonstrate that MKK7 phosphorylates and activates JNK, but not the p38 or extracellular signal-regulated kinase groups of MAP kinase. PMID:9535930 MKK7 phosphorylated and activated JNK1 but failed to activate p38 MAPK in co-expression studies. |
| GO:0004713 protein tyrosine kinase activity | IEA GO_REF:0000116 | MODIFY | Summary: Rhea-derived protein tyrosine kinase activity (RHEA:10596), from the dual-specificity EC 2.7.12.2 reaction set. Reason: MKK7 can phosphorylate Tyr in the JNK TPY motif, but only in the context of MAPK activation-loop phosphorylation and with a strong preference for Thr; it is not a general tyrosine kinase. MAP kinase kinase activity (GO:0004708) captures the dual-specificity reaction correctly, as in the MAP2K3/MAP2K4 reviews. Proposed replacements: MAP kinase kinase activity Supporting Evidence: PMID:16442502 MKK7 activates JNK via phosphorylation of a threonine and tyrosine residue in a Thr-Pro-Tyr motif within kinase subdomain VIII. PMID:11390361 JNK is phosphorylated preferentially on Tyr by MKK4 and on Thr by MKK7. |
| GO:0005515 protein binding | IPI PMID:15299019 Human tribbles, a protein family controlling mitogen-activat... | REMOVE | Summary: MKK7 interaction with TRIB3 reported in the human tribbles paper (Kiss-Toth et al. 2004); abstract only in cache. Reason: Bare protein binding is uninformative. Tribbles are pseudokinases that regulate MAPKK activity and levels; that is a function of TRIB3, not a defined molecular activity of MKK7, so no informative MF for MKK7 can be derived (consistent with the MAP2K4 review). Removal of the generic protein binding term does not imply that the reported interaction is false. Supporting Evidence: PMID:15299019 MAPK kinases interact with Trbs and regulate their steady state levels. |
| GO:0005515 protein binding | IPI PMID:16840345 Vaccinia virus B1R kinase interacts with JIP1 and modulates ... | MODIFY | Summary: MKK7 binds the JNK scaffold JIP1 in a pull-down; vaccinia B1R increased the amount of MKK7 bound to JIP1. Reason: Bare protein binding is uninformative. JIP1 is the canonical scaffold that assembles MLK-MKK7-JNK modules, so scaffold protein binding (GO:0097110) is the informative replacement. Proposed replacements: scaffold protein binding Supporting Evidence: PMID:16840345 MKK7 binds to GST-JIP1, and as the amount of B1R was increased, so did the amount of bound MKK7. PMID:10490659 Both JIP1 and JIP2 strongly potentiate JNK activation by the MLK/MKK7 signaling pathway. file:human/MAP2K7/MAP2K7-uniprot.txt O14733; Q9UQF2: MAPK8IP1; NbExp=5; IntAct=EBI-492605, EBI-78404; |
| GO:0005515 protein binding | IPI PMID:17110930 An antiapoptotic protein, c-FLIPL, directly binds to MKK7 an... | REMOVE | Summary: c-FLIPL directly binds MKK7 in a TNF-dependent manner and inhibits MKK7 interaction with its MAP3Ks. Reason: Bare protein binding is uninformative. The interaction is well documented, but the activity belongs to c-FLIPL (an inhibitor of MKK7 activation); MKK7 does not acquire a distinct molecular function by being bound, and no informative GO MF term applies to MKK7. Removal of the generic protein binding term does not imply that the reported interaction is false. Supporting Evidence: PMID:17110930 c-FLIP L directly interacts with a JNK activator, MAP kinase kinase (MKK)7, in a TNFΞ±-dependent manner and inhibits the interactions of MKK7 with MAP/ERK kinase kinase 1, apoptosis-signal-regulating kinase 1, and TGFΞ²-activated kinase 1. |
| GO:0005515 protein binding | IPI PMID:17110930 An antiapoptotic protein, c-FLIPL, directly binds to MKK7 an... | MODIFY | Summary: MKK7 interaction with TAK1 (MAP3K7), measured in the c-FLIPL study, which showed c-FLIPL inhibits MKK7 binding to MEKK1, ASK1 and TAK1. Reason: Bare protein binding is uninformative. TAK1 is an upstream MAP3K that binds and phosphorylates MKK7 on Ser271/Thr275; MAP kinase kinase kinase binding (GO:0031435) is the informative replacement, as used for MAP3K partners in the MAP2K3/MAP2K4 reviews. Proposed replacements: mitogen-activated protein kinase kinase kinase binding Supporting Evidence: PMID:17110930 c-FLIP L directly interacts with a JNK activator, MAP kinase kinase (MKK)7, in a TNFΞ±-dependent manner and inhibits the interactions of MKK7 with MAP/ERK kinase kinase 1, apoptosis-signal-regulating kinase 1, and TGFΞ²-activated kinase 1. Reactome:R-HSA-450337 Residues involved in activation of these protein kinases correspond to human Ser271, Thr275 in MKK7 file:human/MAP2K7/MAP2K7-uniprot.txt O14733; O43318: MAP3K7; NbExp=3; IntAct=EBI-492605, EBI-358684; |
| GO:0005515 protein binding | IPI PMID:17709393 Vaccinia-related kinase 2 modulates the stress response to h... | MODIFY | Summary: MKK7 interaction with TAK1 in the VRK2/hypoxia study, which describes a TAK1-MKK7-JNK-JIP1 signalosome. Reason: Bare protein binding is uninformative. TAK1 is the upstream MAP3K of MKK7 in this signalosome; MAP kinase kinase kinase binding (GO:0031435) is the informative replacement. Proposed replacements: mitogen-activated protein kinase kinase kinase binding Supporting Evidence: PMID:17709393 This signalosome is formed by TAK1 as the upstream MAPKKK, MKK7 as the MAPKK, and JNK as the last kinase in the cascade 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). file:human/MAP2K7/MAP2K7-uniprot.txt O14733; O43318: MAP3K7; NbExp=3; IntAct=EBI-492605, EBI-358684; |
| GO:0005515 protein binding | IPI PMID:18286207 Modulation of interleukin-1 transcriptional response by the ... | MODIFY | Summary: MKK7-JIP1 interaction in the study of VRK2 modulation of IL-1 signalling through the JIP1 scaffold. Reason: Bare protein binding is uninformative. JIP1 is the scaffold that assembles MLK3, MKK7 and JNK; scaffold protein binding (GO:0097110) is the informative replacement. Proposed replacements: scaffold protein binding Supporting Evidence: PMID:18286207 One likely candidate is the scaffold protein JIP1, which assembles and regulates the MAP kinases of the JNK signal transduction pathway MLK3, MKK7 and JNK PMID:10490659 Both JIP1 and JIP2 strongly potentiate JNK activation by the MLK/MKK7 signaling pathway. file:human/MAP2K7/MAP2K7-uniprot.txt O14733; Q9UQF2: MAPK8IP1; NbExp=5; IntAct=EBI-492605, EBI-78404; |
| GO:0005515 protein binding | IPI PMID:20067578 MKK6 binds and regulates expression of Parkinson's disease-r... | MODIFY | Summary: LRRK2 binds MKK3, MKK6 and MKK7 and can phosphorylate them (Hsu et al. 2010). Reason: Bare protein binding is uninformative. LRRK2 is a protein kinase that binds and phosphorylates MKK7; protein kinase binding (GO:0019901) is the informative replacement, as in the MAP2K3 review. The physiological role of LRRK2 as an MKK7 activator is not established, so the MAP3K binding term is not proposed. Proposed replacements: protein kinase binding Supporting Evidence: PMID:20067578 we show that LRRK2 binds to MAPK kinases (MKK) 3, 6, and 7, and that LRRK2 is able to phosphorylate MKK3, 6 and 7. file:human/MAP2K7/MAP2K7-uniprot.txt O14733; Q5S007: LRRK2; NbExp=3; IntAct=EBI-492605, EBI-5323863; |
| GO:0005515 protein binding | IPI PMID:22939624 Quantitative analysis of HSP90-client interactions reveals p... | MODIFY | Summary: MKK7-HSP90AB1 interaction from a quantitative kinome-wide survey of HSP90-client interactions. Reason: Bare protein binding is uninformative. The screen identifies kinases as the dominant HSP90 client class; Hsp90 protein binding (GO:0051879) records MKK7 as an HSP90 client, reproduced independently (PMID:32707033). This is a chaperone-client relationship, not a core MKK7 function. Proposed replacements: Hsp90 protein binding Supporting Evidence: PMID:22939624 Unexpectedly, many more kinases than transcription factors bound HSP90. file:human/MAP2K7/MAP2K7-uniprot.txt O14733; P08238: HSP90AB1; NbExp=2; IntAct=EBI-492605, EBI-352572; |
| GO:0005515 protein binding | IPI PMID:25241761 Using an in situ proximity ligation assay to systematically ... | MODIFY | Summary: Endogenous MKK7-TAK1 proximity detected in a large-scale in situ proximity ligation assay survey in HeLa cells (abstract only). Reason: Bare protein binding is uninformative. The partner TAK1 is an established upstream MAP3K of MKK7 (independently supported, IntAct NbExp=3); MAP kinase kinase kinase binding (GO:0031435) is the informative replacement. Proposed replacements: mitogen-activated protein kinase kinase kinase binding Supporting Evidence: PMID:25241761 to investigate 1204 endogenous PPIs in HeLa cells, and 557 PPIs of them tested positive Reactome:R-HSA-450337 Residues involved in activation of these protein kinases correspond to human Ser271, Thr275 in MKK7 file:human/MAP2K7/MAP2K7-uniprot.txt O14733; O43318: MAP3K7; NbExp=3; IntAct=EBI-492605, EBI-358684; |
| GO:0005515 protein binding | IPI PMID:25314077 Cancer-selective targeting of the NF-ΞΊB survival pathway wit... | REMOVE | Summary: GADD45beta binds MKK7 and blocks its kinase activity by engaging the catalytic pocket; DTP3 peptides disrupt the complex in myeloma cells. Reason: Bare protein binding is uninformative. The well-established GADD45beta-MKK7 interaction (IntAct NbExp=8) is an inhibitory activity of GADD45beta toward MKK7; no informative GO MF describes MKK7's side of the complex, and a specific function should not be invented from interaction evidence. Removal of the generic protein binding term does not imply that the reported interaction is false. Supporting Evidence: PMID:25314077 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:32707033 Kinase Interaction Network Expands Functional and Disease Ro... | MODIFY | Summary: MKK7-HSP90AB1 association detected in a mass-spectrometry kinase interaction network. Reason: Bare protein binding is uninformative. Hsp90 protein binding (GO:0051879) is the informative replacement, consistent with the HSP90-client survey (PMID:22939624). Proposed replacements: Hsp90 protein 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. file:human/MAP2K7/MAP2K7-uniprot.txt O14733; P08238: HSP90AB1; NbExp=2; IntAct=EBI-492605, EBI-352572; |
| GO:0005515 protein binding | IPI PMID:36931259 A central chaperone-like role for 14-3-3 proteins in human c... | MODIFY | Summary: MKK7-YWHAE interaction from the proteome-wide map of human 14-3-3 interactomes (abstract only). Reason: Bare protein binding is uninformative. The partner is a 14-3-3 protein, so 14-3-3 protein binding (GO:0071889) exactly describes the interaction; no downstream consequence for MKK7 has been demonstrated, so it is non-core. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:36931259 Here, we map the interactomes of all human 14-3-3 paralogs file:human/MAP2K7/MAP2K7-uniprot.txt O14733; P62258: YWHAE; NbExp=2; IntAct=EBI-492605, EBI-356498; |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-derived ATP binding (protein kinase domain). Reason: MKK7 is an active ATP-dependent protein kinase with a canonical ATP-binding site in its kinase domain; ATP is its phosphate donor. Supporting Evidence: file:human/MAP2K7/MAP2K7-uniprot.txt /ligand="ATP" |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping to nucleus. Reason: MKK7 is found in both cytoplasm and nucleus (UniProt, by similarity to mouse); JNK substrates act in both compartments. Supporting Evidence: file:human/MAP2K7/MAP2K7-uniprot.txt SUBCELLULAR LOCATION: Nucleus. Cytoplasm {ECO:0000250}. |
| GO:0005634 nucleus | ISS GO_REF:0000024 | ACCEPT | Summary: ISS nucleus from mouse Mkk7 (Q8CE90). Reason: Consistent with the UniProt location (Nucleus; Cytoplasm). Supporting Evidence: file:human/MAP2K7/MAP2K7-uniprot.txt SUBCELLULAR LOCATION: Nucleus. Cytoplasm {ECO:0000250}. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping to cytoplasm. Reason: Correct; MKK7 is a soluble cytoplasmic kinase that assembles with MAP3Ks, JIP scaffolds and JNK. Cytosol (GO:0005829) is the more specific term, present via Reactome. Supporting Evidence: file:human/MAP2K7/MAP2K7-uniprot.txt SUBCELLULAR LOCATION: Nucleus. Cytoplasm {ECO:0000250}. |
| GO:0005737 cytoplasm | ISS GO_REF:0000024 | ACCEPT | Summary: ISS cytoplasm from mouse Mkk7. Reason: Consistent with the UniProt location and the cytosolic JIP1 scaffold complexes. Supporting Evidence: file:human/MAP2K7/MAP2K7-uniprot.txt SUBCELLULAR LOCATION: Nucleus. Cytoplasm {ECO:0000250}. PMID:18286207 One likely candidate is the scaffold protein JIP1, which assembles and regulates the MAP kinases of the JNK signal transduction pathway MLK3, MKK7 and JNK |
| GO:0005829 cytosol | TAS Reactome:R-HSA-168162 | ACCEPT | Summary: Reactome places MKK7 phosphorylation of JNK in the cytosol. Reason: Correct; the MAP3K-MKK7-JNK module operates in the cytosol. Supporting Evidence: Reactome:R-HSA-168162 MKK7 is the primary activator of JNK in TNF, LPS, and PGN responses. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2730868 | ACCEPT | Summary: Reactome: MEKK1 phosphorylates MKK7 in the cytosol. Reason: Correct; MAP3K phosphorylation of MKK7 occurs in the cytosol. Supporting Evidence: Reactome:R-HSA-2730868 MKK7 is activated by MEKK1 and the residues serine 271 and threonine 275 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-450337 | ACCEPT | Summary: Reactome: activated TAK1 phosphorylates MKK4/MKK7 in the cytosol. Reason: Correct. Supporting Evidence: Reactome:R-HSA-450337 Residues involved in activation of these protein kinases correspond to human Ser271, Thr275 in MKK7 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5211387 | ACCEPT | Summary: Reactome: anthrax lethal factor cleaves MAP2K7 in the target-cell cytosol. Reason: Correct localization; MKK7 is a cytosolic target of anthrax lethal factor. Supporting Evidence: Reactome:R-HSA-5211387 in the target cell cytosol, cleaves MAP2K7 (MEK7, mitogen activated protein kinase kinase 7) |
| GO:0006970 response to osmotic stress | IDA PMID:9535930 Human mitogen-activated protein kinase kinase 7 (MKK7) is a ... | KEEP AS NON CORE | Summary: Endogenous MKK7 activity increased on hyperosmolarity (Foltz et al. 1998). Reason: MKK7 activation by osmotic stress is documented, and it relays this signal to JNK, but the response is a context of the stress-activated JNK cascade rather than a distinct function of MKK7. Supporting Evidence: PMID:9535930 MKK7 was also activated when cells were exposed to heat, UV irradiation, anisomycin, hyperosmolarity or the pro-inflammatory cytokine tumor necrosis factor-alpha. |
| GO:0007165 signal transduction | TAS PMID:9535930 Human mitogen-activated protein kinase kinase 7 (MKK7) is a ... | MODIFY | Summary: TAS signal transduction from the human MKK7 cloning paper. Reason: Correct but uninformative. MKK7 is the JNK-specific MAP2K of the JNK cascade; JNK cascade (GO:0007254) is the appropriate replacement, as in the MAP2K4 review. Proposed replacements: JNK cascade Supporting Evidence: PMID:9535930 MKK7 phosphorylated and activated JNK1 but failed to activate p38 MAPK in co-expression studies. PMID:9207092 MKK7 is therefore established to be a novel component of the JNK signal transduction pathway. |
| GO:0007254 JNK cascade | ISS GO_REF:0000024 | ACCEPT | Summary: ISS JNK cascade from mouse Mkk7. Reason: Core process. MKK7 is an essential component of the JNK cascade; Mkk7 disruption abolishes cytokine-induced JNK activation. Supporting Evidence: PMID:9207092 MKK7 is therefore established to be a novel component of the JNK signal transduction pathway. PMID:11390361 disruption of the Mkk7 gene alone was sufficient to prevent JNK activation caused by proinflammatory cytokines. |
| GO:0007254 JNK cascade | TAS Reactome:R-HSA-450321 | ACCEPT | Summary: Reactome: JNK phosphorylation and activation mediated by activated human TAK1 via MKK4 and MKK7. Reason: Core process. 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). |
| GO:0008545 JUN kinase kinase activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA JUN kinase kinase activity from PAINT node PTN001220492 (MKK7/hemipterous clade), with mouse Map2k7 and rat Map2k7 among the experimental descendants. Reason: Core molecular function. MKK7 is a JNK-specific MAP2K that preferentially phosphorylates the Thr of the JNK TPY motif; the IBD at the MKK7-clade node is well placed and human MKK7 has its own experimental support (PMID:9535930, PMID:9372971). Supporting Evidence: PMID:9207092 In vitro protein kinase assays demonstrate that MKK7 phosphorylates and activates JNK, but not the p38 or extracellular signal-regulated kinase groups of MAP kinase. PMID:9372971 We show that JNKK2 is a highly specific JNK kinase. PMID:11390361 JNK is phosphorylated preferentially on Tyr by MKK4 and on Thr by MKK7. file:human/MAP2K7/MAP2K7-deep-research-falcon.md MKK4 activates both JNK and p38; MKK7 is much more JNK-selective. |
| GO:0008545 JUN kinase kinase activity | ISS GO_REF:0000024 | ACCEPT | Summary: ISS transfer of JUN kinase kinase activity from mouse Mkk7 (Q8CE90). Reason: Core molecular function, consistent with direct evidence for human MKK7 phosphorylating and activating JNK but not p38. Supporting Evidence: PMID:9312068 Unlike JNKK1 that activates both JNK and p38 MAP kinases, JNKK2 stimulated only JNK. PMID:9535930 MKK7 phosphorylated and activated JNK1 but failed to activate p38 MAPK in co-expression studies. |
| GO:0008545 JUN kinase kinase activity | TAS Reactome:R-HSA-168162 | ACCEPT | Summary: Reactome 'Phosphorylation of human JNKs by activated MKK4/MKK7'. Reason: Core molecular function: activated MKK7 phosphorylates the JNK activation loop, with a striking preference for Thr183. Supporting Evidence: Reactome:R-HSA-168162 MKK7 a striking preference for the threonine residue (Thr-183) Reactome:R-HSA-168162 MKK7 is the primary activator of JNK in TNF, LPS, and PGN responses. |
| GO:0009408 response to heat | IDA PMID:9535930 Human mitogen-activated protein kinase kinase 7 (MKK7) is a ... | KEEP AS NON CORE | Summary: Endogenous MKK7 activity increased on heat treatment (Foltz et al. 1998). Reason: Documented activation by heat; a stimulus context of the JNK cascade, not a core function. Supporting Evidence: PMID:9535930 MKK7 was also activated when cells were exposed to heat, UV irradiation, anisomycin, hyperosmolarity or the pro-inflammatory cytokine tumor necrosis factor-alpha. |
| GO:0009411 response to UV | IDA PMID:9535930 Human mitogen-activated protein kinase kinase 7 (MKK7) is a ... | KEEP AS NON CORE | Summary: Endogenous MKK7 activity increased on UV irradiation (Foltz et al. 1998). Reason: Documented activation by UV; in mouse cells, UV-induced JNK activation requires MKK4 and MKK7 together. A stimulus context of the JNK cascade. Supporting Evidence: PMID:9535930 MKK7 was also activated when cells were exposed to heat, UV irradiation, anisomycin, hyperosmolarity or the pro-inflammatory cytokine tumor necrosis factor-alpha. PMID:11390361 Simultaneous disruption of the Mkk4 and Mkk7 genes was required to block JNK activation caused by exposure of cells to environmental stress. |
| GO:0019899 enzyme binding | IPI PMID:14615289 Angiotensin-converting enzyme is involved in outside-in sign... | KEEP AS NON CORE | Summary: MKK7 and JNK co-precipitated with angiotensin-converting enzyme (ACE) in endothelial cells; ACE-inhibitor-stimulated ACE signalling activated JNK. Reason: The co-precipitation supports association of MKK7 with the ACE signalling complex, but enzyme binding is a generic term and the interaction is peripheral to MKK7's function as a JNK kinase. No more informative MF for MKK7 is supported. Supporting Evidence: PMID:14615289 Mitogen-activated protein kinase kinase 7 and c-Jun N-terminal kinase (JNK) coprecipitated with ACE |
| GO:0019901 protein kinase binding | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA machine-learning assignment of protein kinase binding. Reason: Correct in outline - MKK7 docks onto JNK substrates via N-terminal D-sites and onto upstream MAP3Ks via its DVD site - but the binding terms are subsidiary to the catalytic function. The more specific GO:0051019 is supported experimentally. Supporting Evidence: PMID:16533805 We conclude that MKK7 contains three JNK-docking sites that interact to selectively bind JNK and contribute to JNK signal transmission and specificity. PMID:15866172 The DVD sites bind to their specific upstream MAP kinase kinase kinases (MAPKKKs), including MTK1 (MEKK4), ASK1, TAK1, TAO2, MEKK1, and Raf-1. |
| GO:0019901 protein kinase binding | IPI PMID:14697235 SP3 acts as a positive regulator on the core promoter of hum... | KEEP AS NON CORE | Summary: IPI with MAP3K12 (DLK/ZPK); the cached abstract describes the SP3-regulated ZPK promoter and does not mention MKK7. Reason: The interaction evidence cannot be verified from the abstract, but the full text was read by the curator and DLK is an established upstream MAP3K of MKK7 (UniProt ACTIVITY REGULATION; MKK7 is a major DLK target in neurons, PMID:28111074). Protein kinase binding is therefore plausible and is kept as a non-core binding annotation; MAP3K binding (GO:0031435) would be more specific if the full text shows direct binding. Supporting Evidence: PMID:14697235 ZPK (zipper protein kinase)/MUK/DLK/MAP3K12, a member of mixed-lineage kinases (MLKs) PMID:28111074 MKK7, a MAP-kinase kinase that is a major DLK target in neurons file:human/MAP2K7/MAP2K7-uniprot.txt kinase kinases such as MAP3K1/MEKK1, MAP3K3/MEKK3, MAP3K11/MLK3 |
| GO:0019903 protein phosphatase binding | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse Mkk7, based on the MKK7-SKRP1 (DUSP19) interaction (Zama et al. 2002), in which SKRP1 selectively forms complexes with MKK7 and scaffolds ASK1-MKK7. Reason: The source evidence shows specific binding of MKK7 to the MAPK phosphatase SKRP1/DUSP19, which regulates MKK7 activity. This is a genuine regulatory interaction, but it is not a core function of MKK7. Supporting Evidence: PMID:11959862 SKRP1 selectively formed the stable complexes with MKK7 but not with MKK4 |
| GO:0031098 stress-activated protein kinase signaling cascade | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA assignment of stress-activated protein kinase signaling cascade. Reason: Correct parent of the JNK cascade; MKK7 is a core component. Supporting Evidence: file:human/MAP2K7/MAP2K7-uniprot.txt component of the stress-activated protein kinase/c-Jun N-terminal |
| GO:0032206 positive regulation of telomere maintenance | IMP PMID:21531765 High-throughput RNAi screening reveals novel regulators of t... | UNDECIDED | Summary: Kinome RNAi screen for regulators of telomerase activity; MAP2K7 knockdown presumably reduced telomerase activity (acts_upstream_of_or_within). The cached abstract does not mention MKK7. Reason: The cached abstract (full text unavailable) does not describe the MAP2K7 result, so the evidence cannot be evaluated. Even if confirmed, a screen hit for telomerase activity would reflect an indirect downstream effect rather than a core MKK7 function. Supporting Evidence: PMID:21531765 we report the findings of a high-throughput functional RNA interference screen to globally profile the contribution of kinases to telomerase activity (TA) |
| GO:0034612 response to tumor necrosis factor | IDA PMID:9535930 Human mitogen-activated protein kinase kinase 7 (MKK7) is a ... | KEEP AS NON CORE | Summary: Endogenous MKK7 activity increased by TNF-alpha (Foltz et al. 1998). Reason: Well supported: TNF and IL-1 activate MKK7 but not MKK4, and MKK7 is required for cytokine-induced JNK activation (PMID:11390361). Kept as a non-core stimulus-response annotation; the core process is the JNK cascade. Supporting Evidence: PMID:9535930 MKK7 was also activated when cells were exposed to heat, UV irradiation, anisomycin, hyperosmolarity or the pro-inflammatory cytokine tumor necrosis factor-alpha. PMID:11390361 the inflammatory cytokines, tumor necrosis factor (TNF), and interleukin-1 (IL-1) activated only MKK7 PMID:11390361 disruption of the Mkk7 gene alone was sufficient to prevent JNK activation caused by proinflammatory cytokines. |
| GO:0038095 Fc-epsilon receptor signaling pathway | TAS Reactome:R-HSA-2454202 | KEEP AS NON CORE | Summary: Reactome FCERI signalling includes MKK7-mediated JNK activation downstream of the Fc-epsilon receptor. Reason: MKK7 acts in the JNK arm downstream of FcR ligation (endogenous MKK7 is activated by Fc receptor ligation, PMID:9535930), but this is one of many receptor contexts feeding the JNK cascade. Supporting Evidence: Reactome:R-HSA-2454202 These pathways lead to activation of the ERK, JNK and p38 MAP kinases, histamine release and cytokine production. PMID:9535930 or by ligation of CD40, the B-cell antigen receptor, or the receptor for the Fc fragment of immunoglobulin |
| GO:0043410 positive regulation of MAPK cascade | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: ARBA assignment of positive regulation of MAPK cascade. Reason: MKK7 is a component of the JNK MAPK cascade (the MAP2K tier), not a regulator external to it; participation is already captured by JNK cascade (GO:0007254) and stress-activated MAPK cascade. The regulation term is a redundant over-annotation. Supporting Evidence: PMID:9207092 MKK7 is therefore established to be a novel component of the JNK signal transduction pathway. |
| GO:0045893 positive regulation of DNA-templated transcription | IMP PMID:28111074 ApoE2, ApoE3, and ApoE4 Differentially Stimulate APP Transcr... | MARK AS OVER ANNOTATED | Summary: MKK7 CRISPR in human neurons blocked ApoE-induced, AP-1-dependent APP transcription (DLK -> MKK7 -> ERK1/2 -> c-Fos/AP-1). Reason: MKK7 is a kinase several steps upstream of the transcription factors; the transcriptional effect is an indirect consequence of the kinase cascade. Positive regulation of DNA-templated transcription over-states MKK7's role (consistent with the MAP2K3 review for the same term). Supporting Evidence: PMID:28111074 MKK7 CRISPR suppressed baseline ERK1/2 phosphorylation and blocked ApoE3-induced ERK1/2 phosphorylation PMID:28111074 We observed that MKK7 directly phosphorylated ERK2 |
| GO:0051019 mitogen-activated protein kinase binding | EXP PMID:25737554 Structure and dynamics of the MKK7-JNK signaling complex. | ACCEPT | Summary: NMR, ITC and crystallography (Kragelj et al. 2015) of the MKK7 disordered regulatory domain binding JNK1 through three docking motifs; crystal structure of JNK1 with MKK7 D2. Reason: Strong direct evidence that MKK7 binds its MAPK substrate JNK1 via N-terminal D-sites; substrate docking is required for efficient JNK activation (PMID:16533805). Supporting Evidence: PMID:25737554 MKK7 activates the c-Jun N-terminal kinase (JNK) pathway and is the only MKK containing three motifs within its regulatory domain. PMID:25737554 we determine the crystal structure of JNK1 in complex with the second docking site of MKK7 PMID:16533805 We conclude that MKK7 contains three JNK-docking sites that interact to selectively bind JNK and contribute to JNK signal transmission and specificity. |
| GO:0051019 mitogen-activated protein kinase binding | IPI PMID:25737554 Structure and dynamics of the MKK7-JNK signaling complex. | ACCEPT | Summary: IPI (partner JNK1/MAPK8) from the same structural study of the MKK7-JNK1 complex. Reason: Same evidence as the EXP row; MKK7 D-sites bind JNK1 with low-micromolar affinity and a crystal structure of the D2-JNK1 complex was solved. Supporting Evidence: PMID:25737554 we determine the crystal structure of JNK1 in complex with the second docking site of MKK7 PMID:16533805 We conclude that MKK7 contains three JNK-docking sites that interact to selectively bind JNK and contribute to JNK signal transmission and specificity. |
| GO:0051403 stress-activated MAPK cascade | IBA GO_REF:0000033 | ACCEPT | Summary: IBA stress-activated MAPK cascade from PAINT node PTN001220492 (MKK7 clade); human MKK7 is itself an experimental source. Reason: Correct; MKK7 mediates stress- and cytokine-induced JNK activation. JNK cascade (GO:0007254, a child of this term) is the more specific process. Supporting Evidence: PMID:9535930 MKK7 was also activated when cells were exposed to heat, UV irradiation, anisomycin, hyperosmolarity or the pro-inflammatory cytokine tumor necrosis factor-alpha. PMID:11390361 Simultaneous disruption of the Mkk4 and Mkk7 genes was required to block JNK activation caused by exposure of cells to environmental stress. |
| GO:0051403 stress-activated MAPK cascade | IDA PMID:9535930 Human mitogen-activated protein kinase kinase 7 (MKK7) is a ... | ACCEPT | Summary: Endogenous MKK7 activated by heat, UV, anisomycin, hyperosmolarity and TNF, and MKK7 activates JNK (Foltz et al. 1998). Reason: Direct evidence that MKK7 is activated by environmental stresses and relays them to JNK. Supporting Evidence: PMID:9535930 MKK7 was also activated when cells were exposed to heat, UV irradiation, anisomycin, hyperosmolarity or the pro-inflammatory cytokine tumor necrosis factor-alpha. PMID:9535930 MKK7 phosphorylated and activated JNK1 but failed to activate p38 MAPK in co-expression studies. |
| GO:0070374 positive regulation of ERK1 and ERK2 cascade | IMP PMID:28111074 ApoE2, ApoE3, and ApoE4 Differentially Stimulate APP Transcr... | KEEP AS NON CORE | Summary: In human neurons ApoE activates a DLK -> MKK7 -> ERK1/2 pathway; MKK7 CRISPR blocked ApoE-induced ERK1/2 phosphorylation and immunoprecipitated MKK7 phosphorylated ERK2 in vitro. Reason: Experimentally supported in one study, but non-canonical: the authors note it differs from the established JNK-specific activity of MKK7, and classical studies found MKK7 does not activate ERK. Kept as a context-specific non-core annotation. Supporting Evidence: PMID:28111074 MKK7 CRISPR suppressed baseline ERK1/2 phosphorylation and blocked ApoE3-induced ERK1/2 phosphorylation PMID:28111074 We observed that MKK7 directly phosphorylated ERK2 PMID:28111074 this hypothesis differs from current concepts of MAP-kinase signaling pathways which suggest that MKK7 primarily phosphorylates JNKs instead of ERKs PMID:9207092 In vitro protein kinase assays demonstrate that MKK7 phosphorylates and activates JNK, but not the p38 or extracellular signal-regulated kinase groups of MAP kinase. |
| GO:0090398 cellular senescence | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA assignment of cellular senescence. Reason: Derived from the Reactome oxidative-stress-induced senescence pathway, in which MKK7 activates JNK. A downstream pleiotropic outcome of JNK signalling, not a core MKK7 function (consistent with MAP2K3/MAP2K4 reviews). Supporting Evidence: Reactome:R-HSA-2559583 Oxidative stress, which may or may not be caused by oncogenic RAS signaling, can also trigger senescence. |
| GO:0090398 cellular senescence | TAS Reactome:R-HSA-2559583 | KEEP AS NON CORE | Summary: Reactome Cellular Senescence (oxidative-stress-induced senescence branch includes MKK7-JNK). Reason: Pleiotropic downstream outcome of JNK signalling; kept as non-core, consistent with the MAP2K3/MAP2K4 reviews. 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 EC 2.7.12.2 reaction set. Reason: The physiologically relevant reaction is phosphorylation of the Thr (preferentially) and Tyr of the JNK activation loop, not generic serine phosphorylation. MAP kinase kinase activity (GO:0004708) is the appropriate replacement, as in the MAP2K3/MAP2K4 reviews. Proposed replacements: MAP kinase kinase activity Supporting Evidence: PMID:11390361 JNK is phosphorylated preferentially on Tyr by MKK4 and on Thr by MKK7. PMID:16442502 MKK7 activates JNK via phosphorylation of a threonine and tyrosine residue in a Thr-Pro-Tyr motif within kinase subdomain VIII. |
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Download this section (compressed HTML)Q: Does the IPI between MKK7 and MAP3K12/DLK attributed to PMID:14697235 (a ZPK promoter paper) reflect a direct interaction reported in the full text, and should it be re-annotated as MAP kinase kinase kinase binding (GO:0031435)?
Q: Is the DLK -> MKK7 -> ERK1/2 route reported in human neurons (PMID:28111074) reproducible with purified components, and under which physiological conditions does MKK7 phosphorylate ERK rather than JNK?
Q: What MAP2K7 result in the kinome RNAi telomerase screen (PMID:21531765) supports the positive regulation of telomere maintenance annotation, and was it validated with independent reagents?
Experiment: Kinase-dead MKK7 knock-in versus acute degron depletion in human cells, with and without MKK4 loss, to quantify MKK7-specific JNK Thr183 phosphorylation after TNF, IL-1 and UV, and to separate catalytic from scaffolding roles.
Experiment: In vitro kinase assays with purified activated MKK7 and ERK2 versus JNK1 (kcat/Km, with D-site mutants) to test whether ERK phosphorylation by MKK7 is direct and physiologically competitive.
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