MAP2K6 (MKK6, MEK6, SKK3) is a dual-specificity protein kinase of the STE group that forms, with its paralog MKK3, the MAP kinase kinase tier of the p38 stress-activated MAPK cascade. It is activated by phosphorylation of Ser207 and Thr211 in its activation loop by many MAP3Ks, including ASK1 (MAP3K5), TAK1 (MAP3K7), TAO2, MEKK1-4 and MLK3, as well as by PKR in response to double-stranded RNA; MAP3Ks are recruited through a C-terminal DVD docking site. Activated MKK6 docks onto p38 MAPKs through its N-terminal D domain and phosphorylates both the threonine and tyrosine of their Thr-Gly-Tyr activation motif, activating all four p38 isoforms (p38alpha/MAPK14, p38beta/MAPK11, p38gamma/MAPK12 and p38delta/MAPK13) but not ERK or JNK. Unphosphorylated MKK6 can form an autoinhibited homodimer. It is a soluble protein found in cytoplasm and nucleus. Through p38 it relays inflammatory cytokine and environmental stress signals (osmotic shock, UV, gamma irradiation, ribotoxic stress) to outputs such as transcription, cell-cycle checkpoints, apoptosis and senescence. MKK6 is inactivated by bacterial virulence factors (anthrax lethal factor cleavage and Yersinia YopJ acetylation).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000165 MAPK cascade | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference that MAP2K6 participates in a MAPK cascade, from the PANTHER MAP2K family node. Reason: MKK6 is the MAP2K tier of the p38 MAPK cascade. The IBA node covers MAP2Ks across eukaryotes and MAP2K6 lies inside that clade with its own experimental grounding (it appears in its WITH/FROM list). The general term is correct; the more specific p38MAPK cascade (GO:0038066) is separately annotated. Supporting Evidence: file:human/MAP2K6/MAP2K6-uniprot.txt protein kinase family. MAP kinase kinase subfamily. PMID:8622669 Expression of activated MKK3 and MKK6 in cultured cells caused a selective increase in p38 MAP kinase activity. |
| GO:0000165 MAPK cascade | IDA PMID:8663074 A novel kinase cascade mediated by mitogen-activated protein... | ACCEPT | Summary: Moriguchi et al. showed that MAPKK6 is phosphorylated and activated by TAK1 and in turn phosphorylates and activates p38, defining a TAK1-MKK6/MKK3-p38 cascade. Reason: Direct biochemical evidence that MKK6 is a kinase step in a three-tier MAPK cascade. Correct; GO:0038066 p38MAPK cascade is the more specific term, also annotated. Supporting Evidence: PMID:8663074 MAPKK6 was shown to phosphorylate and specifically activate the p38/MPK2 subgroup of the mitogen-activated protein kinase superfamily PMID:8663074 These results indicate the existence of a novel kinase cascade consisting of TAK1, MAPKK6/MKK3, and p38/MPK2. |
| GO:0000165 MAPK cascade | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara projection from mouse Map2k6 of MAPK cascade. Reason: Consistent with the experimental evidence placing human MKK6 in the p38 MAPK cascade. Supporting Evidence: file:human/MAP2K6/MAP2K6-uniprot.txt Dual specificity protein kinase which acts as an essential PMID:8663074 MAPKK6 was shown to phosphorylate and specifically activate the p38/MPK2 subgroup of the mitogen-activated protein kinase superfamily |
| GO:0001649 osteoblast differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara projection from mouse Map2k6 of osteoblast differentiation. Reason: UniProt records roles of MKK6-p38 signalling in skeletal differentiation (osteoclastogenesis via TNFSF11, endochondral ossification via SOX9). The projection comes from an experimentally annotated mouse ortholog and is plausible, but it reflects a tissue-specific downstream outcome of p38 activation, not a core activity of MKK6. Supporting Evidence: file:human/MAP2K6/MAP2K6-uniprot.txt kappa-B transactivation by TNFSF11, and in endochondral ossification file:human/MAP2K6/MAP2K6-deep-research-falcon.md not as the final executor of a single cell fate |
| GO:0004672 protein kinase activity | IEA GO_REF:0000002 | MODIFY | Summary: InterPro-based assignment of generic protein kinase activity from the Ser/Thr kinase active-site signature. Reason: Correct but uninformative. MKK6 is a dual-specificity MAP kinase kinase whose established substrates are the p38 MAPKs; MAP kinase kinase activity (GO:0004708) captures the substrate class, as in the MAP2K3 review. Proposed replacements: MAP kinase kinase activity Supporting Evidence: file:human/MAP2K6/MAP2K6-uniprot.txt Dual specificity protein kinase which acts as an essential file:human/MAP2K6/MAP2K6-uniprot.txt and a tyrosine residue in the MAP kinases p38 MAPK11, MAPK12, MAPK13 |
| GO:0004674 protein serine/threonine kinase activity | TAS Reactome:R-HSA-8877691 | KEEP AS NON CORE | Summary: Reactome reaction in which MAP2K6 phosphorylates PIP4K2B on Ser326 under oxidative stress. Reason: Unlike MAP2K3, MKK6 has reported non-MAPK serine substrates (PIP4K2B Ser326 per Reactome; PAK6 per UniProt), so a Ser/Thr kinase activity is supported. These are secondary substrates compared with the p38 TGY dual phosphorylation that defines the core MAP kinase kinase activity (GO:0004708), so the term is retained as non-core. Supporting Evidence: Reactome:R-HSA-8877691 MAP2K6 (MKK6), and possibly other kinases of the p38 MAPK family, phosphorylates PIP4K2B at serine residue S326. file:human/MAP2K6/MAP2K6-uniprot.txt phosphorylates and activates PAK6. |
| GO:0004708 MAP kinase kinase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of MAP kinase kinase activity from the PANTHER MAP2K family node. Reason: MAP kinase kinase activity is the defining, conserved function of the MAP2K family, and MAP2K6 carries direct experimental support for it (it appears in its own WITH/FROM list). Core function. Supporting Evidence: file:human/MAP2K6/MAP2K6-uniprot.txt protein kinase family. MAP kinase kinase subfamily. file:human/MAP2K6/MAP2K6-uniprot.txt and a tyrosine residue in the MAP kinases p38 MAPK11, MAPK12, MAPK13 |
| GO:0004708 MAP kinase kinase activity | IDA PMID:11460167 TAK1 is a ubiquitin-dependent kinase of MKK and IKK. | ACCEPT | Summary: Wang et al. showed that the TAK1-TAB1-TAB2 complex phosphorylates MKK6 in a K63-polyubiquitin-dependent manner, with MKK6 then activating the p38 pathway. Reason: The paper measured MKK6 activation downstream of TAK1 as part of p38 pathway activation. The cached abstract states MKK6 activates the JNK-p38 pathway; MAP kinase kinase activity toward p38 is well established for MKK6, so the curator's IDA is accepted. Supporting Evidence: PMID:11460167 the activity of TAK1 to phosphorylate MKK6, which activates the JNK-p38 kinase pathway, is directly regulated by K63-linked polyubiquitination Reactome:R-HSA-1247960 All are activated by phosphorylation on a canonical TxY motif by the dual-specificity kinase MKK6, which displays minimal substrate selectivity amongst the p38 isoforms |
| GO:0004708 MAP kinase kinase activity | IDA PMID:8663074 A novel kinase cascade mediated by mitogen-activated protein... | ACCEPT | Summary: Moriguchi et al. showed that MAPKK6 phosphorylates and specifically activates p38. Reason: Direct evidence of MAP kinase kinase activity toward p38. Core function. Supporting Evidence: PMID:8663074 MAPKK6 was shown to phosphorylate and specifically activate the p38/MPK2 subgroup of the mitogen-activated protein kinase superfamily |
| GO:0004708 MAP kinase kinase activity | IDA PMID:8663524 Characterization of the structure and function of a new mito... | ACCEPT | Summary: Jiang et al. showed that p38beta is preferentially activated by MKK6. Reason: Direct evidence that MKK6 activates a p38 isoform (p38beta/MAPK11) via its TGY site. Core function. Supporting Evidence: PMID:8663524 the preferred activation of p38beta by MAP kinase kinase 6 (MKK6) PMID:8663524 It contains a TGY dual phosphorylation site, which is required for its kinase activity. |
| GO:0004708 MAP kinase kinase activity | IDA PMID:9218798 Activation of the novel stress-activated protein kinase SAPK... | ACCEPT | Summary: Goedert et al. showed that SKK3 (MKK6) activates SAPK4 (p38delta/MAPK13) in vitro and in cells. Reason: Direct evidence of MAP kinase kinase activity toward p38delta; MKK6 was the only SAPK4 activator induced by stress or IL-1. Core function. Supporting Evidence: PMID:9218798 SAPK4 was activated in vitro by SKK3 (also called MKK6) or when co-transfected with SKK3 into COS cells. |
| GO:0004708 MAP kinase kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Combined automated (ARBA/ortholog/EC) assignment of MAP kinase kinase activity. Reason: Consistent with extensive experimental evidence. Core function. Supporting Evidence: file:human/MAP2K6/MAP2K6-uniprot.txt Dual specificity protein kinase which acts as an essential file:human/MAP2K6/MAP2K6-uniprot.txt and a tyrosine residue in the MAP kinases p38 MAPK11, MAPK12, MAPK13 |
| GO:0004708 MAP kinase kinase activity | IMP PMID:8622669 MKK3- and MKK6-regulated gene expression is mediated by the ... | ACCEPT | Summary: Raingeaud et al. expressed activated MKK6 and showed it selectively increases p38 MAP kinase activity and p38-dependent gene expression. Reason: Experimental evidence (activated-mutant expression) for MKK6 acting as a p38 MAP kinase kinase. Core function. Supporting Evidence: PMID:8622669 Expression of activated MKK3 and MKK6 in cultured cells caused a selective increase in p38 MAP kinase activity. |
| GO:0004708 MAP kinase kinase activity | TAS PMID:10848581 Involvement of the MKK6-p38gamma cascade in gamma-radiation-... | ACCEPT | Summary: Wang et al. describe MKK6 as the MAP kinase kinase activating p38gamma after gamma irradiation, with MKK6 immunoprecipitates phosphorylating kinase-dead p38 in vitro. Reason: Supported by in vitro kinase assays of immunoprecipitated MKK6 on p38 substrate in the full text. Core function. Supporting Evidence: PMID:10848581 The immunoprecipitates were used to phosphorylate p38(KM) in in vitro kinase assays. PMID:10848581 Two MAP kinase kinases, MKK3 and MKK6, have been identified as immediate upstream activators of the p38 family |
| GO:0004708 MAP kinase kinase activity | TAS Reactome:R-HSA-1247960 | ACCEPT | Summary: Reactome assertion (Reactome:R-HSA-1247960) that activated MKK6 phosphorylates p38 MAPK isoforms on the TGY motif. Reason: MKK6 phosphorylates all four p38 isoforms on the Thr-Gly-Tyr activation motif. Core function. Supporting Evidence: Reactome:R-HSA-1247960 All are activated by phosphorylation on a canonical TxY motif by the dual-specificity kinase MKK6, which displays minimal substrate selectivity amongst the p38 isoforms Reactome:R-HSA-450333 All of those isoforms are activated by phosphorylation of the Thr and Tyr in the Thr-Gly-Tyr motif in their activation loops. |
| GO:0004708 MAP kinase kinase activity | TAS Reactome:R-HSA-3238999 | ACCEPT | Summary: Reactome assertion (Reactome:R-HSA-3238999) that activated MKK6 phosphorylates p38 MAPK isoforms on the TGY motif. Reason: MKK6 phosphorylates all four p38 isoforms on the Thr-Gly-Tyr activation motif. Core function. Supporting Evidence: Reactome:R-HSA-1247960 All are activated by phosphorylation on a canonical TxY motif by the dual-specificity kinase MKK6, which displays minimal substrate selectivity amongst the p38 isoforms Reactome:R-HSA-3238999 Phosphorylation of p38 alpha and p38 beta by MKK3 or MKK6 (Raingeaud et al. 1996), however, is required for the subsequent activation of MAPKAPK5 by p38 MAPK |
| GO:0004708 MAP kinase kinase activity | TAS Reactome:R-HSA-450333 | ACCEPT | Summary: Reactome assertion (Reactome:R-HSA-450333) that activated MKK6 phosphorylates p38 MAPK isoforms on the TGY motif. Reason: MKK6 phosphorylates all four p38 isoforms on the Thr-Gly-Tyr activation motif. Core function. Supporting Evidence: Reactome:R-HSA-1247960 All are activated by phosphorylation on a canonical TxY motif by the dual-specificity kinase MKK6, which displays minimal substrate selectivity amongst the p38 isoforms Reactome:R-HSA-450333 All of those isoforms are activated by phosphorylation of the Thr and Tyr in the Thr-Gly-Tyr motif in their activation loops. |
| GO:0004713 protein tyrosine kinase activity | IEA GO_REF:0000116 | MODIFY | Summary: Rhea-mapping IEA of protein tyrosine kinase activity (RHEA:10596). Reason: MKK6 phosphorylates a tyrosine only as part of dual Thr/Tyr phosphorylation of the p38 TGY motif; it is not a general tyrosine kinase. MAP kinase kinase activity (GO:0004708) describes the reaction more informatively, as in the MAP2K3 review. Proposed replacements: MAP kinase kinase activity Supporting Evidence: file:human/MAP2K6/MAP2K6-uniprot.txt Reaction=L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + file:human/MAP2K6/MAP2K6-uniprot.txt and a tyrosine residue in the MAP kinases p38 MAPK11, MAPK12, MAPK13 file:human/MAP2K6/MAP2K6-deep-research-falcon.md It does not mean that MAP2K6 indiscriminately phosphorylates broad classes of Ser/Thr- and Tyr-containing proteins. |
| GO:0005515 protein binding | IPI PMID:11035004 C-terminal elements control location, activation threshold, ... | MODIFY | Summary: IPI for MAP2K6 binding MAPK14 (p38alpha) from a study of RSKB activation through the p38 pathway (PMID:11035004). Reason: Bare protein binding is uninformative. The partner p38alpha is the principal substrate that MKK6 docks onto via its N-terminal D domain and dually phosphorylates; the interaction is supported by several independent studies (IntAct NbExp=3). Mitogen-activated protein kinase binding (GO:0051019) captures the informative substrate-docking aspect, as in the MAP2K3 review. The cached abstract does not describe the MKK6 assay, but the interaction itself is well established. Proposed replacements: mitogen-activated protein kinase binding Supporting Evidence: file:human/MAP2K6/MAP2K6-uniprot.txt P52564; Q16539: MAPK14; NbExp=3; IntAct=EBI-448135, EBI-73946; file:human/MAP2K6/MAP2K6-uniprot.txt Dimer. Interacts (via its D domain) with its substrates Reactome:R-HSA-1247960 All are activated by phosphorylation on a canonical TxY motif by the dual-specificity kinase MKK6, which displays minimal substrate selectivity amongst the p38 isoforms |
| GO:0005515 protein binding | IPI PMID:15229216 Protein kinase R (PKR) interacts with and activates mitogen-... | MODIFY | Summary: Silva et al. showed that PKR (EIF2AK2) associates with MKK6 after dsRNA stimulation and phosphorylates and activates it. Reason: Bare protein binding is uninformative. PKR is a protein kinase that binds and phosphorylates MKK6 (Ser207/Thr211) to activate p38 in response to dsRNA; protein kinase binding (GO:0019901) is the informative replacement. PKR is not a canonical MAP3K, so the MAPKKK binding term is not proposed (same choice as for LRRK2 in the MAP2K3 review). Proposed replacements: protein kinase binding Supporting Evidence: PMID:15229216 We found that the p38 MAPK activator MKK6, but not its close relatives MKK3 or MKK4, exhibited an increased affinity for PKR following the exposure of cells to poly(rI:rC), a dsRNA analog. PMID:15229216 In vitro kinase assays revealed that MKK6 was efficiently phosphorylated by PKR Reactome:R-HSA-9836322 Activated PKR modifies MKK6 at residues S207 and T211 |
| GO:0005515 protein binding | IPI PMID:17255949 Mxi2 promotes stimulus-independent ERK nuclear translocation... | MODIFY | Summary: IPI for MAP2K6 binding MAPK14 (p38alpha / Mxi2 variant) reported in a study of Mxi2 nuclear translocation (PMID:17255949). Reason: Bare protein binding is uninformative. p38alpha (and its splice variant Mxi2) is the substrate MKK6 docks onto and phosphorylates. Mitogen-activated protein kinase binding (GO:0051019) is the informative replacement, as in the MAP2K3 review. Proposed replacements: mitogen-activated protein kinase binding Supporting Evidence: PMID:17255949 Mxi2 is capable of interacting with MKK 3 and 6 file:human/MAP2K6/MAP2K6-uniprot.txt P52564; Q16539: MAPK14; NbExp=3; IntAct=EBI-448135, EBI-73946; file:human/MAP2K6/MAP2K6-uniprot.txt Dimer. Interacts (via its D domain) with its substrates |
| GO:0005515 protein binding | IPI PMID:20067578 MKK6 binds and regulates expression of Parkinson's disease-r... | MODIFY | Summary: Hsu et al. showed that LRRK2 binds MKK3, MKK6 and MKK7 and can phosphorylate them. Reason: Bare protein binding is uninformative. LRRK2 is a protein kinase that binds and can phosphorylate MKK6, so protein kinase binding (GO:0019901) is the informative replacement. LRRK2 is not an established physiological MAP3K for MKK6, so MAPKKK binding is not proposed (consistent with the MAP2K3 review). 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/MAP2K6/MAP2K6-uniprot.txt P52564; Q5S007: LRRK2; NbExp=4; IntAct=EBI-448135, EBI-5323863; |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: MAP2K6-PICK1 interaction detected in the HuRI systematic binary yeast two-hybrid map. Reason: Bare protein binding is uninformative, and this screen-derived interaction has no functional follow-up for MKK6 that would support a more specific molecular function term. Removal does not imply the interaction is false; only that the generic term adds no functional information. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. file:human/MAP2K6/MAP2K6-uniprot.txt P52564; Q9NRD5: PICK1; NbExp=3; IntAct=EBI-448135, EBI-79165; |
| GO:0005515 protein binding | IPI PMID:32707033 Kinase Interaction Network Expands Functional and Disease Ro... | MODIFY | Summary: MAP2K6-MAPK14 association detected in a mass-spectrometry kinase interaction network. Reason: Bare protein binding is uninformative. p38alpha/MAPK14 is the principal substrate of MKK6, and the association is reproduced in independent studies. Mitogen-activated protein kinase binding (GO:0051019) is the informative replacement, as in the MAP2K3 review. 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. file:human/MAP2K6/MAP2K6-uniprot.txt P52564; Q16539: MAPK14; NbExp=3; IntAct=EBI-448135, EBI-73946; file:human/MAP2K6/MAP2K6-uniprot.txt Dimer. Interacts (via its D domain) with its substrates |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: MAP2K6-WFS1 interaction detected in a yeast two-hybrid interactome screen of neurodegenerative disease proteins. Reason: Bare protein binding is uninformative, and there is no functional follow-up for the MKK6-WFS1 interaction supporting a more specific molecular function. Removal does not imply the interaction is false. Supporting Evidence: PMID:32814053 generated by systematic yeast two-hybrid interaction screening of βΌ500 ND-related proteins and integration of literature interactions file:human/MAP2K6/MAP2K6-uniprot.txt P52564; O76024: WFS1; NbExp=3; IntAct=EBI-448135, EBI-720609; |
| GO:0005515 protein binding | IPI PMID:32911434 A functionally defined high-density NRF2 interactome reveals... | REMOVE | Summary: MAP2K6 identified as a weak NRF2 (NFE2L2) binding partner in a high-density NRF2 interactome, enhancing ARE-luciferase activity only in NRF2-derepressed cells. Reason: Bare protein binding is uninformative. MAP2K6 was among the weakest NRF2 binders and its effect on ARE reporter activity was conditional; the data do not establish a specific molecular function for MKK6 in this interaction. Removal does not imply the interaction is false. Supporting Evidence: PMID:32911434 six novel partners (CEBPG, FOSB, ELF3, FOSL2, DDIT3, and MAP2K6) exhibiting weak binding to NRF2 file:human/MAP2K6/MAP2K6-uniprot.txt P52564; Q16236: NFE2L2; NbExp=5; IntAct=EBI-448135, EBI-2007911; |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based assignment of ATP binding from the protein kinase domain. Reason: ATP is the phosphate donor for MKK6-catalysed phosphorylation of p38; the kinase domain contains the canonical ATP-binding site. Correct supporting function. Supporting Evidence: file:human/MAP2K6/MAP2K6-uniprot.txt Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + |
| GO:0005634 nucleus | EXP PMID:9768359 Nuclear export of the stress-activated protein kinase p38 me... | ACCEPT | Summary: Ben-Levy et al. found MKK6 in both nucleus and cytoplasm. Reason: Experimental localization consistent with MKK6 activating nuclear p38. Supporting Evidence: PMID:9768359 The p38 activators MKK3 and MKK6 were present in both the nucleus and the cytoplasm, consistent with a role in activating p38 in the nucleus. file:human/MAP2K6/MAP2K6-uniprot.txt SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:9768359}. Cytoplasm |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping to nucleus. Reason: Based on the same experimental observation (PMID:9768359). Supporting Evidence: file:human/MAP2K6/MAP2K6-uniprot.txt SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:9768359}. Cytoplasm PMID:9768359 The p38 activators MKK3 and MKK6 were present in both the nucleus and the cytoplasm, consistent with a role in activating p38 in the nucleus. |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | ACCEPT | Summary: Human Protein Atlas immunofluorescence localizes MAP2K6 to the nucleoplasm. Reason: Consistent with the nuclear pool of MKK6 that can activate nuclear p38. Supporting Evidence: PMID:9768359 The p38 activators MKK3 and MKK6 were present in both the nucleus and the cytoplasm, consistent with a role in activating p38 in the nucleus. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-3238999 | ACCEPT | Summary: Reactome places MKK6 in the nucleoplasm (Reactome:R-HSA-3238999). Reason: MKK6 is present in both nucleus and cytoplasm, consistent with a role in activating nuclear p38. Acceptable location annotation. Supporting Evidence: Reactome:R-HSA-450296 The p38 activators MKK3 (MAP2K3) and MKK6 (MAP2K6) were present in both the nucleus and the cytoplasm, consistent with a role in activating p38 in the nucleus. file:human/MAP2K6/MAP2K6-deep-research-falcon.md MAP2K6 is a soluble intracellular kinase, generally placed in the |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-450296 | ACCEPT | Summary: Reactome places MKK6 in the nucleoplasm (Reactome:R-HSA-450296). Reason: MKK6 is present in both nucleus and cytoplasm, consistent with a role in activating nuclear p38. Acceptable location annotation. Supporting Evidence: Reactome:R-HSA-450296 The p38 activators MKK3 (MAP2K3) and MKK6 (MAP2K6) were present in both the nucleus and the cytoplasm, consistent with a role in activating p38 in the nucleus. file:human/MAP2K6/MAP2K6-deep-research-falcon.md MAP2K6 is a soluble intracellular kinase, generally placed in the |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-450333 | ACCEPT | Summary: Reactome places MKK6 in the nucleoplasm (Reactome:R-HSA-450333). Reason: MKK6 is present in both nucleus and cytoplasm, consistent with a role in activating nuclear p38. Acceptable location annotation. Supporting Evidence: Reactome:R-HSA-450296 The p38 activators MKK3 (MAP2K3) and MKK6 (MAP2K6) were present in both the nucleus and the cytoplasm, consistent with a role in activating p38 in the nucleus. file:human/MAP2K6/MAP2K6-deep-research-falcon.md MAP2K6 is a soluble intracellular kinase, generally placed in the |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8877691 | ACCEPT | Summary: Reactome places MKK6 in the nucleoplasm (Reactome:R-HSA-8877691). Reason: MKK6 is present in both nucleus and cytoplasm, consistent with a role in activating nuclear p38. Acceptable location annotation. Supporting Evidence: Reactome:R-HSA-450296 The p38 activators MKK3 (MAP2K3) and MKK6 (MAP2K6) were present in both the nucleus and the cytoplasm, consistent with a role in activating p38 in the nucleus. file:human/MAP2K6/MAP2K6-deep-research-falcon.md MAP2K6 is a soluble intracellular kinase, generally placed in the |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping to cytoplasm. Reason: MKK6 is a soluble intracellular kinase detected in the cytoplasm. Supporting Evidence: file:human/MAP2K6/MAP2K6-uniprot.txt SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:9768359}. Cytoplasm file:human/MAP2K6/MAP2K6-deep-research-falcon.md MAP2K6 is a soluble intracellular kinase, generally placed in the |
| GO:0005737 cytoplasm | TAS PMID:9768359 Nuclear export of the stress-activated protein kinase p38 me... | ACCEPT | Summary: Statement that MKK6 acts in the cytoplasm, based on Ben-Levy et al. Reason: MKK6 is a soluble kinase detected in cytoplasm (and nucleus), where it is engaged by MAP3K signalling complexes. Supporting Evidence: PMID:9768359 The p38 activators MKK3 and MKK6 were present in both the nucleus and the cytoplasm, consistent with a role in activating p38 in the nucleus. file:human/MAP2K6/MAP2K6-deep-research-falcon.md MAP2K6 is a soluble intracellular kinase, generally placed in the |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Human Protein Atlas immunofluorescence localizes MAP2K6 to the cytosol. Reason: Consistent with MKK6 being a soluble cytoplasmic kinase. Supporting Evidence: file:human/MAP2K6/MAP2K6-deep-research-falcon.md MAP2K6 is a soluble intracellular kinase, generally placed in the |
| GO:0005829 cytosol | IDA PMID:9768359 Nuclear export of the stress-activated protein kinase p38 me... | ACCEPT | Summary: MGI IDA placing MKK6 in the cytosol based on Ben-Levy et al. Reason: Ben-Levy et al. found MKK6 in the cytoplasmic (and nuclear) compartments; MKK6 is a soluble cytosolic kinase. Accept. Supporting Evidence: PMID:9768359 The p38 activators MKK3 and MKK6 were present in both the nucleus and the cytoplasm, consistent with a role in activating p38 in the nucleus. file:human/MAP2K6/MAP2K6-deep-research-falcon.md MAP2K6 is a soluble intracellular kinase, generally placed in the |
| GO:0005829 cytosol | IDA PMID:9768359 Nuclear export of the stress-activated protein kinase p38 me... | ACCEPT | Summary: MGI IDA placing MKK6 in the cytosol based on Ben-Levy et al. Reason: Ben-Levy et al. found MKK6 in the cytoplasmic (and nuclear) compartments; MKK6 is a soluble cytosolic kinase. Accept. Supporting Evidence: PMID:9768359 The p38 activators MKK3 and MKK6 were present in both the nucleus and the cytoplasm, consistent with a role in activating p38 in the nucleus. file:human/MAP2K6/MAP2K6-deep-research-falcon.md MAP2K6 is a soluble intracellular kinase, generally placed in the |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1247960 | ACCEPT | Summary: Reactome places MKK6 in the cytosol, where it is phosphorylated by MAP3Ks or other activating kinases, or cleaved by anthrax lethal factor (Reactome:R-HSA-1247960). Reason: MKK6 is a soluble cytoplasmic kinase activated by cytosolic upstream kinases. Accept. Supporting Evidence: file:human/MAP2K6/MAP2K6-deep-research-falcon.md MAP2K6 is a soluble intracellular kinase, generally placed in the Reactome:R-HSA-3228469 MAP3K5 (ASK1) phosphorylates and activates MAP2K3 (MKK3) and MAP2K6 (MKK6) |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3228469 | ACCEPT | Summary: Reactome places MKK6 in the cytosol, where it is phosphorylated by MAP3Ks or other activating kinases, or cleaved by anthrax lethal factor (Reactome:R-HSA-3228469). Reason: MKK6 is a soluble cytoplasmic kinase activated by cytosolic upstream kinases. Accept. Supporting Evidence: file:human/MAP2K6/MAP2K6-deep-research-falcon.md MAP2K6 is a soluble intracellular kinase, generally placed in the Reactome:R-HSA-3228469 MAP3K5 (ASK1) phosphorylates and activates MAP2K3 (MKK3) and MAP2K6 (MKK6) |
| GO:0005829 cytosol | TAS Reactome:R-HSA-450296 | ACCEPT | Summary: Reactome places MKK6 in the cytosol, where it is phosphorylated by MAP3Ks or other activating kinases, or cleaved by anthrax lethal factor (Reactome:R-HSA-450296). Reason: MKK6 is a soluble cytoplasmic kinase activated by cytosolic upstream kinases. Accept. Supporting Evidence: file:human/MAP2K6/MAP2K6-deep-research-falcon.md MAP2K6 is a soluble intracellular kinase, generally placed in the Reactome:R-HSA-3228469 MAP3K5 (ASK1) phosphorylates and activates MAP2K3 (MKK3) and MAP2K6 (MKK6) |
| GO:0005829 cytosol | TAS Reactome:R-HSA-450346 | ACCEPT | Summary: Reactome places MKK6 in the cytosol, where it is phosphorylated by MAP3Ks or other activating kinases, or cleaved by anthrax lethal factor (Reactome:R-HSA-450346). Reason: MKK6 is a soluble cytoplasmic kinase activated by cytosolic upstream kinases. Accept. Supporting Evidence: file:human/MAP2K6/MAP2K6-deep-research-falcon.md MAP2K6 is a soluble intracellular kinase, generally placed in the Reactome:R-HSA-3228469 MAP3K5 (ASK1) phosphorylates and activates MAP2K3 (MKK3) and MAP2K6 (MKK6) |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5211405 | ACCEPT | Summary: Reactome places MKK6 in the cytosol, where it is phosphorylated by MAP3Ks or other activating kinases, or cleaved by anthrax lethal factor (Reactome:R-HSA-5211405). Reason: MKK6 is a soluble cytoplasmic kinase activated by cytosolic upstream kinases. Accept. Supporting Evidence: file:human/MAP2K6/MAP2K6-deep-research-falcon.md MAP2K6 is a soluble intracellular kinase, generally placed in the Reactome:R-HSA-3228469 MAP3K5 (ASK1) phosphorylates and activates MAP2K3 (MKK3) and MAP2K6 (MKK6) |
| GO:0005829 cytosol | TAS Reactome:R-HSA-727819 | ACCEPT | Summary: Reactome places MKK6 in the cytosol, where it is phosphorylated by MAP3Ks or other activating kinases, or cleaved by anthrax lethal factor (Reactome:R-HSA-727819). Reason: MKK6 is a soluble cytoplasmic kinase activated by cytosolic upstream kinases. Accept. Supporting Evidence: file:human/MAP2K6/MAP2K6-deep-research-falcon.md MAP2K6 is a soluble intracellular kinase, generally placed in the Reactome:R-HSA-3228469 MAP3K5 (ASK1) phosphorylates and activates MAP2K3 (MKK3) and MAP2K6 (MKK6) |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9836322 | ACCEPT | Summary: Reactome places MKK6 in the cytosol, where it is phosphorylated by MAP3Ks or other activating kinases, or cleaved by anthrax lethal factor (Reactome:R-HSA-9836322). Reason: MKK6 is a soluble cytoplasmic kinase activated by cytosolic upstream kinases. Accept. Supporting Evidence: file:human/MAP2K6/MAP2K6-deep-research-falcon.md MAP2K6 is a soluble intracellular kinase, generally placed in the Reactome:R-HSA-3228469 MAP3K5 (ASK1) phosphorylates and activates MAP2K3 (MKK3) and MAP2K6 (MKK6) |
| GO:0005856 cytoskeleton | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt subcellular-location mapping to cytoskeleton, based on reported microtubule binding. Reason: UniProt notes that MKK6 binds microtubules (from PMID:9768359), and it interacts with DCTN1. This is a minor, poorly characterized association rather than the site of its core activity, so it is retained as non-core. Supporting Evidence: file:human/MAP2K6/MAP2K6-uniprot.txt Note=Binds to microtubules. file:human/MAP2K6/MAP2K6-uniprot.txt Interacts with DCTN1. |
| GO:0007165 signal transduction | TAS PMID:8621675 Characterization of the structure and function of a novel MA... | MODIFY | Summary: Traceable author statement that MKK6 functions in signal transduction (PMID:8621675). Reason: Correct but too general. The paper defines MKK6 as a MAP kinase kinase that selectively phosphorylates p38, so the specific process is the p38MAPK cascade (GO:0038066), as in the MAP2K3 review. Proposed replacements: p38MAPK cascade Supporting Evidence: PMID:8621675 The functional data revealed from co-transfection assays suggests that MKK6, like MKK3, selectively phosphorylates p38. |
| GO:0019901 protein kinase binding | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA machine-learning assignment of protein kinase binding. Reason: MKK6 binds upstream MAP3Ks via its DVD domain and p38 MAPKs via its D domain, so protein kinase binding is correct; it is a consequence of the core MAPKK activity rather than a separate function (as in the MAP2K3 review). Supporting Evidence: file:human/MAP2K6/MAP2K6-uniprot.txt Dimer. Interacts (via its D domain) with its substrates file:human/MAP2K6/MAP2K6-uniprot.txt (MAP3Ks) and are essential for activation. |
| GO:0019901 protein kinase binding | IPI PMID:11279118 Regulation of stress-responsive mitogen-activated protein (M... | KEEP AS NON CORE | Summary: Chen and Cobb showed that endogenous TAO2 (TAOK2) specifically co-immunoprecipitates with MEK3 and MEK6 and activates them toward p38. Reason: Correct and experimentally supported: TAO2 acts as a MAP3K for MKK3/MKK6. Kept as non-core supporting binding, consistent with the paralog MAP2K3 review. Supporting Evidence: PMID:11279118 Coimmunoprecipitation demonstrated that endogenous TAO2 specifically associates with MEK3 and MEK6 providing one mechanism for preferential recognition of MEKs upstream of p38. |
| GO:0031098 stress-activated protein kinase signaling cascade | IDA PMID:35857590 ZAKΞ±-driven ribotoxic stress response activates the human NL... | ACCEPT | Summary: Robinson et al. characterized the ZAKalpha-driven ribotoxic stress response, which activates p38 and JNK stress-activated kinases, in human keratinocytes. Reason: The p38 cascade is a stress-activated protein kinase cascade in which MKK6 is the MAP2K tier. The cached text does not describe the MKK6-specific experiment, but the curator read the full paper and the function is clearly correct for MKK6, so the annotation is accepted. Supporting Evidence: PMID:35857590 UVB induced bona fide RSR activation in N/TERT keratinocytes marked by ZAKΞ±, p38 and JNK phosphorylation Reactome:R-HSA-1247960 All are activated by phosphorylation on a canonical TxY motif by the dual-specificity kinase MKK6, which displays minimal substrate selectivity amongst the p38 isoforms |
| GO:0031098 stress-activated protein kinase signaling cascade | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA machine-learning assignment of stress-activated protein kinase signaling cascade. Reason: Consistent with experimental evidence placing MKK6 in the stress-activated p38 cascade. Supporting Evidence: file:human/MAP2K6/MAP2K6-uniprot.txt Activated by dual phosphorylation on Ser-207 and file:human/MAP2K6/MAP2K6-deep-research-falcon.md MAP2K6 is an intracellular, dual-specificity MAPK kinase whose primary function is to receive stress/inflammatory signals from MAP3Ks and activate p38-family MAPKs. |
| GO:0035872 nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway | TAS Reactome:R-HSA-168638 | KEEP AS NON CORE | Summary: Reactome NOD1/2 signalling pathway, in which the TAK1 complex recruited by RIP2 phosphorylates MKK6 to activate p38. Reason: MKK6 is a downstream kinase of TAK1 in NOD1/2 signalling; this is one of several receptor inputs into the MKK6-p38 module rather than a core function of MKK6. Supporting Evidence: Reactome:R-HSA-727819 The TAK1 complex is also essential for NOD signaling; NOD receptors bind RIP2 which recruits the TAK1 complex Reactome:R-HSA-727819 activated TAK1 phosphorylates IKKB, MAPK kinase 6 (MKK6) and other MAPKs to activate the NFkappaB and MAPK signaling pathways |
| GO:0038066 p38MAPK cascade | IDA PMID:11460167 TAK1 is a ubiquitin-dependent kinase of MKK and IKK. | ACCEPT | Summary: Wang et al. showed that TAK1 phosphorylates MKK6 in a ubiquitin-dependent manner, activating the p38 pathway. Reason: MKK6 directly phosphorylates p38 and thus performs a step of the p38 cascade. Core process. Supporting Evidence: PMID:11460167 the activity of TAK1 to phosphorylate MKK6, which activates the JNK-p38 kinase pathway, is directly regulated by K63-linked polyubiquitination |
| GO:0038066 p38MAPK cascade | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA machine-learning assignment of p38MAPK cascade. Reason: MKK6 is the MAP2K tier of the p38 cascade. Core process. Supporting Evidence: file:human/MAP2K6/MAP2K6-uniprot.txt and a tyrosine residue in the MAP kinases p38 MAPK11, MAPK12, MAPK13 Reactome:R-HSA-1247960 All are activated by phosphorylation on a canonical TxY motif by the dual-specificity kinase MKK6, which displays minimal substrate selectivity amongst the p38 isoforms |
| GO:0038066 p38MAPK cascade | TAS Reactome:R-HSA-450302 | ACCEPT | Summary: Reactome pathway in which TAK1 phosphorylates MKK3/4/6, which in turn activate p38 MAPK. Reason: MKK6 is a direct kinase step in the p38 cascade. Core process. Supporting Evidence: Reactome:R-HSA-450302 Each isoform is activated by upstream kinases including MAP kinase kinases (MKK) 3, 4, and 6, which in turn are phosphorylated by activated TAK1 |
| GO:0042770 signal transduction in response to DNA damage | TAS PMID:10848581 Involvement of the MKK6-p38gamma cascade in gamma-radiation-... | KEEP AS NON CORE | Summary: Wang et al. showed that gamma irradiation activates MKK6, that the MKK6-p38gamma cascade is sufficient for G2 arrest, and that dominant-negative MKK6 abrogates the DNA-damage G2 delay. Reason: Experimentally supported, and MKK6 does perform a kinase step in the signal relayed after DNA damage. It is, however, a context of the core p38-activating function rather than a separate role, so it is kept as non-core. Supporting Evidence: PMID:10848581 Activation of the MKK6-p38Ξ³ cascade is sufficient to induce G 2 arrest in cells, and expression of dominant negative alleles of MKK6 or p38Ξ³ allows cells to escape the DNA damage-induce G 2 delay. |
| GO:0042802 identical protein binding | IPI P52564-1 PMID:19141286 The structure of the MAP2K MEK6 reveals an autoinhibitory di... | MODIFY | Summary: Min et al. solved the MEK6 kinase-domain structure as an autoinhibited dimer, and showed that full-length unphosphorylated wild-type MEK6 dimerizes in solution. Reason: The self-interaction is a specific homodimer with a proposed autoinhibitory role, better described by protein homodimerization activity (GO:0042803). It is a regulatory feature, not the core catalytic function. Proposed replacements: protein homodimerization activity Supporting Evidence: PMID:19141286 Gel filtration and small-angle X-ray scattering analysis confirm that the crystallographically observed ellipsoidal dimer is a feature of MEK6/DeltaN/DD and full-length unphosphorylated wild-type MEK6 in solution. PMID:19141286 The dimer may also serve the function in unphosphorylated MEK6 of preventing activation loop phosphorylation by inappropriate kinases. file:human/MAP2K6/MAP2K6-uniprot.txt P52564-1; P52564-1: MAP2K6; NbExp=3; IntAct=EBI-15750978, EBI-15750978; |
| GO:0051403 stress-activated MAPK cascade | IDA PMID:8663524 Characterization of the structure and function of a new mito... | ACCEPT | Summary: Jiang et al. showed that the stress-activated p38beta is preferentially activated by MKK6. Reason: MKK6 is the MAP2K of the stress-activated p38 cascade. Accept; GO:0038066 is the more specific term. Supporting Evidence: PMID:8663524 Like p38, p38beta is activated by proinflammatory cytokines and environmental stress. PMID:8663524 the preferred activation of p38beta by MAP kinase kinase 6 (MKK6) |
| GO:0051403 stress-activated MAPK cascade | IDA PMID:9218798 Activation of the novel stress-activated protein kinase SAPK... | ACCEPT | Summary: Goedert et al. showed that SKK3/MKK6 mediates the activation of SAPK4 by cellular stresses and IL-1. Reason: Direct evidence that MKK6 is the MAP2K relaying stress signals to p38delta. Accept. Supporting Evidence: PMID:9218798 SKK3 was the only activator of SAPK4 that was induced when KB cells were exposed to a cellular stress or stimulated with interleukin-1. |
| GO:0051726 regulation of cell cycle | TAS PMID:10848581 Involvement of the MKK6-p38gamma cascade in gamma-radiation-... | KEEP AS NON CORE | Summary: Wang et al. showed that the MKK6-p38gamma cascade mediates gamma-irradiation-induced G2 arrest. Reason: Supported, but G2 checkpoint control is a downstream, context-specific outcome of MKK6-p38gamma signalling rather than a core function; retained as non-core. Supporting Evidence: PMID:10848581 Activation of the MKK6-p38Ξ³ cascade is sufficient to induce G 2 arrest in cells, and expression of dominant negative alleles of MKK6 or p38Ξ³ allows cells to escape the DNA damage-induce G 2 delay. |
| GO:0060348 bone development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara projection from mouse Map2k6 of bone development. Reason: UniProt notes roles of MKK6-p38 signalling in endochondral ossification. Plausible physiological context from the mouse ortholog, but a downstream outcome of p38 activation; retained as non-core. Supporting Evidence: file:human/MAP2K6/MAP2K6-uniprot.txt and since SOX9 is another likely downstream target of the p38 MAPK file:human/MAP2K6/MAP2K6-deep-research-falcon.md not as the final executor of a single cell fate |
| GO:0090398 cellular senescence | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA machine-learning assignment of cellular senescence. Reason: p38 signalling downstream of MKK3/MKK6 contributes to stress-induced senescence; this is a downstream outcome of the p38 cascade rather than a core function (consistent with the MAP2K3 review). Supporting Evidence: file:human/MAP2K6/MAP2K6-deep-research-falcon.md cell-cycle arrest, senescence, inflammatory mediator production and apoptosis file:human/MAP2K6/MAP2K6-deep-research-falcon.md not as the final executor of a single cell fate |
| GO:0090398 cellular senescence | TAS Reactome:R-HSA-2559583 | KEEP AS NON CORE | Summary: Reactome Cellular Senescence pathway, which includes MKK3/MKK6-mediated p38 activation in oxidative-stress-induced senescence. Reason: Membership reflects the p38 stress branch of senescence; MKK6 contributes as the p38-activating kinase. Retained as non-core. 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 | KEEP AS NON CORE | Summary: Rhea-mapping IEA of protein serine kinase activity (RHEA:17989). Reason: Although the mapping derives from the generic EC 2.7.12.2 reaction, MKK6 does have reported serine substrates beyond p38 (PIP4K2B Ser326; PAK6), so the term is not wrong. The core reaction is the Thr/Tyr dual phosphorylation of p38 captured by GO:0004708; serine phosphorylation of other substrates is secondary. Supporting Evidence: file:human/MAP2K6/MAP2K6-uniprot.txt Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + Reactome:R-HSA-8877691 MAP2K6 (MKK6), and possibly other kinases of the p38 MAPK family, phosphorylates PIP4K2B at serine residue S326. |
| GO:0120163 negative regulation of cold-induced thermogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara projection from mouse Map2k6 of negative regulation of cold-induced thermogenesis. Reason: Mouse Mkk6-deficient adipose tissue shows elevated UCP1 and increased T3-mediated browning (PMID:29021624). This is a tissue-specific physiological outcome of MKK6-p38 signalling rather than a core function; retained as non-core. Supporting Evidence: PMID:29021624 Lack of MKK6 increases the basal expression of UCP1 and promotes T3-mediated induction of UCP1 expression in WAT. |
| GO:0120163 negative regulation of cold-induced thermogenesis | ISS PMID:29021624 MKK6 controls T3-mediated browning of white adipose tissue. | KEEP AS NON CORE | Summary: ISS from mouse Map2k6 based on Matesanz et al., who found that lack of MKK6 enhances T3-induced browning of white adipose tissue. Reason: Supported in mouse genetics; a physiological, tissue-specific outcome of MKK6-p38 signalling in adipocytes, retained as non-core. Supporting Evidence: PMID:29021624 Lack of MKK6 increases the basal expression of UCP1 and promotes T3-mediated induction of UCP1 expression in WAT. PMID:29021624 These results indicate that MKK6 is a central regulator of WAT browning and is a possible target for obesity treatment. |
| GO:1901796 regulation of signal transduction by p53 class mediator | TAS Reactome:R-HSA-6804758 | MARK AS OVER ANNOTATED | Summary: Reactome 'Regulation of TP53 Activity through Acetylation' pathway, into which MAP2K6 enters via its phosphorylation of PIP4K2B. Reason: MAP2K6 is placed in this pathway only through the reaction in which it phosphorylates PIP4K2B (Reactome:R-HSA-8877691), several steps removed from TP53 acetylation. The pathway summary does not mention MAP2K6 at all, and there is no evidence that MKK6 regulates p53 signalling as a specific function; the link is indirect. Supporting Evidence: Reactome:R-HSA-6804758 Transcriptional activity of TP53 is positively regulated by acetylation of several of its lysine residues. Reactome:R-HSA-8877691 MAP2K6 (MKK6), and possibly other kinases of the p38 MAPK family, phosphorylates PIP4K2B at serine residue S326. |
| GO:1902531 regulation of intracellular signal transduction | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: ARBA machine-learning assignment of regulation of intracellular signal transduction. Reason: MKK6 is a core transducing kinase of the p38 cascade rather than a regulator of signal transduction; its role is captured precisely by p38MAPK cascade (GO:0038066) and MAP kinase kinase activity. This vague regulation term adds no information (consistent with the MAP2K3 review). Supporting Evidence: file:human/MAP2K6/MAP2K6-uniprot.txt and a tyrosine residue in the MAP kinases p38 MAPK11, MAPK12, MAPK13 file:human/MAP2K6/MAP2K6-deep-research-falcon.md MAP2K6 is an intracellular, dual-specificity MAPK kinase whose primary function is to receive stress/inflammatory signals from MAP3Ks and activate p38-family MAPKs. |
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Download this section (compressed HTML)Q: How do MKK6 and MKK3 divide the activation of individual p38 isoforms in vivo, and does the p38beta/p38delta preference of MKK6 hold in primary cells?
Q: Are the non-MAPK substrates reported for MKK6 (PIP4K2B Ser326, PAK6) phosphorylated directly by MKK6 under physiological conditions, and does this represent a distinct function?
Q: Does the autoinhibitory MKK6 homodimer seen in crystal and solution studies exist in cells, and how is it disrupted by upstream MAP3Ks?
Experiment: Quantitative in vitro kinase assays of active MKK6 on each recombinant p38 isoform and on PIP4K2B/PAK6, with phosphosite mapping, compared with MKK3.
Experiment: Isoform-selective MKK6 knockout or rapid degradation (degron) in human cells to separate MKK6-specific p38 activation from MKK3 redundancy across stresses.
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