MAP3K1 encodes MEKK1, a large (1512 aa, ~196 kDa) cytoplasmic serine/threonine mitogen-activated protein kinase kinase kinase of the STE family. Its C-terminal kinase domain directly phosphorylates and activates MAP kinase kinases, with MKK4 (MAP2K4/SEK1/JNKK1) as the preferred substrate and a direct, stable MEKK1:MKK4 complex, and also MKK7, MKK3/MKK6 and, in some contexts, MKK1/2; MEKK1 therefore mainly drives the JNK (stress-activated protein kinase) cascade and, more variably, p38, ERK and IKK/NF-kB outputs. MEKK1 is activated by oligomerisation and activation-loop autophosphorylation downstream of TNF, EGF, TGF-beta, TRAF2/TRAF6 and cytoskeletal or osmotic stress. The large N-terminal regulatory region contains a SWIM zinc finger, a PHD/RING-type zinc finger with E3 ubiquitin ligase activity (ubiquitinating ERK1/2, c-Jun, TAB1 and MEKK1 itself), a tubulin-binding TOG domain, and a caspase-3 cleavage site at Asp878 whose cleavage releases a pro-apoptotic kinase fragment. Germline variants cause 46,XY disorders of sex development, and truncating somatic mutations are frequent in luminal breast cancer.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000165 MAPK cascade | IBA GO_REF:0000033 | ACCEPT | Summary: MEKK1 is a MAP3K that initiates MAPK cascades, principally the MKK4/MKK7-JNK arm and, depending on context, the p38 and ERK arms. Reason: The PAINT node placement for MAPK cascade participation across the MAP3K clade is sound, and MEKK1 performs a step of the cascade (phosphorylation of MAP2Ks). A more specific JNK cascade term is not proposed as NEW because it would be a descendant of this already-carried term; the JNK specificity is described in core_functions. Supporting Evidence: PMID:7997270 We find that MEKK regulates a new signalling cascade by phosphorylating an SAPK activator, SEK1 which in turn phosphorylates and activates SAPK. PMID:9808624 These results confirmed that MEKK1 preferentially activates JNK1 and to a lesser extent p38Ξ±, but is ineffective in ERK2 activation. PMID:12456688 MEKK1 phosphorylates and activates MKK1 and MKK4, leading to ERK1/2 and JNK activation. |
| GO:0004672 protein kinase activity | IDA PMID:15001576 TRAF7 potentiates MEKK3-induced AP1 and CHOP activation and ... | ACCEPT | Summary: Protein kinase activity of MEKK1 reported by MGI from a TRAF7/MEKK3 paper whose cached text is abstract-only; MEKK1 was likely assayed as a comparator MAP3K in the full text. Reason: The cached abstract only discusses MEKK3, but per curation policy we defer to the curator who read the full text; MEKK1 protein kinase activity is independently beyond doubt (direct in vitro phosphorylation of MKK4). The term is general; the specific activity (MAP kinase kinase kinase activity) is captured by other rows and in core_functions. Supporting Evidence: PMID:9808624 Figure 2 B shows that JNKK1 is the preferred substrate for MEKK1. PMID:7997270 We find that MEKK regulates a new signalling cascade by phosphorylating an SAPK activator, SEK1 which in turn phosphorylates and activates SAPK. |
| GO:0004672 protein kinase activity | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based (Ser/Thr kinase active site) mapping to protein kinase activity. Reason: Correct, though general; MEKK1 has a canonical STE-family kinase domain (active site D1369) with experimentally demonstrated activity. Supporting Evidence: file:human/MAP3K1/MAP3K1-uniprot.txt protein kinase superfamily. STE Ser/Thr PMID:9808624 Figure 2 B shows that JNKK1 is the preferred substrate for MEKK1. |
| GO:0004674 protein serine/threonine kinase activity | EXP PMID:7997270 Activation of stress-activated protein kinase by MEKK1 phosp... | ACCEPT | Summary: Yan et al. (1994) showed that MEKK directly phosphorylates SEK1 (MKK4), which in turn activates SAPK/JNK. Reason: Direct phosphorylation of a protein substrate on Ser/Thr by MEKK1 is established; the more specific MAP kinase kinase kinase activity is the core MF. Supporting Evidence: PMID:7997270 We find that MEKK regulates a new signalling cascade by phosphorylating an SAPK activator, SEK1 which in turn phosphorylates and activates SAPK. |
| GO:0004674 protein serine/threonine kinase activity | EXP PMID:9639556 Differential activation of stress-activated protein kinase k... | ACCEPT | Summary: Cuenda & Dorow (1998) showed MEKK1 activates MKK4 (strongly), MKK3 and MKK6, and only weakly MKK7, in transfections and in vitro. Reason: Supports Ser/Thr kinase activity toward MAP2Ks; consistent with the rest of the literature. Supporting Evidence: PMID:9639556 MEKK1 activates SKK1/MKK4 more efficiently than MLK2, but barely activates SKK4/MKK7. PMID:9639556 MLK2 and MEKK1 also activated SKK2/MKK3 and SKK3/MKK6, the direct upstream activators of SAPK2a/p38. |
| GO:0004674 protein serine/threonine kinase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of Ser/Thr kinase activity for the MAP3K clade; Q13233 itself is among the experimental donors. Reason: MEKK1 is an active STE-family Ser/Thr kinase; the IBA is well grounded, including by the gene's own experimental annotation. Supporting Evidence: PMID:7997270 We find that MEKK regulates a new signalling cascade by phosphorylating an SAPK activator, SEK1 which in turn phosphorylates and activates SAPK. PMID:9808624 Figure 2 B shows that JNKK1 is the preferred substrate for MEKK1. |
| GO:0004709 MAP kinase kinase kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Combined automated (ARBA/EC 2.7.11.25) assignment of MAP kinase kinase kinase activity. Reason: Correct and at the appropriate level; MEKK1 directly phosphorylates and activates MAP2Ks, especially MKK4. Supporting Evidence: PMID:9808624 Figure 2 B shows that JNKK1 is the preferred substrate for MEKK1. PMID:12456688 MEKK1 phosphorylates and activates MKK1 and MKK4, leading to ERK1/2 and JNK activation. |
| GO:0004709 MAP kinase kinase kinase activity | NAS PMID:9808624 JNKK1 organizes a MAP kinase module through specific and seq... | ACCEPT | Summary: Xia et al. (1998) cloned full-length human MEKK1 and showed with purified proteins that JNKK1/MKK4 is its preferred MAP2K substrate and that the two form a direct, stable complex. Reason: Although coded NAS, the paper contains direct in vitro kinetic evidence for MAP2K phosphorylation by human MEKK1. This is the core molecular function. Supporting Evidence: PMID:9808624 Figure 2 B shows that JNKK1 is the preferred substrate for MEKK1. PMID:9808624 As purified recombinant MEKK1 and JNKK1 also form a stable complex, the interaction between the two proteins is direct. PMID:9808624 These results confirmed that MEKK1 preferentially activates JNK1 and to a lesser extent p38Ξ±, but is ineffective in ERK2 activation. |
| GO:0004709 MAP kinase kinase kinase activity | TAS Reactome:R-HSA-933530 | ACCEPT | Summary: Reactome reaction in which MEKK1 phosphorylates the IKKalpha/IKKbeta activation loops. Reason: The Reactome event itself describes IKK phosphorylation (IKKs are not MAP2Ks, so strictly this reaction is not MAP3K activity), but MAP kinase kinase kinase activity is correct for MEKK1 on independent evidence (MKK4, MKK7, MKK1 phosphorylation, incl. Reactome R-HSA-2730896/2730868). Supporting Evidence: Reactome:R-HSA-933530 MEKK1 can activate both IKK-alpha (IKKA) and IKK-beta (IKKB) in vivo. 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. PMID:9808624 Figure 2 B shows that JNKK1 is the preferred substrate for MEKK1. |
| GO:0005515 protein binding | IPI PMID:11784851 Direct activation of mitogen-activated protein kinase kinase... | MODIFY | Summary: MEKK1 interacts directly (in vitro and in vivo) with the Ste20-family kinase GCK (MAP4K2), which with TRAF2 activates MEKK1 by inducing oligomerisation and autophosphorylation. Reason: Generic protein binding is uninformative. The partner is a protein kinase (MAP4K2) and the binding is direct and functionally meaningful (upstream activation of MEKK1), so protein kinase binding is the appropriate informative term. Proposed replacements: protein kinase binding Supporting Evidence: PMID:11784851 interact in vivo and in vitro with the STE20 protein homologue germinal center kinase (GCK) PMID:11784851 Here we show that endogenous GCK and MEKK1 associate in vivo. PMID:11784851 Autophosphorylation within the MEKK1 kinase domain activation loop is required for activation. |
| GO:0005515 protein binding | IPI PMID:14743216 A physical and functional map of the human TNF-alpha/NF-kapp... | REMOVE | Summary: High-throughput TAP-MS interaction map of the TNF/NF-kB pathway reporting an association with DCAF7 (Han11); cached text is abstract only. Reason: Bare protein binding from a large-scale screen conveys no functional information. DCAF7 is a WD40 scaffold that couples MEKK1 to HIPK2/DYRK1 (PMID:20940704); the informative function lies with the scaffold, not MEKK1. Removal does not imply the DCAF7-MEKK1 interaction is false. Supporting Evidence: PMID:14743216 We identified 221 molecular associations and 80 previously unknown interactors |
| GO:0005515 protein binding | IPI PMID:16810323 FGF-2 protects small cell lung cancer cells from apoptosis t... | REMOVE | Summary: Reported BRAF interaction (IntAct) from a study of a B-Raf/PKCepsilon/S6K2 complex in SCLC cells; MEKK1 is not mentioned in the cached full text. Reason: Generic protein binding is uninformative and the cached text gives no basis for a specific MF; the BRAF association is not part of the characterised MEKK1 mechanism. Removal does not mean the interaction is false. Supporting Evidence: PMID:16810323 these effects are mediated through the formation of a specific multiprotein complex comprising B-Raf, PKCepsilon and S6K2 |
| GO:0005515 protein binding | IPI PMID:16888650 Glucocorticoids cause rapid dissociation of a T-cell-recepto... | REMOVE | Summary: Reported BRAF interaction (IntAct) from a study of a glucocorticoid-sensitive TCR/LCK/FYN complex; MEKK1 is not mentioned in the cached full text. Reason: Generic protein binding with no evident functional context for MEKK1; no more informative MF can be derived. Removal does not mean the interaction is false. Supporting Evidence: PMID:16888650 the GC receptor is part of a TCR-linked multiprotein complex containing heat-shock protein (HSP)90, LCK and FYN |
| GO:0005515 protein binding | IPI PMID:19270716 ISG15 modification of filamin B negatively regulates the typ... | REMOVE | Summary: Filamin B acts as a scaffold that tethers RAC1 and the MEKK1-MKK4-JNK module during type I IFN signalling; ISGylation of filamin B releases MEKK1. Reason: The informative activity (scaffolding of a JNK module) belongs to filamin B; for MEKK1 the row only records that it is bound. No MEKK1 MF more informative than protein binding is supported. Removal does not mean the interaction is false. Supporting Evidence: PMID:19270716 filamin B tethers RAC1 and a Jun N-terminal kinase (JNK)-specific mitogen-activated protein kinase (MAPK) moduleβMEKK1, MKK4 and JNKβand thereby promotes the activation of JNK |
| GO:0005515 protein binding | IPI PMID:20940704 The WD40-repeat protein Han11 functions as a scaffold protei... | REMOVE | Summary: The WD40 protein Han11/DCAF7 binds MEKK1 directly and bridges it to HIPK2 and DYRK1a/b. Reason: Han11 is the scaffold; MEKK1 is a client. Protein binding is uninformative and no specific MEKK1 MF follows from this interaction. Removal does not mean the interaction is false. Supporting Evidence: PMID:20940704 Han11 was required to allow coupling of MEKK1 to DYRK1 and HIPK2. |
| GO:0005515 protein binding | IPI PMID:9808624 JNKK1 organizes a MAP kinase module through specific and seq... | MODIFY | Summary: MEKK1 forms a direct, stable complex with its preferred substrate MKK4/JNKK1 via the MKK4 N-terminal extension; the complex dissociates upon MKK4 phosphorylation. Reason: The partner is a MAP kinase kinase and the binding is direct and functionally required for efficient MKK4 activation; mitogen-activated protein kinase kinase binding captures this informatively. Proposed replacements: mitogen-activated protein kinase kinase binding Supporting Evidence: PMID:9808624 As purified recombinant MEKK1 and JNKK1 also form a stable complex, the interaction between the two proteins is direct. PMID:9808624 The preferential phosphorylation and activation of JNKK1 by MEKK1 correlates with specific formation of MEKK1:JNKK1 complexes. |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: ATP binding inferred from the protein kinase domain and ATP-binding site signature. Reason: Correct; MEKK1 is an ATP-dependent protein kinase. Supporting Evidence: file:human/MAP3K1/MAP3K1-uniprot.txt protein kinase superfamily. STE Ser/Thr |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: MEKK1 is a soluble cytoplasmic signalling kinase that acts on cytosolic MAP2K substrates. Reason: Cytosol is the principal site of MEKK1 kinase signalling; consistent with Reactome placement of its MAP2K phosphorylation reactions in the cytosol. 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. file:human/MAP3K1/MAP3K1-deep-research-falcon.md MAP3K1 is an intracellular, dynamically recruited signaling protein rather than a constitutive resident of one organelle. |
| GO:0005829 cytosol | IEA GO_REF:0000117 | ACCEPT | Summary: MEKK1 is a soluble cytoplasmic signalling kinase that acts on cytosolic MAP2K substrates. Reason: Cytosol is the principal site of MEKK1 kinase signalling; consistent with Reactome placement of its MAP2K phosphorylation reactions in the cytosol. 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. file:human/MAP3K1/MAP3K1-deep-research-falcon.md MAP3K1 is an intracellular, dynamically recruited signaling protein rather than a constitutive resident of one organelle. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-166869 | ACCEPT | Summary: Reactome locates this MEKK1 reaction in the cytosol. Reason: MEKK1 signalling reactions with MAP2Ks, IKKs and TRAF6 occur in the cytosol. Supporting Evidence: Reactome:R-HSA-166869 TRAF6 binding to MAPK kinase kinase 1 (MEKK1) is mediated by the adapter protein evolutionarily conserved signaling intermediate in Toll pathway |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2730868 | ACCEPT | Summary: Reactome locates this MEKK1 reaction in the cytosol. Reason: MEKK1 signalling reactions with MAP2Ks, IKKs and TRAF6 occur in the cytosol. Supporting Evidence: Reactome:R-HSA-2730868 MKK7 is activated by MEKK1 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2730896 | ACCEPT | Summary: Reactome locates this MEKK1 reaction in the cytosol. Reason: MEKK1 signalling reactions with MAP2Ks, IKKs and TRAF6 occur in the cytosol. 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-933530 | ACCEPT | Summary: Reactome locates this MEKK1 reaction in the cytosol. Reason: MEKK1 signalling reactions with MAP2Ks, IKKs and TRAF6 occur in the cytosol. Supporting Evidence: Reactome:R-HSA-933530 MEKK1 can activate both IKK-alpha (IKKA) and IKK-beta (IKKB) in vivo. |
| GO:0006468 protein phosphorylation | NAS PMID:9808624 JNKK1 organizes a MAP kinase module through specific and seq... | ACCEPT | Summary: Protein phosphorylation as the process accompanying MEKK1 kinase activity toward MAP2Ks. Reason: Correct but generic; MEKK1 directly phosphorylates MKK4 and other MAP2Ks. The informative process is the JNK/MAPK cascade. Supporting Evidence: PMID:9808624 Figure 2 B shows that JNKK1 is the preferred substrate for MEKK1. |
| GO:0007166 cell surface receptor signaling pathway | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA-predicted involvement in cell surface receptor signalling. Reason: MEKK1 relays signals from TNF receptors, EGF receptor, TGF-beta receptors and TLR/TRAF6 to MAPK and NF-kB, so the broad term is not wrong, but it is a very general context term; the core process is the JNK cascade. Supporting Evidence: PMID:9808624 the activation of HAβJNK2 by TNF or epidermal growth factor (EGF) was inhibited almost completely by coexpression of catalytically inactive ΞMEKK1(KM). Reactome:R-HSA-166869 TRAF6 binding to MAPK kinase kinase 1 (MEKK1) is mediated by the adapter protein evolutionarily conserved signaling intermediate in Toll pathway |
| GO:0008270 zinc ion binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Zinc binding inferred from the SWIM-type zinc finger (and, additionally, the RING/PHD zinc finger). Reason: MEKK1 contains SWIM and RING/PHD (C4HC3) zinc-coordinating domains, so zinc binding is structurally sound, but it is a structural cofactor property rather than a functional activity. Supporting Evidence: PMID:17101801 with seven cysteines (Cys) and a histidine (His) spatially arranged in a C 4 HC 3 consensus sequence |
| GO:0019901 protein kinase binding | IPI PMID:17906693 Negative regulation of MEKK1/2 signaling by serine-threonine... | KEEP AS NON CORE | Summary: STK38 physically interacts with the catalytic domain of MEKK1/2 and inhibits their activation. Reason: Direct binding to a protein kinase (STK38) is reported; it is a regulatory interaction (STK38 acting as a negative regulator of MEKK1) rather than a core MEKK1 function. Abstract-only, but the abstract explicitly supports the interaction. Supporting Evidence: PMID:17906693 STK38 negatively regulates the activation of MEKK1/2 by direct interaction with the catalytic domain of MEKK1/2 |
| GO:0038095 Fc-epsilon receptor signaling pathway | TAS Reactome:R-HSA-2454202 | KEEP AS NON CORE | Summary: Reactome includes MEKK1 in the FCERI-to-JNK branch of mast-cell Fc-epsilon receptor signalling. Reason: FCERI signalling activates JNK via a MAP3K relay, and MEKK1 is placed there by Reactome; this is a context-specific receptor pathway rather than the core function (JNK cascade activation), so it is retained as non-core. 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:0061630 ubiquitin protein ligase activity | EXP PMID:17101801 MEKK1 mediates the ubiquitination and degradation of c-Jun i... | ACCEPT | Summary: The MEKK1 PHD/RING domain ubiquitinates c-Jun in vitro with purified E1, UbcH5B and ubiquitin, and promotes c-Jun ubiquitination and degradation in cells during osmotic stress; a C433A PHD mutant abolishes activity. Reason: Direct biochemical demonstration of E3 ligase activity with a catalytic-site mutant control; corroborated for ERK2 (PMID:12049732) and TAB1 (PMID:25260751). A core, distinctive function of MEKK1 among MAP3Ks. Supporting Evidence: PMID:17101801 ubiquitination-dependent degradation by the PHD/RING finger domain of MEKK1, which exhibited E3 ubiquitin ligase activity toward c-Jun in vitro and in vivo. PMID:17101801 Purified bacterially expressed His-c-Jun was incubated with purified E1, E2 (UbcH5B), Ub, and GST-MEKK1 PHD/RING finger domain WT protein or the C433A mutant protein PMID:12049732 The PHD domain of MEKK1, a RING finger-like structure, exhibited E3 ubiquitin ligase activity toward ERK2 in vitro and in vivo. |
| GO:0061630 ubiquitin protein ligase activity | IEA GO_REF:0000003 | ACCEPT | Summary: EC 2.3.2.27 (RING-type E3 ubiquitin transferase) mapping to ubiquitin protein ligase activity. Reason: Consistent with experimental evidence for the PHD/RING domain E3 activity. Supporting Evidence: PMID:12049732 The PHD domain of MEKK1, a RING finger-like structure, exhibited E3 ubiquitin ligase activity toward ERK2 in vitro and in vivo. PMID:17101801 ubiquitination-dependent degradation by the PHD/RING finger domain of MEKK1, which exhibited E3 ubiquitin ligase activity toward c-Jun in vitro and in vivo. |
| GO:0070160 tight junction | IDA PMID:24567356 MarvelD3 couples tight junctions to the MEKK1-JNK pathway to... | KEEP AS NON CORE | Summary: In epithelial cells MarvelD3 recruits MEKK1 to tight junctions, where it is kept inactive, down-regulating JNK signalling. Reason: The localization is supported by imaging, but it is partial, MarvelD3-dependent and represents a regulatory sequestration site rather than where MEKK1 carries out its kinase function. Supporting Evidence: PMID:24567356 MEKK1 was indeed partially recruited to cellβcell contacts when MarvelD3 was expressed in MiaPaca-2 cells but not in control cells, indicating that reexpression of the junctional membrane protein is sufficient to stimulate membrane recruitment of MEKK1. PMID:24567356 MarvelD3 recruited MEKK1 to junctions, leading to down-regulation of JNK phosphorylation |
| GO:0071260 cellular response to mechanical stimulus | IEP PMID:19593445 Expression of the Bcl-2 protein BAD promotes prostate cancer... | UNDECIDED | Summary: IEP annotation to cellular response to mechanical stimulus from a paper on BAD expression in prostate cancer. Reason: The cached full text of PMID:19593445 does not mention MEKK1/MAP3K1 or mechanical stimulation, and the same reference supports the identical IEP term on several unrelated JNK-pathway genes (FAS, GADD45A, MAP2K4, MAP3K2, MAPK8, TNFRSF1A), suggesting a batch annotation whose basis we cannot see (possibly supplementary data or a mis-cited reference). MEKK1 is plausibly activated by cytoskeletal and shape-changing stresses, but IEP in any case records a response, not participation. Unable to verify, hence UNDECIDED. Supporting Evidence: PMID:19593445 Expression of the Bcl-2 protein BAD promotes prostate cancer growth. |
| GO:0106310 protein serine kinase activity | IEA GO_REF:0000116 | ACCEPT | Summary: Rhea-based mapping (RHEA:17989, protein serine phosphorylation) to protein serine kinase activity. Reason: MEKK1 phosphorylates serine residues in MAP2K activation loops (e.g. MKK4 Ser257) and in IKKs; correct. 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:0015631 tubulin binding | IDA PMID:32817551 A cryptic tubulin-binding domain links MEKK1 to curved tubul... | NEW | Summary: The MEKK1 TOG domain (residues ~542-888, crystal structure solved) binds soluble alpha/beta-tubulin heterodimers 1:1 with KD ~0.63 uM by ITC, preferring curved (non-polymerised) tubulin over paclitaxel-stabilised microtubules. Reason: Direct, quantitative binding of purified human MEKK1 TOG domain to tubulin, with structural and mutational support; not represented in GOA. This is a binding MF of MEKK1 itself (not a process claim), and plausibly links MEKK1 activation to microtubule perturbation. Supporting Evidence: PMID:32817551 Here we show that MEKK1 contains a previously unidentified tumor overexpressed gene (TOG) domain. PMID:32817551 clearly shows 1:1 stoichiometric binding with a calculated dissociation constant KD = 0.63 ΞΌM |
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Download this section (compressed HTML)Q: Which MEKK1 functions depend on its PHD/RING E3 activity in human cells (c-Jun, ERK1/2 and TAB1 ubiquitination), and are these substrates targeted by the same E2 (UbcH5 versus UBE2N) and chain type?
Q: Does tubulin binding by the TOG domain regulate MEKK1 kinase activation in response to microtubule-targeting drugs, and do tumor-derived TOG-interface mutations alter JNK output?
Q: Is IKK phosphorylation by MEKK1 (Reactome R-HSA-933530) physiologically relevant in human cells, given that MAP3K7/TAK1 is the dominant IKK kinase in most receptor pathways?
Q: What is the evidential basis of the IEP annotation to cellular response to mechanical stimulus citing PMID:19593445, which does not appear to discuss MAP3K1?
Experiment: Knock-in of E3-dead (C433A/C478A) versus kinase-dead (D1369A) MAP3K1 into human MAP3K1-null epithelial cells, followed by phosphoproteomics and ubiquitinomics after osmotic stress and TNF, to separate kinase-dependent and E3-dependent outputs.
Experiment: In vitro reconstitution with purified full-length MEKK1, MKK4, MKK7 and JNK, with and without tubulin, to test whether curved-tubulin binding by the TOG domain modulates MEKK1 autophosphorylation and MAP2K phosphorylation.
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