MAP3K2 (MEKK2) is a STE11-family serine/threonine protein kinase of the MAP kinase kinase kinase (MAP3K) tier. It has an N-terminal PB1 domain, a regulatory linker and a C-terminal kinase domain that is about 94% identical to that of its paralog MEKK3. MEKK2 phosphorylates and activates MAP kinase kinases on their activation loops. Its best-established substrate is MEK5 (MAP2K5): the PB1 domains of MEKK2 and MEK5 heterodimerize, and MEKK2 phosphorylates MEK5 on Ser311/Thr315 to drive the MEK5-ERK5 (BMK1) cascade. MEKK2 can also phosphorylate MKK6 (p38 pathway) and, depending on cell type, MKK7 (JNK pathway) and MEK1. Activation involves dimerization through an alphaG-helix surface and trans-autophosphorylation of the activation loop (Ser519). Activity and abundance are tuned by phospho-Thr283-dependent 14-3-3 binding, binding of the kinase STK38, SMYD3 methylation, and ubiquitination and degradation by the E3 ligases CHIP (STUB1) and NEDD4L. MEKK2 is mainly cytosolic and can enter the nucleus after growth-factor stimulation. It relays signals from the mast-cell IgE receptor, the T-cell receptor (where it is recruited with the adaptor Lad/RIBP), EGF and IL-17 receptors, and hyperosmotic stress. Mekk2-deficient mice are viable and fertile, in contrast to the embryonic lethality of Mekk3 loss.
| 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: MEKK2 is a MAP3K acting at the top of MAPK modules (principally MEK5-ERK5; also MKK7-JNK and MKK6-p38 in some contexts). The general term is correct at the family node; the specific ERK5 cascade (GO:0070375) is proposed via the MODIFY of the IDA intracellular signal transduction annotation. Supporting Evidence: file:human/MAP3K2/MAP3K2-uniprot.txt Regulates the JNK and ERK5 pathways by phosphorylating and activating MAP2K5 and MAP2K7 PMID:11274363 We describe an alternative pathway by which MEKK2 activates MEK5 and big MAP kinase1/extracellular signal-regulated kinase 5 in addition to MKK7 and JNK |
| GO:0004672 protein kinase activity | IDA PMID:15001576 TRAF7 potentiates MEKK3-induced AP1 and CHOP activation and ... | ACCEPT | Summary: Protein kinase activity attributed to MEKK2 from a study of TRAF7 potentiation of MEKK3 signalling. Reason: The cached abstract of PMID:15001576 only describes MEKK3, but the full text (not available here) may have assayed MEKK2 as a comparator; per curation policy the experimental annotation is not overruled. Protein kinase activity is unquestionably correct for MEKK2, which phosphorylates MEK5 and MKK6 in purified and cellular assays; the more informative GO:0004709 is annotated separately. Supporting Evidence: PMID:41318559 we find that MEKK2 efficiently phosphorylates MEK5, but that its inactivation by D483N mutation results in loss of MEK5 phosphorylation PMID:41318559 we find that MEKK2 efficiently phosphorylates MKK6, but that its inactivation by D483N mutation results in loss of MKK6 phosphorylation |
| 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: MEKK2 is an active STE11-family Ser/Thr kinase that phosphorylates activation-loop Ser/Thr residues of MAP2Ks (MEK5 Ser311/Thr315, MKK6 Ser207). Correct, if general. Supporting Evidence: PMID:41318559 we find that MEKK2 efficiently phosphorylates MEK5, but that its inactivation by D483N mutation results in loss of MEK5 phosphorylation PMID:41318559 we find that MEKK2 efficiently phosphorylates MKK6, but that its inactivation by D483N mutation results in loss of MKK6 phosphorylation |
| GO:0004674 protein serine/threonine kinase activity | TAS PMID:8621389 Molecular cloning of mitogen-activated protein/ERK kinase ki... | ACCEPT | Summary: Traceable author statement from the original cloning of MEKK2 and MEKK3. Reason: Blank et al. showed immunoprecipitated MEKK2 phosphorylates the MAP2Ks MEK1 and JNKK, i.e. Ser/Thr kinase activity toward MAP2Ks. Supporting Evidence: PMID:8621389 Immunoprecipitated MEKK 2 phosphorylated the MAP kinase kinases, MEK 1, and JNK kinase. |
| GO:0004709 MAP kinase kinase kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Combined IEA (orthology/EC 2.7.11.25) assignment of MAP kinase kinase kinase activity. Reason: This is the core molecular function of MEKK2: it phosphorylates and activates the MAP2Ks MEK5 and MKK6 (and MKK7/MEK1 in some settings), with direct evidence from purified-protein and cellular kinase assays. Supporting Evidence: PMID:41318559 we find that MEKK2 efficiently phosphorylates MEK5, but that its inactivation by D483N mutation results in loss of MEK5 phosphorylation PMID:41318559 we find that MEKK2 efficiently phosphorylates MKK6, but that its inactivation by D483N mutation results in loss of MKK6 phosphorylation file:human/MAP3K2/MAP3K2-uniprot.txt Regulates the JNK and ERK5 pathways by phosphorylating and activating MAP2K5 and MAP2K7 |
| GO:0005515 protein binding | IPI PMID:15778465 Targeted proteomic analysis of 14-3-3 sigma, a p53 effector ... | MODIFY | Summary: Affinity-purification/mass-spectrometry interaction of MEKK2 with the 14-3-3 isoform SFN (14-3-3 sigma) (PMID:15778465). Reason: Bare protein binding is uninformative. The partner is a 14-3-3 protein; phospho-dependent 14-3-3 docking is a well-documented regulatory mode for MEKK2 and its paralog MEKK3 (14-3-3 binds MEKK2 phospho-Thr283 and restrains Ser519 trans-autophosphorylation, PMID:23963453; for MEKK3 via pThr294/pSer526, PMID:18308725, PMID:16407301), and 14-3-3 isoforms are recovered repeatedly with MEKK2 across independent interactome studies. 14-3-3 protein binding (GO:0071889) captures the specific, recurrent interaction. This is a regulatory property, not a core function. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:23963453 We have found that MEKK2 is regulated through a phosphorylation-dependent association with 14-3-3 PMID:23963453 Enforced binding with 14-3-3 reduced Ser-519 trans-autophosphorylation. PMID:9452471 14-3-3 proteins also interacted with MEKK1 and MEKK2, but not MEKK4. PMID:15778465 The majority of identified proteins contained one or several phosphorylatable 14-3-3-binding sites indicating a potential direct interaction with 14-3-3 sigma. |
| GO:0005515 protein binding | IPI PMID:20588253 CHIP-dependent termination of MEKK2 regulates temporal ERK a... | MODIFY | Summary: Interaction of MEKK2 with the E3 ubiquitin ligase CHIP (STUB1), which targets MEKK2 for degradation to terminate ERK activation during hyperosmotic stress. Reason: Bare protein binding is uninformative. The partner is the E3 ubiquitin ligase CHIP, identified as a binding partner that controls MEKK2 turnover. Ubiquitin protein ligase binding (GO:0031625) describes the interaction; it reflects regulation of MEKK2 (MEKK2 as E3 substrate), not a core activity. Proposed replacements: ubiquitin protein ligase binding Supporting Evidence: PMID:20588253 we identified the E3 ubiquitin ligase carboxyl terminus of Hsc70-interacting protein (CHIP) as a binding partner of MEKK2 |
| GO:0005515 protein binding | IPI PMID:21988832 Toward an understanding of the protein interaction network o... | MODIFY | Summary: Interaction of MEKK2 with its substrate MAP2K5/MEK5 (PMID:21988832). Reason: Bare protein binding is uninformative. MEK5 is the principal physiological substrate of MEKK2, 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 itself is captured by MAP kinase kinase kinase activity (GO:0004709). Proposed replacements: protein kinase binding Supporting Evidence: PMID:12912994 Deletion or mutation of the MEKK2 PB1 domain abolishes MEKK2-MEK5 complexes, demonstrating that the PB1 domain interaction is required for MEKK2-MEK5 interactions PMID:11073940 we have identified MEK5, the MAPK kinase in the big mitogen-activated protein kinase 1 (BMK1)/ERK5 pathway, as a binding partner for MEKK2 |
| GO:0005515 protein binding | IPI PMID:26496610 A human interactome in three quantitative dimensions organiz... | MODIFY | Summary: High-throughput interaction of MEKK2 with the 14-3-3 isoform SFN (14-3-3 sigma) (PMID:26496610). Reason: Bare protein binding is uninformative. The partner is a 14-3-3 protein; phospho-dependent 14-3-3 docking is a well-documented regulatory mode for MEKK2 and its paralog MEKK3 (14-3-3 binds MEKK2 phospho-Thr283 and restrains Ser519 trans-autophosphorylation, PMID:23963453; for MEKK3 via pThr294/pSer526, PMID:18308725, PMID:16407301), and 14-3-3 isoforms are recovered repeatedly with MEKK2 across independent interactome studies. 14-3-3 protein binding (GO:0071889) captures the specific, recurrent interaction. This is a regulatory property, not a core function. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:23963453 We have found that MEKK2 is regulated through a phosphorylation-dependent association with 14-3-3 PMID:23963453 Enforced binding with 14-3-3 reduced Ser-519 trans-autophosphorylation. PMID:9452471 14-3-3 proteins also interacted with MEKK1 and MEKK2, but not MEKK4. |
| GO:0005515 protein binding | IPI PMID:26496610 A human interactome in three quantitative dimensions organiz... | MODIFY | Summary: High-throughput interaction of MEKK2 with the 14-3-3 isoform YWHAE (14-3-3 epsilon) (PMID:26496610). Reason: Bare protein binding is uninformative. The partner is a 14-3-3 protein; phospho-dependent 14-3-3 docking is a well-documented regulatory mode for MEKK2 and its paralog MEKK3 (14-3-3 binds MEKK2 phospho-Thr283 and restrains Ser519 trans-autophosphorylation, PMID:23963453; for MEKK3 via pThr294/pSer526, PMID:18308725, PMID:16407301), and 14-3-3 isoforms are recovered repeatedly with MEKK2 across independent interactome studies. 14-3-3 protein binding (GO:0071889) captures the specific, recurrent interaction. This is a regulatory property, not a core function. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:23963453 We have found that MEKK2 is regulated through a phosphorylation-dependent association with 14-3-3 PMID:23963453 Enforced binding with 14-3-3 reduced Ser-519 trans-autophosphorylation. PMID:9452471 14-3-3 proteins also interacted with MEKK1 and MEKK2, but not MEKK4. |
| GO:0005515 protein binding | IPI PMID:27066749 Structure-Based Design of a Novel SMYD3 Inhibitor that Bridg... | REMOVE | Summary: Interaction of MEKK2 with the lysine methyltransferase SMYD3 (co-crystal of SMYD3 with a MEKK2 substrate peptide). Reason: Bare protein binding is uninformative, and MEKK2 is here the substrate of SMYD3 methylation (Lys260) rather than contributing a binding function of its own; there is no informative MEKK2 molecular-function term for being a methylation substrate. Removal does not imply the interaction is false: the SMYD3-MEKK2 enzyme-substrate relationship is well supported. Supporting Evidence: PMID:27066749 a co-crystal structure of SMYD3 with a MEKK2-peptide substrate bound file:human/MAP3K2/MAP3K2-deep-research-falcon.md In Ras-driven cancer models, the methyltransferase **SMYD3 methylates MAP3K2 Lys260**. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MODIFY | Summary: Interaction of MEKK2 with its substrate MAP2K5/MEK5 (PMID:28514442). Reason: Bare protein binding is uninformative. MEK5 is the principal physiological substrate of MEKK2, 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 itself is captured by MAP kinase kinase kinase activity (GO:0004709). Proposed replacements: protein kinase binding Supporting Evidence: PMID:12912994 Deletion or mutation of the MEKK2 PB1 domain abolishes MEKK2-MEK5 complexes, demonstrating that the PB1 domain interaction is required for MEKK2-MEK5 interactions PMID:11073940 we have identified MEK5, the MAPK kinase in the big mitogen-activated protein kinase 1 (BMK1)/ERK5 pathway, as a binding partner for MEKK2 |
| GO:0005515 protein binding | IPI PMID:31980649 Extensive rewiring of the EGFR network in colorectal cancer ... | MODIFY | Summary: Interaction of MEKK2 with its substrate MAP2K5/MEK5 (PMID:31980649). Reason: Bare protein binding is uninformative. MEK5 is the principal physiological substrate of MEKK2, 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 itself is captured by MAP kinase kinase kinase activity (GO:0004709). Proposed replacements: protein kinase binding Supporting Evidence: PMID:12912994 Deletion or mutation of the MEKK2 PB1 domain abolishes MEKK2-MEK5 complexes, demonstrating that the PB1 domain interaction is required for MEKK2-MEK5 interactions PMID:11073940 we have identified MEK5, the MAPK kinase in the big mitogen-activated protein kinase 1 (BMK1)/ERK5 pathway, as a binding partner for MEKK2 |
| GO:0005515 protein binding | IPI PMID:32707033 Kinase Interaction Network Expands Functional and Disease Ro... | MODIFY | Summary: High-throughput interaction of MEKK2 with the 14-3-3 isoform YWHAE (14-3-3 epsilon) (PMID:32707033). Reason: Bare protein binding is uninformative. The partner is a 14-3-3 protein; phospho-dependent 14-3-3 docking is a well-documented regulatory mode for MEKK2 and its paralog MEKK3 (14-3-3 binds MEKK2 phospho-Thr283 and restrains Ser519 trans-autophosphorylation, PMID:23963453; for MEKK3 via pThr294/pSer526, PMID:18308725, PMID:16407301), and 14-3-3 isoforms are recovered repeatedly with MEKK2 across independent interactome studies. 14-3-3 protein binding (GO:0071889) captures the specific, recurrent interaction. This is a regulatory property, not a core function. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:23963453 We have found that MEKK2 is regulated through a phosphorylation-dependent association with 14-3-3 PMID:23963453 Enforced binding with 14-3-3 reduced Ser-519 trans-autophosphorylation. PMID:9452471 14-3-3 proteins also interacted with MEKK1 and MEKK2, but not MEKK4. |
| GO:0005515 protein binding | IPI PMID:32707033 Kinase Interaction Network Expands Functional and Disease Ro... | MODIFY | Summary: Interaction of MEKK2 with its substrate MAP2K5/MEK5 (PMID:32707033). Reason: Bare protein binding is uninformative. MEK5 is the principal physiological substrate of MEKK2, 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 itself is captured by MAP kinase kinase kinase activity (GO:0004709). Proposed replacements: protein kinase binding Supporting Evidence: PMID:12912994 Deletion or mutation of the MEKK2 PB1 domain abolishes MEKK2-MEK5 complexes, demonstrating that the PB1 domain interaction is required for MEKK2-MEK5 interactions PMID:11073940 we have identified MEK5, the MAPK kinase in the big mitogen-activated protein kinase 1 (BMK1)/ERK5 pathway, as a binding partner for MEKK2 |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MODIFY | Summary: Interaction of MEKK2 with its substrate MAP2K5/MEK5 (PMID:33961781). Reason: Bare protein binding is uninformative. MEK5 is the principal physiological substrate of MEKK2, 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 itself is captured by MAP kinase kinase kinase activity (GO:0004709). Proposed replacements: protein kinase binding Supporting Evidence: PMID:12912994 Deletion or mutation of the MEKK2 PB1 domain abolishes MEKK2-MEK5 complexes, demonstrating that the PB1 domain interaction is required for MEKK2-MEK5 interactions PMID:11073940 we have identified MEK5, the MAPK kinase in the big mitogen-activated protein kinase 1 (BMK1)/ERK5 pathway, as a binding partner for MEKK2 |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | MODIFY | Summary: High-throughput interaction of MEKK2 with the 14-3-3 isoform YWHAE (14-3-3 epsilon) (PMID:35271311). Reason: Bare protein binding is uninformative. The partner is a 14-3-3 protein; phospho-dependent 14-3-3 docking is a well-documented regulatory mode for MEKK2 and its paralog MEKK3 (14-3-3 binds MEKK2 phospho-Thr283 and restrains Ser519 trans-autophosphorylation, PMID:23963453; for MEKK3 via pThr294/pSer526, PMID:18308725, PMID:16407301), and 14-3-3 isoforms are recovered repeatedly with MEKK2 across independent interactome studies. 14-3-3 protein binding (GO:0071889) captures the specific, recurrent interaction. This is a regulatory property, not a core function. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:23963453 We have found that MEKK2 is regulated through a phosphorylation-dependent association with 14-3-3 PMID:23963453 Enforced binding with 14-3-3 reduced Ser-519 trans-autophosphorylation. PMID:9452471 14-3-3 proteins also interacted with MEKK1 and MEKK2, but not MEKK4. |
| GO:0005515 protein binding | IPI PMID:36931259 A central chaperone-like role for 14-3-3 proteins in human c... | MODIFY | Summary: High-throughput interaction of MEKK2 with the 14-3-3 isoform SFN (14-3-3 sigma) (PMID:36931259). Reason: Bare protein binding is uninformative. The partner is a 14-3-3 protein; phospho-dependent 14-3-3 docking is a well-documented regulatory mode for MEKK2 and its paralog MEKK3 (14-3-3 binds MEKK2 phospho-Thr283 and restrains Ser519 trans-autophosphorylation, PMID:23963453; for MEKK3 via pThr294/pSer526, PMID:18308725, PMID:16407301), and 14-3-3 isoforms are recovered repeatedly with MEKK2 across independent interactome studies. 14-3-3 protein binding (GO:0071889) captures the specific, recurrent interaction. This is a regulatory property, not a core function. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:23963453 We have found that MEKK2 is regulated through a phosphorylation-dependent association with 14-3-3 PMID:23963453 Enforced binding with 14-3-3 reduced Ser-519 trans-autophosphorylation. PMID:9452471 14-3-3 proteins also interacted with MEKK1 and MEKK2, but not MEKK4. |
| GO:0005515 protein binding | IPI PMID:36931259 A central chaperone-like role for 14-3-3 proteins in human c... | MODIFY | Summary: High-throughput interaction of MEKK2 with the 14-3-3 isoform YWHAE (14-3-3 epsilon) (PMID:36931259). Reason: Bare protein binding is uninformative. The partner is a 14-3-3 protein; phospho-dependent 14-3-3 docking is a well-documented regulatory mode for MEKK2 and its paralog MEKK3 (14-3-3 binds MEKK2 phospho-Thr283 and restrains Ser519 trans-autophosphorylation, PMID:23963453; for MEKK3 via pThr294/pSer526, PMID:18308725, PMID:16407301), and 14-3-3 isoforms are recovered repeatedly with MEKK2 across independent interactome studies. 14-3-3 protein binding (GO:0071889) captures the specific, recurrent interaction. This is a regulatory property, not a core function. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:23963453 We have found that MEKK2 is regulated through a phosphorylation-dependent association with 14-3-3 PMID:23963453 Enforced binding with 14-3-3 reduced Ser-519 trans-autophosphorylation. PMID:9452471 14-3-3 proteins also interacted with MEKK1 and MEKK2, but not MEKK4. |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based ATP binding from the protein kinase domain and ATP-binding-site signature. Reason: MEKK2 is an active ATP-dependent kinase (kinase-dead D483N control abolishes substrate phosphorylation; ponatinib-bound ATP-site structure). Correct cofactor-binding annotation, not a core function in itself. Supporting Evidence: PMID:41318559 we find that MEKK2 efficiently phosphorylates MEK5, but that its inactivation by D483N mutation results in loss of MEK5 phosphorylation |
| GO:0005634 nucleus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt subcellular-location mapping to nucleus. Reason: MEKK2 is mainly cytosolic at rest but translocates into the nucleus on EGF stimulation, where it can signal to nuclear MEK5. Nuclear localization is stimulus-dependent rather than the principal site of action. Supporting Evidence: PMID:15075238 their upstream activator MEKK2 is localized mainly in the cytosol of resting cells, and translocates into the nucleus upon EGF stimulation |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: Human Protein Atlas immunofluorescence localization to nucleoplasm. Reason: Nuclear MEKK2 is observed, particularly after EGF stimulation, but the predominant resting localization is cytosolic. Retained as a real but non-core location. Supporting Evidence: PMID:15075238 their upstream activator MEKK2 is localized mainly in the cytosol of resting cells, and translocates into the nucleus upon EGF stimulation |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping to cytoplasm. Reason: MEKK2 is localized mainly in the cytosol of resting cells, consistent with its role in cytoplasmic MAPK signalling complexes. Supporting Evidence: PMID:15075238 their upstream activator MEKK2 is localized mainly in the cytosol of resting cells, and translocates into the nucleus upon EGF stimulation |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT/IBA assignment of cytosol as site of activity. Reason: MEKK2 acts as a cytosolic signalling kinase at rest, consistent with the phylogenetic inference; MEKK2 itself appears among the WITH/FROM sources, marking experimental grounding on the target. Supporting Evidence: PMID:15075238 their upstream activator MEKK2 is localized mainly in the cytosol of resting cells, and translocates into the nucleus upon EGF stimulation |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Human Protein Atlas immunofluorescence localization to cytosol. Reason: Concordant with fractionation/imaging showing MEKK2 is mainly cytosolic in resting cells. Supporting Evidence: PMID:15075238 their upstream activator MEKK2 is localized mainly in the cytosol of resting cells, and translocates into the nucleus upon EGF stimulation |
| GO:0019901 protein kinase binding | IPI PMID:17906693 Negative regulation of MEKK1/2 signaling by serine-threonine... | KEEP AS NON CORE | Summary: MEKK2 binds the Ser/Thr kinase STK38 (NDR1) through its catalytic domain; STK38 inhibits MEKK2 activation. Reason: Informative binding term supported by a targeted study: STK38 interacts with the MEKK1/2 catalytic domain and suppresses MEKK2 autophosphorylation. This is a negative-regulatory interaction rather than a core MEKK2 activity. Supporting Evidence: PMID:17906693 STK38 negatively regulates the activation of MEKK1/2 by direct interaction with the catalytic domain of MEKK1/2 |
| GO:0035556 intracellular signal transduction | IDA PMID:14515274 MEF2C regulates c-Jun but not TNF-alpha gene expression in s... | MODIFY | Summary: Intracellular signal transduction based on MEKK2-dependent MEF2C activation via MEK5-ERK5 in mast cells. Reason: The paper defines a specific MEKK2-MEK5-ERK5-MEF2C module; MEKK2-deficient mast cells lose MEF2C phosphorylation. The informative process term is ERK5 cascade (GO:0070375). MEKK2 performs the MEK5-phosphorylation step of this cascade (participation, not mere requirement), and PB1-mediated MEKK2-MEK5 assembly is specifically required for ERK5 activation. Proposed replacements: ERK5 cascade Supporting Evidence: PMID:14515274 these data define an activation module, MEKK2-MEK5-ERK5-MEF2C in the transcriptional activation of c-Jun in mast cells PMID:14515274 it requires sequential activation of the signaling cascade of MEKK2-MEK5-ERK5 PMID:12912994 The free PB1 domain of MEKK2 or MEKK3 functions effectively to inhibit the ERK5 pathway but not the p38 or JNK pathways PMID:11073940 MEKK2 expression stimulates BMK1/ERK5 activity, the downstream substrate for MEK5. |
| GO:0035556 intracellular signal transduction | IEA GO_REF:0000117 | MODIFY | Summary: ARBA machine-learning assignment of intracellular signal transduction. Reason: Correct but uninformative; MEKK2 is an intracellular signalling kinase whose best-defined process is the MEK5-ERK5 cascade, in which it phosphorylates MEK5. Replaced by ERK5 cascade (GO:0070375), consistent with the MODIFY of the IDA annotation to the same term. Proposed replacements: ERK5 cascade Supporting Evidence: file:human/MAP3K2/MAP3K2-uniprot.txt Regulates the JNK and ERK5 pathways by phosphorylating and activating MAP2K5 and MAP2K7 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:0071260 cellular response to mechanical stimulus | IEP PMID:19593445 Expression of the Bcl-2 protein BAD promotes prostate cancer... | UNDECIDED | Summary: UniProt IEP annotation of cellular response to mechanical stimulus citing a paper on BAD in prostate cancer. Reason: The cached full text of PMID:19593445 (Smith et al. 2009, "Expression of the Bcl-2 protein BAD promotes prostate cancer growth") contains no mention of MEKK2/MAP3K2 or of any mechanical stimulus, so the cited paper does not visibly support this annotation; it may reflect an identifier error. Without access to the curator source we do not remove it, but it should not be used as evidence of MEKK2 mechanoresponsiveness. Supporting Evidence: PMID:19593445 BAD, a pro-apoptotic protein of the Bcl-2 family, has recently been identified as an integrator of several anti-apoptotic signaling pathways in prostate cancer cells. |
| GO:0106310 protein serine kinase activity | IEA GO_REF:0000116 | ACCEPT | Summary: Rhea-based assignment of protein serine kinase activity (RHEA:17989). Reason: MEKK2 phosphorylates serine residues in MAP2K activation loops (e.g. MKK6 Ser207, MEK5 Ser311); consistent with the UniProt catalytic-activity annotation. Supporting Evidence: PMID:41318559 we find that MEKK2 efficiently phosphorylates MKK6, but that its inactivation by D483N mutation results in loss of MKK6 phosphorylation |
Loading supporting content…
Download this section (compressed HTML)Q: Under which physiological stimuli is MEKK2, rather than MEKK3, the dominant MAP3K for MEK5-ERK5 activation, given that kinase-inactive MEKK3 but not MEKK2 blocked EGF-induced ERK5 activation in Cos7/HEK293 cells whereas the reverse held in T cells?
Q: Is the MKK7-JNK branch a direct physiological output of MEKK2 only in specific cell types (mast cells), given that Mekk2-/- T cells show enhanced rather than reduced JNK activation?
Q: Does the PMID:19593445 citation for MAP3K2 "cellular response to mechanical stimulus" reflect an identifier error, and is there primary evidence for MEKK2 responding to mechanical stimuli?
Experiment: Quantitative in vitro kinase assays of purified full-length MEKK2 and MEKK3 against MEK5, MKK6, MKK7, MKK4 and MEK1, with and without PB1 mutations, to define relative substrate preference.
Experiment: Endothelial and immune-cell MAP3K2/MAP3K3 single and double knockouts with phospho-MEK5/ERK5, p38 and JNK read-outs to separate paralog-specific from redundant functions.
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)