MAP3K3 (MEKK3) is a STE11-family serine/threonine protein kinase of the MAP kinase kinase kinase (MAP3K) tier. It has an N-terminal amphiphilic helix that binds the CCM adaptor CCM2, an N-terminal PB1 domain, a regulatory region and a C-terminal kinase domain nearly identical to that of its paralog MEKK2. MEKK3 phosphorylates and activates MAP kinase kinases; its best-established substrate is MEK5 (MAP2K5), which it binds by PB1-PB1 heterodimerization and activates to drive the MEK5-ERK5 (BMK1) cascade. It can also activate SEK1/MKK4 (JNK pathway), MEK1 (ERK1/2 pathway) and MKK6 (p38 pathway), and in TNF, IL-1 and LPS signalling it is recruited to RIP1 and TRAF6 complexes and directly phosphorylates IKK to activate NF-kappaB. MEKK3 activity depends on autophosphorylation of activation-loop Ser526 and is restrained by phospho-Thr294-dependent 14-3-3 binding and by the CCM complex (KRIT1-CCM2-PDCD10) and STRIPAK; TRAF7 binds MEKK3 and promotes its signalling. MEKK3 acts in cytoplasmic signalling complexes. In endothelial and endocardial cells MEKK3-MEK5-ERK5 signalling drives KLF2 and KLF4 expression; Map3k3-null mice die around E11 with defective blood vessel development, loss of the CCM complex causes MEKK3 gain of function, and activating somatic MAP3K3 variants (e.g. I441M) cause sporadic cerebral cavernous malformations (CCM5).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000165 MAPK cascade | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT/IBA assignment of MAPK cascade participation from the MAP3K node of the PANTHER family. Reason: MEKK3 is a MAP3K at the top of MAPK modules, principally MEK5-ERK5 and also SEK1/MKK4-JNK, MEK1-ERK and MKK6-p38 depending on context. The general term is correct at the family node; the more specific ERK5 cascade (GO:0070375) is proposed via the MODIFY of the ARBA intracellular signal transduction annotation. Supporting Evidence: PMID:10593883 a dominant active form of MEKK3 stimulates BMK1 activity through MEK5 PMID:9006902 We now demonstrate that MEKK3 activates SEK and MEK, the known kinases targeting SAPK and ERK, respectively. |
| GO:0000165 MAPK cascade | TAS PMID:9006902 Direct activation of the stress-activated protein kinase (SA... | ACCEPT | Summary: Traceable author statement from the cloning of human MEKK3 showing activation of the SAPK/JNK and ERK pathways. Reason: Ellinger-Ziegelbauer et al. showed MEKK3 activates SEK and MEK, placing it at the MAP3K tier of MAPK cascades. Supporting Evidence: PMID:9006902 We now demonstrate that MEKK3 activates SEK and MEK, the known kinases targeting SAPK and ERK, respectively. |
| GO:0004672 protein kinase activity | IDA PMID:15001576 TRAF7 potentiates MEKK3-induced AP1 and CHOP activation and ... | ACCEPT | Summary: Protein kinase activity of MEKK3 from the TRAF7 study (TRAF7 potentiates MEKK3 signalling). Reason: The cached abstract does not detail the kinase assay, but MEKK3 kinase activity is established independently (autophosphorylation of Ser526, MKK6 phosphorylation in vitro, direct IKK phosphorylation). Correct; the more informative GO:0004709 is annotated separately. Supporting Evidence: PMID:15001576 TRAF7 specifically interacted with MEKK3 and potentiated MEKK3-mediated AP1 and CHOP activation. PMID:16407301 phosphorylation of Ser526 was required for MKK6 phosphorylation in vitro PMID:11429546 MEKK3 interacts with RIP and directly phosphorylates IKK |
| GO:0004672 protein kinase activity | IMP PMID:33729480 Somatic MAP3K3 and PIK3CA mutations in sporadic cerebral and... | ACCEPT | Summary: Protein kinase activity inferred from activating somatic MAP3K3 mutations in sporadic cavernous malformations. Reason: Somatic MAP3K3 variants (I441M) found in sporadic CCM are activating, and overexpression perturbs angiogenesis; the mutant phenotype depends on MEKK3 kinase activity. Correct, if general. Supporting Evidence: PMID:33729480 We identified activating MAP3K3 and PIK3CA somatic mutations in the majority (90.1%) of sporadic cavernous malformations PMID:33891857 MEKK3 p.Ile441Met (MAP3K3 encodes MEKK3) also activates ERK1/2, JNK, and p38 pathways because of mutation-induced MEKK3 kinase activity enhancement |
| GO:0004672 protein kinase activity | IMP PMID:33891857 Somatic MAP3K3 mutation defines a subclass of cerebral caver... | ACCEPT | Summary: Protein kinase activity inferred from the CCM-associated MEKK3 I441M gain-of-function variant. Reason: MEKK3 I441M enhances kinase activity and hyperactivates ERK5 and also ERK1/2, JNK and p38 pathways in endothelial cells, directly implicating MEKK3 catalytic activity. Correct, if general. Supporting Evidence: PMID:33891857 MEKK3 p.Ile441Met (MAP3K3 encodes MEKK3) also activates ERK1/2, JNK, and p38 pathways because of mutation-induced MEKK3 kinase activity enhancement |
| GO:0004674 protein serine/threonine kinase activity | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT/IBA assignment of protein serine/threonine kinase activity from the PANTHER STE-kinase node. Reason: MEKK3 is an active STE11-family Ser/Thr kinase: it autophosphorylates activation-loop Ser526, phosphorylates MKK6 in vitro and directly phosphorylates IKK. Correct, if general. Supporting Evidence: PMID:16407301 phosphorylation of Ser526 occurs via autophosphorylation PMID:16407301 phosphorylation of Ser526 was required for MKK6 phosphorylation in vitro PMID:11429546 MEKK3 interacts with RIP and directly phosphorylates IKK |
| GO:0004709 MAP kinase kinase kinase activity | IEA GO_REF:0000003 | ACCEPT | Summary: EC-mapping IEA (EC 2.7.11.25) assignment of MAP kinase kinase kinase activity. Reason: Core molecular function of MEKK3: it phosphorylates and activates the MAP2Ks MEK5 (its best-defined substrate), SEK1/MKK4, MEK1 and MKK6. Supporting Evidence: PMID:9006902 We now demonstrate that MEKK3 activates SEK and MEK, the known kinases targeting SAPK and ERK, respectively. PMID:10593883 a dominant active form of MEKK3 stimulates BMK1 activity through MEK5 PMID:16407301 phosphorylation of Ser526 was required for MKK6 phosphorylation in vitro file:human/MAP3K3/MAP3K3-deep-research-falcon.md MEKK3 binds the N-terminal region of **MAP2K5/MEK5** and phosphorylates its activation loop at **Ser311 and Thr315**. |
| GO:0004709 MAP kinase kinase kinase activity | TAS PMID:9006902 Direct activation of the stress-activated protein kinase (SA... | ACCEPT | Summary: Traceable author statement of MAP3K activity from the cloning of human MEKK3. Reason: Ellinger-Ziegelbauer et al. showed MEKK3 activates the MAP2Ks SEK and MEK directly. Core function. Supporting Evidence: PMID:9006902 We now demonstrate that MEKK3 activates SEK and MEK, the known kinases targeting SAPK and ERK, respectively. |
| GO:0005515 protein binding | IPI PMID:12392720 Phosphorylation of the stress-activated protein kinase, MEKK... | MODIFY | Summary: Interaction of MEKK3 with the 14-3-3 protein YWHAE (14-3-3 epsilon) (PMID:12392720; targeted study). Reason: Bare protein binding is uninformative. The partner is a 14-3-3 protein. MEKK3 binding to 14-3-3 is a targeted, phosphorylation-dependent regulatory interaction: 14-3-3 docks on phospho-Thr294 (restraining TNF-induced NF-kappaB activity) and protects activation-loop phospho-Ser526 from PP2A, and all six 14-3-3 isoforms are recovered with MEKK3 across independent interactome studies. 14-3-3 protein binding (GO:0071889) is the informative term; it is a regulatory property, not a core MEKK3 activity. Consistent with the treatment of the same interactions for MAP3K2. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:12392720 We identified 14-3-3 proteins as interacting with MEKK3 PMID:18308725 Mutation of Thr(294) to alanine abolished 14-3-3-MEKK3 association PMID:16407301 the association between MEKK3 and 14-3-3 was dependent on Ser526 and prevented dephosphorylation of Ser526 PMID:9452471 The 14-3-3zeta and 14-3-3epsilon isoforms were isolated in a two-hybrid screen for proteins interacting with the N-terminal regulatory domain of MEKK3. |
| GO:0005515 protein binding | IPI PMID:14743216 A physical and functional map of the human TNF-alpha/NF-kapp... | MODIFY | Summary: Interaction of MEKK3 with the 14-3-3 protein YWHAQ (14-3-3 theta) (PMID:14743216; TAP-MS mapping of the TNF-alpha/NF-kappaB pathway interactome). Reason: Bare protein binding is uninformative. The partner is a 14-3-3 protein. MEKK3 binding to 14-3-3 is a targeted, phosphorylation-dependent regulatory interaction: 14-3-3 docks on phospho-Thr294 (restraining TNF-induced NF-kappaB activity) and protects activation-loop phospho-Ser526 from PP2A, and all six 14-3-3 isoforms are recovered with MEKK3 across independent interactome studies. 14-3-3 protein binding (GO:0071889) is the informative term; it is a regulatory property, not a core MEKK3 activity. Consistent with the treatment of the same interactions for MAP3K2. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:18308725 Mutation of Thr(294) to alanine abolished 14-3-3-MEKK3 association PMID:16407301 the association between MEKK3 and 14-3-3 was dependent on Ser526 and prevented dephosphorylation of Ser526 PMID:9452471 The 14-3-3zeta and 14-3-3epsilon isoforms were isolated in a two-hybrid screen for proteins interacting with the N-terminal regulatory domain of MEKK3. |
| GO:0005515 protein binding | IPI PMID:14743216 A physical and functional map of the human TNF-alpha/NF-kapp... | MODIFY | Summary: Interaction of MEKK3 with the 14-3-3 protein YWHAB (14-3-3 beta/alpha) (PMID:14743216; TAP-MS mapping of the TNF-alpha/NF-kappaB pathway interactome). Reason: Bare protein binding is uninformative. The partner is a 14-3-3 protein. MEKK3 binding to 14-3-3 is a targeted, phosphorylation-dependent regulatory interaction: 14-3-3 docks on phospho-Thr294 (restraining TNF-induced NF-kappaB activity) and protects activation-loop phospho-Ser526 from PP2A, and all six 14-3-3 isoforms are recovered with MEKK3 across independent interactome studies. 14-3-3 protein binding (GO:0071889) is the informative term; it is a regulatory property, not a core MEKK3 activity. Consistent with the treatment of the same interactions for MAP3K2. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:18308725 Mutation of Thr(294) to alanine abolished 14-3-3-MEKK3 association PMID:16407301 the association between MEKK3 and 14-3-3 was dependent on Ser526 and prevented dephosphorylation of Ser526 PMID:9452471 The 14-3-3zeta and 14-3-3epsilon isoforms were isolated in a two-hybrid screen for proteins interacting with the N-terminal regulatory domain of MEKK3. |
| GO:0005515 protein binding | IPI PMID:14743216 A physical and functional map of the human TNF-alpha/NF-kapp... | MODIFY | Summary: Interaction of MEKK3 with the 14-3-3 protein YWHAG (14-3-3 gamma) (PMID:14743216; TAP-MS mapping of the TNF-alpha/NF-kappaB pathway interactome). Reason: Bare protein binding is uninformative. The partner is a 14-3-3 protein. MEKK3 binding to 14-3-3 is a targeted, phosphorylation-dependent regulatory interaction: 14-3-3 docks on phospho-Thr294 (restraining TNF-induced NF-kappaB activity) and protects activation-loop phospho-Ser526 from PP2A, and all six 14-3-3 isoforms are recovered with MEKK3 across independent interactome studies. 14-3-3 protein binding (GO:0071889) is the informative term; it is a regulatory property, not a core MEKK3 activity. Consistent with the treatment of the same interactions for MAP3K2. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:18308725 Mutation of Thr(294) to alanine abolished 14-3-3-MEKK3 association PMID:16407301 the association between MEKK3 and 14-3-3 was dependent on Ser526 and prevented dephosphorylation of Ser526 PMID:9452471 The 14-3-3zeta and 14-3-3epsilon isoforms were isolated in a two-hybrid screen for proteins interacting with the N-terminal regulatory domain of MEKK3. |
| GO:0005515 protein binding | IPI PMID:14743216 A physical and functional map of the human TNF-alpha/NF-kapp... | MODIFY | Summary: Interaction of MEKK3 with the 14-3-3 protein YWHAE (14-3-3 epsilon) (PMID:14743216; TAP-MS mapping of the TNF-alpha/NF-kappaB pathway interactome). Reason: Bare protein binding is uninformative. The partner is a 14-3-3 protein. MEKK3 binding to 14-3-3 is a targeted, phosphorylation-dependent regulatory interaction: 14-3-3 docks on phospho-Thr294 (restraining TNF-induced NF-kappaB activity) and protects activation-loop phospho-Ser526 from PP2A, and all six 14-3-3 isoforms are recovered with MEKK3 across independent interactome studies. 14-3-3 protein binding (GO:0071889) is the informative term; it is a regulatory property, not a core MEKK3 activity. Consistent with the treatment of the same interactions for MAP3K2. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:18308725 Mutation of Thr(294) to alanine abolished 14-3-3-MEKK3 association PMID:16407301 the association between MEKK3 and 14-3-3 was dependent on Ser526 and prevented dephosphorylation of Ser526 PMID:9452471 The 14-3-3zeta and 14-3-3epsilon isoforms were isolated in a two-hybrid screen for proteins interacting with the N-terminal regulatory domain of MEKK3. |
| GO:0005515 protein binding | IPI PMID:14743216 A physical and functional map of the human TNF-alpha/NF-kapp... | MODIFY | Summary: Interaction of MEKK3 with the 14-3-3 protein YWHAZ (14-3-3 zeta/delta) (PMID:14743216; TAP-MS mapping of the TNF-alpha/NF-kappaB pathway interactome). Reason: Bare protein binding is uninformative. The partner is a 14-3-3 protein. MEKK3 binding to 14-3-3 is a targeted, phosphorylation-dependent regulatory interaction: 14-3-3 docks on phospho-Thr294 (restraining TNF-induced NF-kappaB activity) and protects activation-loop phospho-Ser526 from PP2A, and all six 14-3-3 isoforms are recovered with MEKK3 across independent interactome studies. 14-3-3 protein binding (GO:0071889) is the informative term; it is a regulatory property, not a core MEKK3 activity. Consistent with the treatment of the same interactions for MAP3K2. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:18308725 Mutation of Thr(294) to alanine abolished 14-3-3-MEKK3 association PMID:16407301 the association between MEKK3 and 14-3-3 was dependent on Ser526 and prevented dephosphorylation of Ser526 PMID:9452471 The 14-3-3zeta and 14-3-3epsilon isoforms were isolated in a two-hybrid screen for proteins interacting with the N-terminal regulatory domain of MEKK3. |
| GO:0005515 protein binding | IPI PMID:14743216 A physical and functional map of the human TNF-alpha/NF-kapp... | MODIFY | Summary: Interaction of MEKK3 with the 14-3-3 protein YWHAH (14-3-3 eta) (PMID:14743216; TAP-MS mapping of the TNF-alpha/NF-kappaB pathway interactome). Reason: Bare protein binding is uninformative. The partner is a 14-3-3 protein. MEKK3 binding to 14-3-3 is a targeted, phosphorylation-dependent regulatory interaction: 14-3-3 docks on phospho-Thr294 (restraining TNF-induced NF-kappaB activity) and protects activation-loop phospho-Ser526 from PP2A, and all six 14-3-3 isoforms are recovered with MEKK3 across independent interactome studies. 14-3-3 protein binding (GO:0071889) is the informative term; it is a regulatory property, not a core MEKK3 activity. Consistent with the treatment of the same interactions for MAP3K2. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:18308725 Mutation of Thr(294) to alanine abolished 14-3-3-MEKK3 association PMID:16407301 the association between MEKK3 and 14-3-3 was dependent on Ser526 and prevented dephosphorylation of Ser526 PMID:9452471 The 14-3-3zeta and 14-3-3epsilon isoforms were isolated in a two-hybrid screen for proteins interacting with the N-terminal regulatory domain of MEKK3. |
| GO:0005515 protein binding | IPI PMID:14743216 A physical and functional map of the human TNF-alpha/NF-kapp... | MODIFY | Summary: Interaction of MEKK3 with its substrate MAP2K5/MEK5 (PMID:14743216; TAP-MS mapping of the TNF-alpha/NF-kappaB pathway interactome). Reason: Bare protein binding is uninformative. MEK5 is the principal substrate of MEKK3, recruited by PB1-PB1 heterodimerization; the binding is the enzyme-substrate docking step of the ERK5 cascade. Protein kinase binding (GO:0019901) is the informative binding term; the catalytic function is captured by MAP kinase kinase kinase activity (GO:0004709). Consistent with the MAP3K2 review. Proposed replacements: protein kinase binding Supporting Evidence: PMID:10593883 we have identified MEKK3 as a molecule that physically interacts with MEK5 PMID:12912994 the PB1 domain mediates the association of MEKK2 and MEKK3 with MEK5 file:human/MAP3K3/MAP3K3-uniprot.txt Interacts with MAP2K5 and SPAG9 |
| GO:0005515 protein binding | IPI PMID:14743216 A physical and functional map of the human TNF-alpha/NF-kapp... | MODIFY | Summary: Interaction of MEKK3 with the RING-type E3 ligase TRAF7 (PMID:14743216; TAP-MS mapping of the TNF-alpha/NF-kappaB pathway interactome). Reason: Bare protein binding is uninformative. TRAF7 is a RING-finger/WD40 E3 ubiquitin ligase that binds MEKK3 specifically (via its WD40 region) and potentiates MEKK3-dependent AP1/CHOP signalling and, in endothelium, shear-induced MEK5-ERK5 activation. Ubiquitin protein ligase binding (GO:0031625) describes the partner class; the functional consequence is regulation of MEKK3 rather than a MEKK3 activity, so it is non-core. Proposed replacements: ubiquitin protein ligase binding Supporting Evidence: PMID:15001576 TRAF7 specifically interacted with MEKK3 and potentiated MEKK3-mediated AP1 and CHOP activation. PMID:15001576 TRAF7, which contains a RING finger domain file:human/MAP3K3/MAP3K3-deep-research-falcon.md TRAF7 binds MEKK3 through its C-terminal WD40 region and also associates with MEK5 and SCRIB. |
| GO:0005515 protein binding | IPI PMID:15001576 TRAF7 potentiates MEKK3-induced AP1 and CHOP activation and ... | MODIFY | Summary: Interaction of MEKK3 with the RING-type E3 ligase TRAF7 (PMID:15001576; targeted study). Reason: Bare protein binding is uninformative. TRAF7 is a RING-finger/WD40 E3 ubiquitin ligase that binds MEKK3 specifically (via its WD40 region) and potentiates MEKK3-dependent AP1/CHOP signalling and, in endothelium, shear-induced MEK5-ERK5 activation. Ubiquitin protein ligase binding (GO:0031625) describes the partner class; the functional consequence is regulation of MEKK3 rather than a MEKK3 activity, so it is non-core. Proposed replacements: ubiquitin protein ligase binding Supporting Evidence: PMID:15001576 TRAF7 specifically interacted with MEKK3 and potentiated MEKK3-mediated AP1 and CHOP activation. PMID:15001576 TRAF7, which contains a RING finger domain file:human/MAP3K3/MAP3K3-deep-research-falcon.md TRAF7 binds MEKK3 through its C-terminal WD40 region and also associates with MEK5 and SCRIB. |
| GO:0005515 protein binding | IPI PMID:16407301 Phosphorylation of serine 526 is required for MEKK3 activity... | MODIFY | Summary: Interaction of MEKK3 with the 14-3-3 protein YWHAE (14-3-3 epsilon) (PMID:16407301; targeted study). Reason: Bare protein binding is uninformative. The partner is a 14-3-3 protein. MEKK3 binding to 14-3-3 is a targeted, phosphorylation-dependent regulatory interaction: 14-3-3 docks on phospho-Thr294 (restraining TNF-induced NF-kappaB activity) and protects activation-loop phospho-Ser526 from PP2A, and all six 14-3-3 isoforms are recovered with MEKK3 across independent interactome studies. 14-3-3 protein binding (GO:0071889) is the informative term; it is a regulatory property, not a core MEKK3 activity. Consistent with the treatment of the same interactions for MAP3K2. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:16407301 the association between MEKK3 and 14-3-3 was dependent on Ser526 and prevented dephosphorylation of Ser526 PMID:18308725 Mutation of Thr(294) to alanine abolished 14-3-3-MEKK3 association PMID:9452471 The 14-3-3zeta and 14-3-3epsilon isoforms were isolated in a two-hybrid screen for proteins interacting with the N-terminal regulatory domain of MEKK3. |
| GO:0005515 protein binding | IPI PMID:18308725 Phosphorylation of MEKK3 at threonine 294 promotes 14-3-3 as... | MODIFY | Summary: Interaction of MEKK3 with the 14-3-3 protein YWHAB (14-3-3 beta/alpha) (PMID:18308725; targeted study). Reason: Bare protein binding is uninformative. The partner is a 14-3-3 protein. MEKK3 binding to 14-3-3 is a targeted, phosphorylation-dependent regulatory interaction: 14-3-3 docks on phospho-Thr294 (restraining TNF-induced NF-kappaB activity) and protects activation-loop phospho-Ser526 from PP2A, and all six 14-3-3 isoforms are recovered with MEKK3 across independent interactome studies. 14-3-3 protein binding (GO:0071889) is the informative term; it is a regulatory property, not a core MEKK3 activity. Consistent with the treatment of the same interactions for MAP3K2. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:18308725 Mutation of Thr(294) to alanine abolished 14-3-3-MEKK3 association PMID:18308725 suggesting that Thr(294) phosphorylation and 14-3-3 binding negatively regulate MEKK3 PMID:16407301 the association between MEKK3 and 14-3-3 was dependent on Ser526 and prevented dephosphorylation of Ser526 PMID:9452471 The 14-3-3zeta and 14-3-3epsilon isoforms were isolated in a two-hybrid screen for proteins interacting with the N-terminal regulatory domain of MEKK3. |
| GO:0005515 protein binding | IPI PMID:25241761 Using an in situ proximity ligation assay to systematically ... | MODIFY | Summary: Interaction of MEKK3 with its substrate MAP2K5/MEK5 (PMID:25241761; systematic in situ proximity-ligation profiling of endogenous interactions). Reason: Bare protein binding is uninformative. MEK5 is the principal substrate of MEKK3, recruited by PB1-PB1 heterodimerization; the binding is the enzyme-substrate docking step of the ERK5 cascade. Protein kinase binding (GO:0019901) is the informative binding term; the catalytic function is captured by MAP kinase kinase kinase activity (GO:0004709). Consistent with the MAP3K2 review. Proposed replacements: protein kinase binding Supporting Evidence: PMID:10593883 we have identified MEKK3 as a molecule that physically interacts with MEK5 PMID:12912994 the PB1 domain mediates the association of MEKK2 and MEKK3 with MEK5 file:human/MAP3K3/MAP3K3-uniprot.txt Interacts with MAP2K5 and SPAG9 |
| GO:0005515 protein binding | IPI PMID:25982527 Structural Insights into the Molecular Recognition between C... | MODIFY | Summary: Direct interaction of the MEKK3 N-terminal amphiphilic helix with the CCM2 harmonin-homology/C-terminal domain (PMID:25982527). Reason: Bare protein binding is uninformative. CCM2 is an adaptor/scaffold of the CCM complex that binds the MEKK3 N-terminal helix and restrains MEKK3 signalling in endothelium; a disease-causing CCM2 mutation that abolishes MEKK3 binding causes CCM. Scaffold protein binding (GO:0097110) captures that MEKK3 is bound by a scaffold/adaptor; the interaction is regulatory but of high physiological importance. Proposed replacements: scaffold protein binding Supporting Evidence: PMID:25982527 we identified the N-terminal amphiphilic helix of MEKK3 (MEKK3-nhelix) as the essential structural element for CCM2ct binding PMID:25982527 Cerebral cavernous malformation 2 (CCM2) functions as an adaptor protein PMID:27027284 a disease-causing human CCM2 mutation abrogates the MEKK3 interaction without affecting CCM complex formation |
| GO:0005515 protein binding | IPI PMID:27027284 Cerebral cavernous malformations arise from endothelial gain... | MODIFY | Summary: Direct interaction of the MEKK3 N-terminal amphiphilic helix with the CCM2 harmonin-homology/C-terminal domain (PMID:27027284). Reason: Bare protein binding is uninformative. CCM2 is an adaptor/scaffold of the CCM complex that binds the MEKK3 N-terminal helix and restrains MEKK3 signalling in endothelium; a disease-causing CCM2 mutation that abolishes MEKK3 binding causes CCM. Scaffold protein binding (GO:0097110) captures that MEKK3 is bound by a scaffold/adaptor; the interaction is regulatory but of high physiological importance. Proposed replacements: scaffold protein binding Supporting Evidence: PMID:25982527 we identified the N-terminal amphiphilic helix of MEKK3 (MEKK3-nhelix) as the essential structural element for CCM2ct binding PMID:25982527 Cerebral cavernous malformation 2 (CCM2) functions as an adaptor protein PMID:27027284 a disease-causing human CCM2 mutation abrogates the MEKK3 interaction without affecting CCM complex formation |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MODIFY | Summary: Interaction of MEKK3 with the 14-3-3 protein YWHAQ (14-3-3 theta) (PMID:28514442; BioPlex AP-MS interactome). Reason: Bare protein binding is uninformative. The partner is a 14-3-3 protein. MEKK3 binding to 14-3-3 is a targeted, phosphorylation-dependent regulatory interaction: 14-3-3 docks on phospho-Thr294 (restraining TNF-induced NF-kappaB activity) and protects activation-loop phospho-Ser526 from PP2A, and all six 14-3-3 isoforms are recovered with MEKK3 across independent interactome studies. 14-3-3 protein binding (GO:0071889) is the informative term; it is a regulatory property, not a core MEKK3 activity. Consistent with the treatment of the same interactions for MAP3K2. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:18308725 Mutation of Thr(294) to alanine abolished 14-3-3-MEKK3 association PMID:16407301 the association between MEKK3 and 14-3-3 was dependent on Ser526 and prevented dephosphorylation of Ser526 PMID:9452471 The 14-3-3zeta and 14-3-3epsilon isoforms were isolated in a two-hybrid screen for proteins interacting with the N-terminal regulatory domain of MEKK3. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MODIFY | Summary: Interaction of MEKK3 with the 14-3-3 protein YWHAG (14-3-3 gamma) (PMID:28514442; BioPlex AP-MS interactome). Reason: Bare protein binding is uninformative. The partner is a 14-3-3 protein. MEKK3 binding to 14-3-3 is a targeted, phosphorylation-dependent regulatory interaction: 14-3-3 docks on phospho-Thr294 (restraining TNF-induced NF-kappaB activity) and protects activation-loop phospho-Ser526 from PP2A, and all six 14-3-3 isoforms are recovered with MEKK3 across independent interactome studies. 14-3-3 protein binding (GO:0071889) is the informative term; it is a regulatory property, not a core MEKK3 activity. Consistent with the treatment of the same interactions for MAP3K2. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:18308725 Mutation of Thr(294) to alanine abolished 14-3-3-MEKK3 association PMID:16407301 the association between MEKK3 and 14-3-3 was dependent on Ser526 and prevented dephosphorylation of Ser526 PMID:9452471 The 14-3-3zeta and 14-3-3epsilon isoforms were isolated in a two-hybrid screen for proteins interacting with the N-terminal regulatory domain of MEKK3. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MODIFY | Summary: Interaction of MEKK3 with the 14-3-3 protein YWHAZ (14-3-3 zeta/delta) (PMID:28514442; BioPlex AP-MS interactome). Reason: Bare protein binding is uninformative. The partner is a 14-3-3 protein. MEKK3 binding to 14-3-3 is a targeted, phosphorylation-dependent regulatory interaction: 14-3-3 docks on phospho-Thr294 (restraining TNF-induced NF-kappaB activity) and protects activation-loop phospho-Ser526 from PP2A, and all six 14-3-3 isoforms are recovered with MEKK3 across independent interactome studies. 14-3-3 protein binding (GO:0071889) is the informative term; it is a regulatory property, not a core MEKK3 activity. Consistent with the treatment of the same interactions for MAP3K2. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:18308725 Mutation of Thr(294) to alanine abolished 14-3-3-MEKK3 association PMID:16407301 the association between MEKK3 and 14-3-3 was dependent on Ser526 and prevented dephosphorylation of Ser526 PMID:9452471 The 14-3-3zeta and 14-3-3epsilon isoforms were isolated in a two-hybrid screen for proteins interacting with the N-terminal regulatory domain of MEKK3. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MODIFY | Summary: Interaction of MEKK3 with the 14-3-3 protein YWHAH (14-3-3 eta) (PMID:28514442; BioPlex AP-MS interactome). Reason: Bare protein binding is uninformative. The partner is a 14-3-3 protein. MEKK3 binding to 14-3-3 is a targeted, phosphorylation-dependent regulatory interaction: 14-3-3 docks on phospho-Thr294 (restraining TNF-induced NF-kappaB activity) and protects activation-loop phospho-Ser526 from PP2A, and all six 14-3-3 isoforms are recovered with MEKK3 across independent interactome studies. 14-3-3 protein binding (GO:0071889) is the informative term; it is a regulatory property, not a core MEKK3 activity. Consistent with the treatment of the same interactions for MAP3K2. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:18308725 Mutation of Thr(294) to alanine abolished 14-3-3-MEKK3 association PMID:16407301 the association between MEKK3 and 14-3-3 was dependent on Ser526 and prevented dephosphorylation of Ser526 PMID:9452471 The 14-3-3zeta and 14-3-3epsilon isoforms were isolated in a two-hybrid screen for proteins interacting with the N-terminal regulatory domain of MEKK3. |
| GO:0005515 protein binding | IPI PMID:32707033 Kinase Interaction Network Expands Functional and Disease Ro... | MODIFY | Summary: Interaction of MEKK3 with the 14-3-3 protein YWHAG (14-3-3 gamma) (PMID:32707033; kinase interaction network (AP-MS)). Reason: Bare protein binding is uninformative. The partner is a 14-3-3 protein. MEKK3 binding to 14-3-3 is a targeted, phosphorylation-dependent regulatory interaction: 14-3-3 docks on phospho-Thr294 (restraining TNF-induced NF-kappaB activity) and protects activation-loop phospho-Ser526 from PP2A, and all six 14-3-3 isoforms are recovered with MEKK3 across independent interactome studies. 14-3-3 protein binding (GO:0071889) is the informative term; it is a regulatory property, not a core MEKK3 activity. Consistent with the treatment of the same interactions for MAP3K2. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:18308725 Mutation of Thr(294) to alanine abolished 14-3-3-MEKK3 association PMID:16407301 the association between MEKK3 and 14-3-3 was dependent on Ser526 and prevented dephosphorylation of Ser526 PMID:9452471 The 14-3-3zeta and 14-3-3epsilon isoforms were isolated in a two-hybrid screen for proteins interacting with the N-terminal regulatory domain of MEKK3. |
| GO:0005515 protein binding | IPI PMID:32707033 Kinase Interaction Network Expands Functional and Disease Ro... | MODIFY | Summary: Interaction of MEKK3 with the 14-3-3 protein YWHAH (14-3-3 eta) (PMID:32707033; kinase interaction network (AP-MS)). Reason: Bare protein binding is uninformative. The partner is a 14-3-3 protein. MEKK3 binding to 14-3-3 is a targeted, phosphorylation-dependent regulatory interaction: 14-3-3 docks on phospho-Thr294 (restraining TNF-induced NF-kappaB activity) and protects activation-loop phospho-Ser526 from PP2A, and all six 14-3-3 isoforms are recovered with MEKK3 across independent interactome studies. 14-3-3 protein binding (GO:0071889) is the informative term; it is a regulatory property, not a core MEKK3 activity. Consistent with the treatment of the same interactions for MAP3K2. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:18308725 Mutation of Thr(294) to alanine abolished 14-3-3-MEKK3 association PMID:16407301 the association between MEKK3 and 14-3-3 was dependent on Ser526 and prevented dephosphorylation of Ser526 PMID:9452471 The 14-3-3zeta and 14-3-3epsilon isoforms were isolated in a two-hybrid screen for proteins interacting with the N-terminal regulatory domain of MEKK3. |
| GO:0005515 protein binding | IPI PMID:32707033 Kinase Interaction Network Expands Functional and Disease Ro... | MODIFY | Summary: Interaction of MEKK3 with its substrate MAP2K5/MEK5 (PMID:32707033; kinase interaction network (AP-MS)). Reason: Bare protein binding is uninformative. MEK5 is the principal substrate of MEKK3, recruited by PB1-PB1 heterodimerization; the binding is the enzyme-substrate docking step of the ERK5 cascade. Protein kinase binding (GO:0019901) is the informative binding term; the catalytic function is captured by MAP kinase kinase kinase activity (GO:0004709). Consistent with the MAP3K2 review. Proposed replacements: protein kinase binding Supporting Evidence: PMID:10593883 we have identified MEKK3 as a molecule that physically interacts with MEK5 PMID:12912994 the PB1 domain mediates the association of MEKK2 and MEKK3 with MEK5 file:human/MAP3K3/MAP3K3-uniprot.txt Interacts with MAP2K5 and SPAG9 |
| GO:0005515 protein binding | IPI PMID:32707033 Kinase Interaction Network Expands Functional and Disease Ro... | MODIFY | Summary: Interaction of MEKK3 with the RING-type E3 ligase TRAF7 (PMID:32707033; kinase interaction network (AP-MS)). Reason: Bare protein binding is uninformative. TRAF7 is a RING-finger/WD40 E3 ubiquitin ligase that binds MEKK3 specifically (via its WD40 region) and potentiates MEKK3-dependent AP1/CHOP signalling and, in endothelium, shear-induced MEK5-ERK5 activation. Ubiquitin protein ligase binding (GO:0031625) describes the partner class; the functional consequence is regulation of MEKK3 rather than a MEKK3 activity, so it is non-core. Proposed replacements: ubiquitin protein ligase binding Supporting Evidence: PMID:15001576 TRAF7 specifically interacted with MEKK3 and potentiated MEKK3-mediated AP1 and CHOP activation. PMID:15001576 TRAF7, which contains a RING finger domain file:human/MAP3K3/MAP3K3-deep-research-falcon.md TRAF7 binds MEKK3 through its C-terminal WD40 region and also associates with MEK5 and SCRIB. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MODIFY | Summary: Interaction of MEKK3 with the 14-3-3 protein YWHAQ (14-3-3 theta) (PMID:33961781; BioPlex dual cell-line interactome). Reason: Bare protein binding is uninformative. The partner is a 14-3-3 protein. MEKK3 binding to 14-3-3 is a targeted, phosphorylation-dependent regulatory interaction: 14-3-3 docks on phospho-Thr294 (restraining TNF-induced NF-kappaB activity) and protects activation-loop phospho-Ser526 from PP2A, and all six 14-3-3 isoforms are recovered with MEKK3 across independent interactome studies. 14-3-3 protein binding (GO:0071889) is the informative term; it is a regulatory property, not a core MEKK3 activity. Consistent with the treatment of the same interactions for MAP3K2. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:18308725 Mutation of Thr(294) to alanine abolished 14-3-3-MEKK3 association PMID:16407301 the association between MEKK3 and 14-3-3 was dependent on Ser526 and prevented dephosphorylation of Ser526 PMID:9452471 The 14-3-3zeta and 14-3-3epsilon isoforms were isolated in a two-hybrid screen for proteins interacting with the N-terminal regulatory domain of MEKK3. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MODIFY | Summary: Interaction of MEKK3 with the 14-3-3 protein YWHAB (14-3-3 beta/alpha) (PMID:33961781; BioPlex dual cell-line interactome). Reason: Bare protein binding is uninformative. The partner is a 14-3-3 protein. MEKK3 binding to 14-3-3 is a targeted, phosphorylation-dependent regulatory interaction: 14-3-3 docks on phospho-Thr294 (restraining TNF-induced NF-kappaB activity) and protects activation-loop phospho-Ser526 from PP2A, and all six 14-3-3 isoforms are recovered with MEKK3 across independent interactome studies. 14-3-3 protein binding (GO:0071889) is the informative term; it is a regulatory property, not a core MEKK3 activity. Consistent with the treatment of the same interactions for MAP3K2. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:18308725 Mutation of Thr(294) to alanine abolished 14-3-3-MEKK3 association PMID:16407301 the association between MEKK3 and 14-3-3 was dependent on Ser526 and prevented dephosphorylation of Ser526 PMID:9452471 The 14-3-3zeta and 14-3-3epsilon isoforms were isolated in a two-hybrid screen for proteins interacting with the N-terminal regulatory domain of MEKK3. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MODIFY | Summary: Interaction of MEKK3 with the 14-3-3 protein YWHAG (14-3-3 gamma) (PMID:33961781; BioPlex dual cell-line interactome). Reason: Bare protein binding is uninformative. The partner is a 14-3-3 protein. MEKK3 binding to 14-3-3 is a targeted, phosphorylation-dependent regulatory interaction: 14-3-3 docks on phospho-Thr294 (restraining TNF-induced NF-kappaB activity) and protects activation-loop phospho-Ser526 from PP2A, and all six 14-3-3 isoforms are recovered with MEKK3 across independent interactome studies. 14-3-3 protein binding (GO:0071889) is the informative term; it is a regulatory property, not a core MEKK3 activity. Consistent with the treatment of the same interactions for MAP3K2. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:18308725 Mutation of Thr(294) to alanine abolished 14-3-3-MEKK3 association PMID:16407301 the association between MEKK3 and 14-3-3 was dependent on Ser526 and prevented dephosphorylation of Ser526 PMID:9452471 The 14-3-3zeta and 14-3-3epsilon isoforms were isolated in a two-hybrid screen for proteins interacting with the N-terminal regulatory domain of MEKK3. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MODIFY | Summary: Interaction of MEKK3 with the 14-3-3 protein YWHAZ (14-3-3 zeta/delta) (PMID:33961781; BioPlex dual cell-line interactome). Reason: Bare protein binding is uninformative. The partner is a 14-3-3 protein. MEKK3 binding to 14-3-3 is a targeted, phosphorylation-dependent regulatory interaction: 14-3-3 docks on phospho-Thr294 (restraining TNF-induced NF-kappaB activity) and protects activation-loop phospho-Ser526 from PP2A, and all six 14-3-3 isoforms are recovered with MEKK3 across independent interactome studies. 14-3-3 protein binding (GO:0071889) is the informative term; it is a regulatory property, not a core MEKK3 activity. Consistent with the treatment of the same interactions for MAP3K2. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:18308725 Mutation of Thr(294) to alanine abolished 14-3-3-MEKK3 association PMID:16407301 the association between MEKK3 and 14-3-3 was dependent on Ser526 and prevented dephosphorylation of Ser526 PMID:9452471 The 14-3-3zeta and 14-3-3epsilon isoforms were isolated in a two-hybrid screen for proteins interacting with the N-terminal regulatory domain of MEKK3. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MODIFY | Summary: Interaction of MEKK3 with the 14-3-3 protein YWHAH (14-3-3 eta) (PMID:33961781; BioPlex dual cell-line interactome). Reason: Bare protein binding is uninformative. The partner is a 14-3-3 protein. MEKK3 binding to 14-3-3 is a targeted, phosphorylation-dependent regulatory interaction: 14-3-3 docks on phospho-Thr294 (restraining TNF-induced NF-kappaB activity) and protects activation-loop phospho-Ser526 from PP2A, and all six 14-3-3 isoforms are recovered with MEKK3 across independent interactome studies. 14-3-3 protein binding (GO:0071889) is the informative term; it is a regulatory property, not a core MEKK3 activity. Consistent with the treatment of the same interactions for MAP3K2. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:18308725 Mutation of Thr(294) to alanine abolished 14-3-3-MEKK3 association PMID:16407301 the association between MEKK3 and 14-3-3 was dependent on Ser526 and prevented dephosphorylation of Ser526 PMID:9452471 The 14-3-3zeta and 14-3-3epsilon isoforms were isolated in a two-hybrid screen for proteins interacting with the N-terminal regulatory domain of MEKK3. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MODIFY | Summary: Interaction of MEKK3 with its substrate MAP2K5/MEK5 (PMID:33961781; BioPlex dual cell-line interactome). Reason: Bare protein binding is uninformative. MEK5 is the principal substrate of MEKK3, recruited by PB1-PB1 heterodimerization; the binding is the enzyme-substrate docking step of the ERK5 cascade. Protein kinase binding (GO:0019901) is the informative binding term; the catalytic function is captured by MAP kinase kinase kinase activity (GO:0004709). Consistent with the MAP3K2 review. Proposed replacements: protein kinase binding Supporting Evidence: PMID:10593883 we have identified MEKK3 as a molecule that physically interacts with MEK5 PMID:12912994 the PB1 domain mediates the association of MEKK2 and MEKK3 with MEK5 file:human/MAP3K3/MAP3K3-uniprot.txt Interacts with MAP2K5 and SPAG9 |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | MODIFY | Summary: Interaction of MEKK3 with the 14-3-3 protein YWHAE (14-3-3 epsilon) (PMID:35271311; OpenCell endogenous-tagging interactome). Reason: Bare protein binding is uninformative. The partner is a 14-3-3 protein. MEKK3 binding to 14-3-3 is a targeted, phosphorylation-dependent regulatory interaction: 14-3-3 docks on phospho-Thr294 (restraining TNF-induced NF-kappaB activity) and protects activation-loop phospho-Ser526 from PP2A, and all six 14-3-3 isoforms are recovered with MEKK3 across independent interactome studies. 14-3-3 protein binding (GO:0071889) is the informative term; it is a regulatory property, not a core MEKK3 activity. Consistent with the treatment of the same interactions for MAP3K2. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:18308725 Mutation of Thr(294) to alanine abolished 14-3-3-MEKK3 association PMID:16407301 the association between MEKK3 and 14-3-3 was dependent on Ser526 and prevented dephosphorylation of Ser526 PMID:9452471 The 14-3-3zeta and 14-3-3epsilon isoforms were isolated in a two-hybrid screen for proteins interacting with the N-terminal regulatory domain of MEKK3. |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | MODIFY | Summary: Interaction of MEKK3 with the 14-3-3 protein YWHAZ (14-3-3 zeta/delta) (PMID:35271311; OpenCell endogenous-tagging interactome). Reason: Bare protein binding is uninformative. The partner is a 14-3-3 protein. MEKK3 binding to 14-3-3 is a targeted, phosphorylation-dependent regulatory interaction: 14-3-3 docks on phospho-Thr294 (restraining TNF-induced NF-kappaB activity) and protects activation-loop phospho-Ser526 from PP2A, and all six 14-3-3 isoforms are recovered with MEKK3 across independent interactome studies. 14-3-3 protein binding (GO:0071889) is the informative term; it is a regulatory property, not a core MEKK3 activity. Consistent with the treatment of the same interactions for MAP3K2. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:18308725 Mutation of Thr(294) to alanine abolished 14-3-3-MEKK3 association PMID:16407301 the association between MEKK3 and 14-3-3 was dependent on Ser526 and prevented dephosphorylation of Ser526 PMID:9452471 The 14-3-3zeta and 14-3-3epsilon isoforms were isolated in a two-hybrid screen for proteins interacting with the N-terminal regulatory domain of MEKK3. |
| GO:0005515 protein binding | IPI PMID:36931259 A central chaperone-like role for 14-3-3 proteins in human c... | MODIFY | Summary: Interaction of MEKK3 with the 14-3-3 protein YWHAQ (14-3-3 theta) (PMID:36931259; 14-3-3 client interactome). Reason: Bare protein binding is uninformative. The partner is a 14-3-3 protein. MEKK3 binding to 14-3-3 is a targeted, phosphorylation-dependent regulatory interaction: 14-3-3 docks on phospho-Thr294 (restraining TNF-induced NF-kappaB activity) and protects activation-loop phospho-Ser526 from PP2A, and all six 14-3-3 isoforms are recovered with MEKK3 across independent interactome studies. 14-3-3 protein binding (GO:0071889) is the informative term; it is a regulatory property, not a core MEKK3 activity. Consistent with the treatment of the same interactions for MAP3K2. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:18308725 Mutation of Thr(294) to alanine abolished 14-3-3-MEKK3 association PMID:16407301 the association between MEKK3 and 14-3-3 was dependent on Ser526 and prevented dephosphorylation of Ser526 PMID:9452471 The 14-3-3zeta and 14-3-3epsilon isoforms were isolated in a two-hybrid screen for proteins interacting with the N-terminal regulatory domain of MEKK3. |
| GO:0005515 protein binding | IPI PMID:36931259 A central chaperone-like role for 14-3-3 proteins in human c... | MODIFY | Summary: Interaction of MEKK3 with the 14-3-3 protein YWHAB (14-3-3 beta/alpha) (PMID:36931259; 14-3-3 client interactome). Reason: Bare protein binding is uninformative. The partner is a 14-3-3 protein. MEKK3 binding to 14-3-3 is a targeted, phosphorylation-dependent regulatory interaction: 14-3-3 docks on phospho-Thr294 (restraining TNF-induced NF-kappaB activity) and protects activation-loop phospho-Ser526 from PP2A, and all six 14-3-3 isoforms are recovered with MEKK3 across independent interactome studies. 14-3-3 protein binding (GO:0071889) is the informative term; it is a regulatory property, not a core MEKK3 activity. Consistent with the treatment of the same interactions for MAP3K2. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:18308725 Mutation of Thr(294) to alanine abolished 14-3-3-MEKK3 association PMID:16407301 the association between MEKK3 and 14-3-3 was dependent on Ser526 and prevented dephosphorylation of Ser526 PMID:9452471 The 14-3-3zeta and 14-3-3epsilon isoforms were isolated in a two-hybrid screen for proteins interacting with the N-terminal regulatory domain of MEKK3. |
| GO:0005515 protein binding | IPI PMID:36931259 A central chaperone-like role for 14-3-3 proteins in human c... | MODIFY | Summary: Interaction of MEKK3 with the 14-3-3 protein YWHAG (14-3-3 gamma) (PMID:36931259; 14-3-3 client interactome). Reason: Bare protein binding is uninformative. The partner is a 14-3-3 protein. MEKK3 binding to 14-3-3 is a targeted, phosphorylation-dependent regulatory interaction: 14-3-3 docks on phospho-Thr294 (restraining TNF-induced NF-kappaB activity) and protects activation-loop phospho-Ser526 from PP2A, and all six 14-3-3 isoforms are recovered with MEKK3 across independent interactome studies. 14-3-3 protein binding (GO:0071889) is the informative term; it is a regulatory property, not a core MEKK3 activity. Consistent with the treatment of the same interactions for MAP3K2. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:18308725 Mutation of Thr(294) to alanine abolished 14-3-3-MEKK3 association PMID:16407301 the association between MEKK3 and 14-3-3 was dependent on Ser526 and prevented dephosphorylation of Ser526 PMID:9452471 The 14-3-3zeta and 14-3-3epsilon isoforms were isolated in a two-hybrid screen for proteins interacting with the N-terminal regulatory domain of MEKK3. |
| GO:0005515 protein binding | IPI PMID:36931259 A central chaperone-like role for 14-3-3 proteins in human c... | MODIFY | Summary: Interaction of MEKK3 with the 14-3-3 protein YWHAE (14-3-3 epsilon) (PMID:36931259; 14-3-3 client interactome). Reason: Bare protein binding is uninformative. The partner is a 14-3-3 protein. MEKK3 binding to 14-3-3 is a targeted, phosphorylation-dependent regulatory interaction: 14-3-3 docks on phospho-Thr294 (restraining TNF-induced NF-kappaB activity) and protects activation-loop phospho-Ser526 from PP2A, and all six 14-3-3 isoforms are recovered with MEKK3 across independent interactome studies. 14-3-3 protein binding (GO:0071889) is the informative term; it is a regulatory property, not a core MEKK3 activity. Consistent with the treatment of the same interactions for MAP3K2. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:18308725 Mutation of Thr(294) to alanine abolished 14-3-3-MEKK3 association PMID:16407301 the association between MEKK3 and 14-3-3 was dependent on Ser526 and prevented dephosphorylation of Ser526 PMID:9452471 The 14-3-3zeta and 14-3-3epsilon isoforms were isolated in a two-hybrid screen for proteins interacting with the N-terminal regulatory domain of MEKK3. |
| GO:0005515 protein binding | IPI PMID:36931259 A central chaperone-like role for 14-3-3 proteins in human c... | MODIFY | Summary: Interaction of MEKK3 with the 14-3-3 protein YWHAZ (14-3-3 zeta/delta) (PMID:36931259; 14-3-3 client interactome). Reason: Bare protein binding is uninformative. The partner is a 14-3-3 protein. MEKK3 binding to 14-3-3 is a targeted, phosphorylation-dependent regulatory interaction: 14-3-3 docks on phospho-Thr294 (restraining TNF-induced NF-kappaB activity) and protects activation-loop phospho-Ser526 from PP2A, and all six 14-3-3 isoforms are recovered with MEKK3 across independent interactome studies. 14-3-3 protein binding (GO:0071889) is the informative term; it is a regulatory property, not a core MEKK3 activity. Consistent with the treatment of the same interactions for MAP3K2. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:18308725 Mutation of Thr(294) to alanine abolished 14-3-3-MEKK3 association PMID:16407301 the association between MEKK3 and 14-3-3 was dependent on Ser526 and prevented dephosphorylation of Ser526 PMID:9452471 The 14-3-3zeta and 14-3-3epsilon isoforms were isolated in a two-hybrid screen for proteins interacting with the N-terminal regulatory domain of MEKK3. |
| GO:0005515 protein binding | IPI PMID:36931259 A central chaperone-like role for 14-3-3 proteins in human c... | MODIFY | Summary: Interaction of MEKK3 with the 14-3-3 protein YWHAH (14-3-3 eta) (PMID:36931259; 14-3-3 client interactome). Reason: Bare protein binding is uninformative. The partner is a 14-3-3 protein. MEKK3 binding to 14-3-3 is a targeted, phosphorylation-dependent regulatory interaction: 14-3-3 docks on phospho-Thr294 (restraining TNF-induced NF-kappaB activity) and protects activation-loop phospho-Ser526 from PP2A, and all six 14-3-3 isoforms are recovered with MEKK3 across independent interactome studies. 14-3-3 protein binding (GO:0071889) is the informative term; it is a regulatory property, not a core MEKK3 activity. Consistent with the treatment of the same interactions for MAP3K2. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:18308725 Mutation of Thr(294) to alanine abolished 14-3-3-MEKK3 association PMID:16407301 the association between MEKK3 and 14-3-3 was dependent on Ser526 and prevented dephosphorylation of Ser526 PMID:9452471 The 14-3-3zeta and 14-3-3epsilon isoforms were isolated in a two-hybrid screen for proteins interacting with the N-terminal regulatory domain of MEKK3. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | MODIFY | Summary: Interaction of MEKK3 with the 14-3-3 protein YWHAQ (14-3-3 theta) (PMID:40205054; multimodal cell-map interactome). Reason: Bare protein binding is uninformative. The partner is a 14-3-3 protein. MEKK3 binding to 14-3-3 is a targeted, phosphorylation-dependent regulatory interaction: 14-3-3 docks on phospho-Thr294 (restraining TNF-induced NF-kappaB activity) and protects activation-loop phospho-Ser526 from PP2A, and all six 14-3-3 isoforms are recovered with MEKK3 across independent interactome studies. 14-3-3 protein binding (GO:0071889) is the informative term; it is a regulatory property, not a core MEKK3 activity. Consistent with the treatment of the same interactions for MAP3K2. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:18308725 Mutation of Thr(294) to alanine abolished 14-3-3-MEKK3 association PMID:16407301 the association between MEKK3 and 14-3-3 was dependent on Ser526 and prevented dephosphorylation of Ser526 PMID:9452471 The 14-3-3zeta and 14-3-3epsilon isoforms were isolated in a two-hybrid screen for proteins interacting with the N-terminal regulatory domain of MEKK3. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | MODIFY | Summary: Interaction of MEKK3 with the 14-3-3 protein YWHAB (14-3-3 beta/alpha) (PMID:40205054; multimodal cell-map interactome). Reason: Bare protein binding is uninformative. The partner is a 14-3-3 protein. MEKK3 binding to 14-3-3 is a targeted, phosphorylation-dependent regulatory interaction: 14-3-3 docks on phospho-Thr294 (restraining TNF-induced NF-kappaB activity) and protects activation-loop phospho-Ser526 from PP2A, and all six 14-3-3 isoforms are recovered with MEKK3 across independent interactome studies. 14-3-3 protein binding (GO:0071889) is the informative term; it is a regulatory property, not a core MEKK3 activity. Consistent with the treatment of the same interactions for MAP3K2. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:18308725 Mutation of Thr(294) to alanine abolished 14-3-3-MEKK3 association PMID:16407301 the association between MEKK3 and 14-3-3 was dependent on Ser526 and prevented dephosphorylation of Ser526 PMID:9452471 The 14-3-3zeta and 14-3-3epsilon isoforms were isolated in a two-hybrid screen for proteins interacting with the N-terminal regulatory domain of MEKK3. |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based ATP binding from the protein kinase domain. Reason: MEKK3 is an active ATP-dependent kinase (catalytically inactive K391M mutant fails to autophosphorylate). Correct cofactor-binding annotation, not a core function in itself. Supporting Evidence: PMID:16407301 phosphorylation of Ser526 occurs via autophosphorylation |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT/IBA assignment of cytosol as site of activity. Reason: MEKK3 functions in cytoplasmic signalling complexes (CCM2/CCM complex, p62:TRAF6, TRAF7), consistent with the phylogenetic inference seeded partly from its paralog MEKK2 (Q9Y2U5), which is cytosolic at rest. Supporting Evidence: Reactome:R-HSA-507719 p62, MEKK3 and TRAF6 co-localize in cytoplasmic aggregates |
| GO:0005829 cytosol | TAS Reactome:R-HSA-507719 | ACCEPT | Summary: Reactome placement of the MEKK3:p62:TRAF6 complex in the cytosol. Reason: MEKK3 co-localises with p62 and TRAF6 in cytoplasmic signalling aggregates in IL-1 signalling. Supporting Evidence: Reactome:R-HSA-507719 p62, MEKK3 and TRAF6 co-localize in cytoplasmic aggregates |
| GO:0035556 intracellular signal transduction | IDA PMID:15001576 TRAF7 potentiates MEKK3-induced AP1 and CHOP activation and ... | MODIFY | Summary: Intracellular signal transduction (acts upstream of or within) from TRAF7-potentiated MEKK3-dependent AP1/CHOP activation. Reason: Correct but very general; the experiment measured AP1 and CHOP activation downstream of MEKK3, and AP1 activation by MEKK3 proceeds through its MAP2K substrates (SEK/MKK4-JNK, MEK-ERK). The informative replacement is MAPK cascade (GO:0000165), which MEKK3 already carries by IBA and TAS; the more specific ERK5 cascade is proposed via the ARBA annotation. Proposed replacements: MAPK cascade Supporting Evidence: PMID:9006902 We now demonstrate that MEKK3 activates SEK and MEK, the known kinases targeting SAPK and ERK, respectively. PMID:15001576 TRAF7 specifically interacted with MEKK3 and potentiated MEKK3-mediated AP1 and CHOP activation. |
| GO:0035556 intracellular signal transduction | IEA GO_REF:0000117 | MODIFY | Summary: ARBA machine-learning assignment of intracellular signal transduction. Reason: Correct but uninformative. The best-defined process for MEKK3 is the MEK5-ERK5 cascade, in which MEKK3 performs the MEK5-phosphorylation step (participation, not just requirement): MEKK3 binds MEK5 via PB1 domains, active MEKK3 drives ERK5 through MEK5, and MEKK3 activity is required for growth-factor activation of endogenous ERK5. ERK5 cascade (GO:0070375) is already carried by MAP2K5 and MAPK7, and is proposed identically for MAP3K2. Proposed replacements: ERK5 cascade Supporting Evidence: PMID:10593883 a dominant active form of MEKK3 stimulates BMK1 activity through MEK5 PMID:10593883 MEKK3 activity is required for growth factor mediated cellular activation of endogenous BMK1 PMID:12912994 The free PB1 domain of MEKK2 or MEKK3 functions effectively to inhibit the ERK5 pathway but not the p38 or JNK pathways |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | IEP PMID:12761501 Large-scale identification and characterization of human gen... | ACCEPT | Summary: Positive regulation of canonical NF-kappaB signal transduction from a large-scale cDNA overexpression reporter screen. Reason: The IEP evidence itself (NF-kappaB reporter activation on overexpression) is weak, but the conclusion is strongly supported by loss-of-function data: MEKK3-deficient cells fail to activate IKK/NF-kappaB in response to TNF, IL-1 and LPS, and MEKK3 directly phosphorylates IKK. A real, physiologically important MEKK3 role. Supporting Evidence: PMID:12761501 we identified 299 cDNAs that activate the NF-kappaB pathway PMID:11429546 MEKK3 plays a critical role in TNF-induced NF-kappaB activation PMID:11429546 MEKK3 interacts with RIP and directly phosphorylates IKK PMID:14661019 MEKK3 is crucial for IL-1- and LPS-induced activation of NF-kappaB and JNK-p38 but not ERK |
| GO:0046777 protein autophosphorylation | IDA PMID:15001576 TRAF7 potentiates MEKK3-induced AP1 and CHOP activation and ... | ACCEPT | Summary: Protein autophosphorylation (acts upstream of or within) from the TRAF7-MEKK3 study. Reason: MEKK3 autophosphorylates its activation-loop Ser526, a modification required for its activity; the catalytically inactive mutant is not phosphorylated at this site. Autophosphorylation is a genuine, regulatory property of MEKK3. Supporting Evidence: PMID:16407301 phosphorylation of Ser526 occurs via autophosphorylation PMID:15001576 TRAF7 specifically interacted with MEKK3 and potentiated MEKK3-mediated AP1 and CHOP activation. |
| GO:0106310 protein serine kinase activity | IEA GO_REF:0000116 | ACCEPT | Summary: Rhea-based assignment of protein serine kinase activity (RHEA:17989). Reason: MEKK3 phosphorylates serine residues (activation-loop Ser526 by autophosphorylation; MAP2K activation-loop serines). Supporting Evidence: PMID:16407301 phosphorylation of Ser526 occurs via autophosphorylation PMID:16407301 phosphorylation of Ser526 was required for MKK6 phosphorylation in vitro |
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Download this section (compressed HTML)Q: Human MAP3K3 lacks the blood vessel development annotation that mouse Map3k3 carries (IMP, PMID:10700190, acts_upstream_of_or_within). Should the endothelial MEKK3-MEK5-ERK5-KLF2/4 role be represented for human MAP3K3 through a more specific process (e.g. a flow/shear-stress response term) rather than a broad developmental term?
Q: Does MEKK3 directly phosphorylate IKKbeta as its physiological NF-kappaB output in TNF signalling, or does it act together with other MAP3Ks such as TAK1 in the RIP1/TRAF6 complexes?
Q: Which MEKK3 outputs (MEK5-ERK5 versus MKK3/6-p38, JNK or Hippo LATS1/2) are driven by the CCM-associated I441M variant in endothelium in vivo, and which are responsible for lesion formation?
Experiment: In vitro kinase assays with purified full-length MEKK3 (wild type, K391M, I441M) against MEK5, MKK3, MKK6, MKK4, MEK1, IKKbeta and LATS1 to establish direct substrate preference and the effect of the I441M variant.
Experiment: Endothelial-specific MAP3K3 knockout or PB1-mutant knock-in with phospho-MEK5/ERK5, KLF2/KLF4 and shear-response readouts, compared with MAP3K2 loss, to separate paralog-specific from redundant functions.
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