Map2k2 (MEK2) is a dual-specificity protein kinase of the STE7/MAP2K family that, together with its paralog Map2k1 (MEK1), forms the middle tier of the RAF-MEK-ERK cascade. Activated by RAF phosphorylation of two activation-loop serines (Ser222 and Ser226), it phosphorylates the threonine and tyrosine of the Thr-Glu-Tyr motif of ERK1 (Mapk3) and ERK2 (Mapk1), activating them. Mouse MEK2 is largely cytosolic, with a pool recruited to membranes by scaffolds such as KSR1, and it forms a heterodimer with MEK1 through which MEK1 feedback phosphorylation tunes the strength and duration of the ERK signal. Mek2-null mice are viable and fertile, because Mek1 compensates; combined loss of Mek1 and Mek2 shows that the MEK tier is required for ERK signalling in placenta, neural crest, respiratory tract, peripheral nervous system and axon growth.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000165 MAPK cascade | IBA GO_REF:0000033 | MODIFY | Summary: IBA from PAINT node PTN000684494, the MAP2K node spanning yeast, fly, worm and vertebrate MAP2Ks; Map2k2 sits inside it in the MEK2 subfamily PTHR47448:SF3. Reason: The node placement is sound: Map2k2 is a MAP2K in the MEK2 subfamily (PTHR47448:SF3) under the PAINT MAP2K node, and every member acts in a MAPK cascade. For Map2k2 the mouse evidence identifies the cascade: recombinant mouse MEK2 phosphorylates Erk-1 on Thr and Tyr (PMID:8297798) and Mek2 mediates Erk1/Erk2 activation in mouse cells and embryos (PMID:19219045). The term is correct but less specific than supported, so refine to ERK1 and ERK2 cascade (GO:0070371), which this gene already carries (IGI, ISO, IEA rows). Proposed replacements: ERK1 and ERK2 cascade Supporting Evidence: file:mouse/Map2k2/Map2k2-uniprot.txt PTHR47448:SF3; MITOGEN-ACTIVATED PROTEIN KINASE KINASE 2; 1. PMID:8297798 Recombinant MEK2 produced in bacteria phosphorylates a kinase-inactive Erk-1 on tyrosine and threonine, whereas a kinase-inactive mutant MEK2 does not. PMID:19219045 Mek1 and Mek2 (also known as Map2k1 and Map2k2, respectively) are evolutionarily conserved, dual-specificity kinases that mediate Erk1 and Erk2 activation during adhesion and growth factor signaling. |
| GO:0000165 MAPK cascade | IGI PMID:21220101 Specific functions for ERK/MAPK signaling during PNS develop... | MODIFY | Summary: IGI from Mek1fl/fl;Mek2-/- conditional mutants in the developing PNS (Newbern et al. 2011), with Map2k1 as the interacting gene. Reason: The compound Mek1/Mek2 deletion removes MEK1/2 protein and phenocopies Erk1/2 deletion, placing Mek2 (redundantly with Mek1) in the ERK branch of MAPK signalling. The cascade concerned is specifically ERK1/ERK2, so refine to GO:0070371. Proposed replacements: ERK1 and ERK2 cascade Supporting Evidence: PMID:21220101 Mek1fl/fl Mek2-/- Wnt1:Cre (Mek1/2CKO(Wnt1)) mice PMID:21220101 Western blotting of E12.5 Erk1/2CKO(Wnt1) or Mek1/2CKO(Wnt1) DRG lysates shows a near complete loss of ERK1/2 or MEK1/2 protein, respectively |
| GO:0002931 response to ischemia | ISO GO_REF:0000096 | MARK AS OVER ANNOTATED | Summary: ISO transfer from rat Map2k2 (RGD:61888) of response to ischemia. Reason: A tissue-level physiological response, presumably based on altered MEK2 expression or phosphorylation after ischemia in rat. Such observations show that the ERK pathway responds to ischemia, not that MEK2 does work specific to an ischemia response beyond its general ERK-activating kinase role. No mouse evidence; non-informative about Map2k2 function. Supporting Evidence: PMID:19219045 Mek1 and Mek2 (also known as Map2k1 and Map2k2, respectively) are evolutionarily conserved, dual-specificity kinases that mediate Erk1 and Erk2 activation during adhesion and growth factor signaling. |
| GO:0004672 protein kinase activity | IEA GO_REF:0000002 | MODIFY | Summary: InterPro (Ser/Thr kinase active site) mapping to protein kinase activity. Reason: Correct but general. Map2k2 is a dual-specificity MAP kinase kinase: mouse recombinant MEK2 phosphorylates kinase-inactive Erk-1 on tyrosine and threonine and a K101M mutant is inactive (PMID:8297798). Refine to MAP kinase kinase activity (GO:0004708), an is_a descendant via protein serine/threonine/tyrosine kinase activity. Proposed replacements: MAP kinase kinase activity Supporting Evidence: PMID:8297798 Recombinant MEK2 produced in bacteria phosphorylates a kinase-inactive Erk-1 on tyrosine and threonine, whereas a kinase-inactive mutant MEK2 does not. file:mouse/Map2k2/Map2k2-uniprot.txt K->M: Inactivation. |
| GO:0004674 protein serine/threonine kinase activity | ISO PMID:33331896 Merlin cooperates with neurofibromin and Spred1 to suppress ... | MODIFY | Summary: ISO from human MAP2K2 (PMID:33331896), a Merlin/NF1/Spred1 Ras-Erk paper. Reason: MEK2 is a dual-specificity kinase whose physiological substrates are the Thr and Tyr of the ERK TEY motif; protein serine/threonine kinase activity captures only half the reaction and in current GO is not an ancestor of MAP kinase kinase activity. The cached abstract of the source paper does not describe a MEK2 kinase assay. The function itself is experimentally established for the mouse protein (PMID:8297798), so represent it with MAP kinase kinase activity (GO:0004708). Proposed replacements: MAP kinase kinase activity Supporting Evidence: PMID:8297798 Recombinant MEK2 produced in bacteria phosphorylates a kinase-inactive Erk-1 on tyrosine and threonine, whereas a kinase-inactive mutant MEK2 does not. file:mouse/Map2k2/Map2k2-uniprot.txt a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases. |
| GO:0004708 MAP kinase kinase activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA from PAINT node PTN000684494 (MAP2K node). Reason: Map2k2 is inside the PAINT MAP2K clade (PTHR47448:SF3, MEK2 subfamily), with catalytic K101, D194 and the RAF-phosphorylated activation-loop S222/S226 conserved (RESULTS.md). The phylogenetic inference agrees with direct mouse evidence (PMID:8297798). Core function. Supporting Evidence: file:mouse/Map2k2/Map2k2-uniprot.txt PTHR47448:SF3; MITOGEN-ACTIVATED PROTEIN KINASE KINASE 2; 1. file:mouse/Map2k2/Map2k2-bioinformatics/RESULTS.md the residues required for catalysis and for RAF-dependent activation are conserved PMID:8297798 Recombinant MEK2 produced in bacteria phosphorylates a kinase-inactive Erk-1 on tyrosine and threonine, whereas a kinase-inactive mutant MEK2 does not. |
| GO:0004708 MAP kinase kinase activity | IDA PMID:8297798 MEK2 is a kinase related to MEK1 and is differentially expre... | ACCEPT | Summary: Brott et al. 1993 cloned mouse Mek2 and showed recombinant MEK2 phosphorylates kinase-inactive Erk-1 on Tyr and Thr; a kinase-inactive MEK2 mutant does not. Reason: Direct biochemical evidence with the mouse protein for the defining MAP2K reaction (dual Thr/Tyr phosphorylation of an ERK). Core function, experimentally established in this species. Supporting Evidence: PMID:8297798 Recombinant MEK2 produced in bacteria phosphorylates a kinase-inactive Erk-1 on tyrosine and threonine, whereas a kinase-inactive mutant MEK2 does not. |
| GO:0004708 MAP kinase kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: IEA via EC 2.7.12.2 / ARBA combined mapping. Reason: Consistent with direct mouse evidence (PMID:8297798) and the PAINT MAP2K placement. Supporting Evidence: PMID:8297798 Recombinant MEK2 produced in bacteria phosphorylates a kinase-inactive Erk-1 on tyrosine and threonine, whereas a kinase-inactive mutant MEK2 does not. file:mouse/Map2k2/Map2k2-uniprot.txt a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases. |
| GO:0004708 MAP kinase kinase activity | ISO GO_REF:0000096 | ACCEPT | Summary: ISO from rat Map2k2 (RGD:61888). Reason: Rat Map2k2 is the same MEK2 ortholog; consistent with direct mouse evidence (PMID:8297798). Supporting Evidence: PMID:8297798 Recombinant MEK2 produced in bacteria phosphorylates a kinase-inactive Erk-1 on tyrosine and threonine, whereas a kinase-inactive mutant MEK2 does not. |
| GO:0004708 MAP kinase kinase activity | ISO GO_REF:0000119 | ACCEPT | Summary: ISO from human MAP2K2 (P36507), same PANTHER subfamily PTHR47448:SF3. Reason: Human and mouse MEK2 are orthologs in PTHR47448:SF3 (94% identity, RESULTS.md); consistent with direct mouse evidence. Supporting Evidence: file:mouse/Map2k2/Map2k2-uniprot.txt PTHR47448:SF3; MITOGEN-ACTIVATED PROTEIN KINASE KINASE 2; 1. PMID:8297798 Recombinant MEK2 produced in bacteria phosphorylates a kinase-inactive Erk-1 on tyrosine and threonine, whereas a kinase-inactive mutant MEK2 does not. |
| GO:0004712 protein serine/threonine/tyrosine kinase activity | TAS PMID:19565474 The ERK signaling cascade--views from different subcellular ... | MODIFY | Summary: TAS from a review on ERK cascade compartmentalization (Yao & Seger 2009). Reason: Correct but general: MEK2 is a dual-specificity kinase whose substrates are MAP kinases. Refine to MAP kinase kinase activity (GO:0004708), an is_a child of protein serine/threonine/tyrosine kinase activity. Proposed replacements: MAP kinase kinase activity Supporting Evidence: PMID:8297798 Recombinant MEK2 produced in bacteria phosphorylates a kinase-inactive Erk-1 on tyrosine and threonine, whereas a kinase-inactive mutant MEK2 does not. file:mouse/Map2k2/Map2k2-uniprot.txt a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases. |
| GO:0004713 protein tyrosine kinase activity | EXP PMID:10409742 Kinase suppressor of Ras forms a multiprotein signaling comp... | MODIFY | Summary: UniProt EXP annotation from the Rhea-split EC 2.7.12.2 reaction (tyrosine phosphorylation), citing Stewart et al. 1999 (KSR-MEK complex; MEK kinase activity measured). Reason: MEK2 phosphorylates tyrosine only as part of concomitant Thr/Tyr phosphorylation of the MAP kinase TEY motif; it is not a general protein tyrosine kinase. The residue-split Rhea term is better represented by MAP kinase kinase activity (GO:0004708). In current GO this is a lateral rather than strictly descendant refinement. Proposed replacements: MAP kinase kinase activity Supporting Evidence: file:mouse/Map2k2/Map2k2-uniprot.txt a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases. PMID:8297798 Recombinant MEK2 produced in bacteria phosphorylates a kinase-inactive Erk-1 on tyrosine and threonine, whereas a kinase-inactive mutant MEK2 does not. |
| GO:0004713 protein tyrosine kinase activity | IEA GO_REF:0000116 | MODIFY | Summary: IEA from Rhea mapping (RHEA:10596, tyrosine phosphorylation). Reason: MEK2 phosphorylates tyrosine only as part of concomitant Thr/Tyr phosphorylation of the MAP kinase TEY motif; it is not a general protein tyrosine kinase. The residue-split Rhea term is better represented by MAP kinase kinase activity (GO:0004708). In current GO this is a lateral rather than strictly descendant refinement. Proposed replacements: MAP kinase kinase activity Supporting Evidence: file:mouse/Map2k2/Map2k2-uniprot.txt a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases. PMID:8297798 Recombinant MEK2 produced in bacteria phosphorylates a kinase-inactive Erk-1 on tyrosine and threonine, whereas a kinase-inactive mutant MEK2 does not. |
| GO:0004713 protein tyrosine kinase activity | ISO GO_REF:0000119 | MODIFY | Summary: ISO from human MAP2K2 tyrosine kinase activity. Reason: MEK2 phosphorylates tyrosine only as part of concomitant Thr/Tyr phosphorylation of the MAP kinase TEY motif; it is not a general protein tyrosine kinase. The residue-split Rhea term is better represented by MAP kinase kinase activity (GO:0004708). In current GO this is a lateral rather than strictly descendant refinement. Proposed replacements: MAP kinase kinase activity Supporting Evidence: file:mouse/Map2k2/Map2k2-uniprot.txt a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases. PMID:8297798 Recombinant MEK2 produced in bacteria phosphorylates a kinase-inactive Erk-1 on tyrosine and threonine, whereas a kinase-inactive mutant MEK2 does not. |
| GO:0005078 MAP kinase scaffold activity | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: ISO from human MAP2K2 (IMP in human), reflecting the non-catalytic role of MEK bound to KSR in promoting KSR-BRAF dimerization and BRAF activation. Reason: For mouse MEK2 the supporting observations are that mammalian KSR binds MEKs and shifts them into a >700 kDa membrane-associated complex (PMID:10409742) and that active Mek2 bridges Pin1 and BPGAP1 (PMID:20179103). The KSR-dependent BRAF activation is stated by similarity to human in UniProt, not shown for mouse MEK2. A genuine but secondary non-catalytic role; non-core relative to MAP2K catalysis. Supporting Evidence: PMID:10409742 Both nematode and mammalian KSRs are capable of binding to MEKs PMID:20179103 only active Mek2 could bind Pin1, acting as a scaffold to bridge Pin1 and BPGAP1 |
| GO:0005515 protein binding | IPI PMID:17380122 Selective role for RGS12 as a Ras/Raf/MEK scaffold in nerve ... | MODIFY | Summary: IntAct IPI: mouse Map2k2 with Rgs12 (Willard et al. 2007). Reason: Bare protein binding is uninformative. RGS12 acts as a Ras/Raf/MEK scaffold that associates with MEK2 and coordinates prolonged ERK activation, so the interaction is better captured as scaffold protein binding (GO:0097110), which this gene already carries. Proposed replacements: scaffold protein binding Supporting Evidence: PMID:17380122 RGS12 associates with the nerve growth factor (NGF) receptor tyrosine kinase TrkA, activated H-Ras, B-Raf, and MEK2 and facilitates their coordinated signaling to prolonged ERK activation. |
| GO:0005515 protein binding | IPI PMID:20179103 Active Mek2 as a regulatory scaffold that promotes Pin1 bind... | REMOVE | Summary: IntAct IPI: mouse Map2k2 with human BPGAP1 (ARHGAP8 isoform) (Pan et al. 2010). Reason: Bare protein binding is uninformative; the functional content of this paper (active Mek2 bridging Pin1 and BPGAP1) is captured by the molecular adaptor activity row from the same paper. Removal does not dispute the interaction. Supporting Evidence: PMID:20179103 BPGAP1 also interacted with wild-type and constitutively active Mek2, but not with its kinase-dead mutant. |
| GO:0005515 protein binding | IPI PMID:20179103 Active Mek2 as a regulatory scaffold that promotes Pin1 bind... | REMOVE | Summary: IntAct IPI: mouse Map2k2 with human PIN1 (Pan et al. 2010). Reason: Bare protein binding is uninformative; the adaptor role is captured by the molecular adaptor activity row from the same paper. Removal does not dispute the interaction. Supporting Evidence: PMID:20179103 only active Mek2 could bind Pin1, acting as a scaffold to bridge Pin1 and BPGAP1 |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro kinase domain / ATP-binding signature mapping. Reason: True of an active protein kinase (K101 ATP-binding lysine; K101M inactivates, PMID:8297798), but a cofactor property subsumed by the catalytic activity. Supporting Evidence: file:mouse/Map2k2/Map2k2-uniprot.txt K->M: Inactivation. PMID:8297798 Recombinant MEK2 produced in bacteria phosphorylates a kinase-inactive Erk-1 on tyrosine and threonine, whereas a kinase-inactive mutant MEK2 does not. |
| GO:0005524 ATP binding | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: ISO from rat Map2k2. Reason: True of an active protein kinase (K101 ATP-binding lysine; K101M inactivates, PMID:8297798), but a cofactor property subsumed by the catalytic activity. Supporting Evidence: file:mouse/Map2k2/Map2k2-uniprot.txt K->M: Inactivation. |
| GO:0005634 nucleus | TAS PMID:19565474 The ERK signaling cascade--views from different subcellular ... | KEEP AS NON CORE | Summary: TAS from the Yao & Seger 2009 review of ERK cascade compartments. Reason: MEKs are predominantly cytoplasmic but shuttle through the nucleus; the review discusses localization of cascade components without MEK2-specific mouse data in the cached abstract. Kept as a minor, non-core location. Supporting Evidence: PMID:19565474 we discuss the intracellular localizations of different components of the ERK cascade |
| GO:0005737 cytoplasm | EXP PMID:10409742 Kinase suppressor of Ras forms a multiprotein signaling comp... | MODIFY | Summary: UniProt EXP: cytoplasmic localization from Stewart et al. 1999. Reason: Correct but general. The soluble pool of MEK2 is cytosolic (cytosol is carried by ISO and TAS rows in this review); the remainder is membrane-associated via scaffolds such as KSR (kept as membrane). Refine to cytosol (GO:0005829). Proposed replacements: cytosol Supporting Evidence: file:mouse/Map2k2/Map2k2-uniprot.txt Cytoplasm {ECO:0000269|PubMed:10409742}. Membrane PMID:10409742 this results in the appearance of MEK in membrane-associated fractions |
| GO:0005737 cytoplasm | IDA PMID:23920377 Reduction of Nipbl impairs cohesin loading locally and affec... | MODIFY | Summary: IDA (MGI): Mek2 antibody used on mouse cell fractions in a Nipbl/cohesin study (Remeseiro et al. 2013), consistent with a cytoplasmic marker. Reason: Consistent with soluble cytoplasmic MEK2; refine to cytosol (GO:0005829) as for the other cytoplasm rows. Low-information evidence (MEK2 used as a fractionation marker). Proposed replacements: cytosol Supporting Evidence: PMID:23920377 Mek2 (BD, M24520) |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | MODIFY | Summary: IEA from UniProt subcellular location (Cytoplasm). Reason: Correct but general. The soluble pool of MEK2 is cytosolic (cytosol is carried by ISO and TAS rows in this review); the remainder is membrane-associated via scaffolds such as KSR (kept as membrane). Refine to cytosol (GO:0005829). Proposed replacements: cytosol Supporting Evidence: file:mouse/Map2k2/Map2k2-uniprot.txt Cytoplasm {ECO:0000269|PubMed:10409742}. Membrane |
| GO:0005737 cytoplasm | ISO GO_REF:0000119 | MODIFY | Summary: ISO from human MAP2K2. Reason: Correct but general. The soluble pool of MEK2 is cytosolic (cytosol is carried by ISO and TAS rows in this review); the remainder is membrane-associated via scaffolds such as KSR (kept as membrane). Refine to cytosol (GO:0005829). Proposed replacements: cytosol Supporting Evidence: file:mouse/Map2k2/Map2k2-uniprot.txt Cytoplasm {ECO:0000269|PubMed:10409742}. Membrane |
| GO:0005739 mitochondrion | IEA GO_REF:0000117 | UNDECIDED | Summary: ARBA machine-learning rule for mitochondrion. Reason: Localization of ERK-cascade components to mitochondrion is described in reviews of pathway compartmentalization, mostly from MEK1 or pan-MEK1/2 antibodies in non-mouse cells. The cached review abstract does not show MEK2-specific data, and there is no mouse Map2k2 experiment for this location. The ARBA rule is not independent evidence. Undecided pending paralog-specific data. Supporting Evidence: PMID:19565474 we discuss the intracellular localizations of different components of the ERK cascade |
| GO:0005739 mitochondrion | TAS PMID:19565474 The ERK signaling cascade--views from different subcellular ... | UNDECIDED | Summary: TAS from the Yao & Seger 2009 review for mitochondrion. Reason: Localization of ERK-cascade components to mitochondrion is described in reviews of pathway compartmentalization, mostly from MEK1 or pan-MEK1/2 antibodies in non-mouse cells. The cached review abstract does not show MEK2-specific data, and there is no mouse Map2k2 experiment for this location. The ARBA rule is not independent evidence. Undecided pending paralog-specific data. Supporting Evidence: PMID:19565474 we discuss the intracellular localizations of different components of the ERK cascade |
| GO:0005769 early endosome | IEA GO_REF:0000117 | UNDECIDED | Summary: ARBA machine-learning rule for early endosome. Reason: Localization of ERK-cascade components to early endosome is described in reviews of pathway compartmentalization, mostly from MEK1 or pan-MEK1/2 antibodies in non-mouse cells. The cached review abstract does not show MEK2-specific data, and there is no mouse Map2k2 experiment for this location. The ARBA rule is not independent evidence. Undecided pending paralog-specific data. Supporting Evidence: PMID:19565474 we discuss the intracellular localizations of different components of the ERK cascade |
| GO:0005769 early endosome | TAS PMID:19565474 The ERK signaling cascade--views from different subcellular ... | UNDECIDED | Summary: TAS from the Yao & Seger 2009 review for early endosome. Reason: Localization of ERK-cascade components to early endosome is described in reviews of pathway compartmentalization, mostly from MEK1 or pan-MEK1/2 antibodies in non-mouse cells. The cached review abstract does not show MEK2-specific data, and there is no mouse Map2k2 experiment for this location. The ARBA rule is not independent evidence. Undecided pending paralog-specific data. Supporting Evidence: PMID:19565474 we discuss the intracellular localizations of different components of the ERK cascade |
| GO:0005770 late endosome | IEA GO_REF:0000117 | UNDECIDED | Summary: ARBA machine-learning rule for late endosome. Reason: Localization of ERK-cascade components to late endosome is described in reviews of pathway compartmentalization, mostly from MEK1 or pan-MEK1/2 antibodies in non-mouse cells. The cached review abstract does not show MEK2-specific data, and there is no mouse Map2k2 experiment for this location. The ARBA rule is not independent evidence. Undecided pending paralog-specific data. Supporting Evidence: PMID:19565474 we discuss the intracellular localizations of different components of the ERK cascade |
| GO:0005770 late endosome | TAS PMID:19565474 The ERK signaling cascade--views from different subcellular ... | UNDECIDED | Summary: TAS from the Yao & Seger 2009 review for late endosome. Reason: Localization of ERK-cascade components to late endosome is described in reviews of pathway compartmentalization, mostly from MEK1 or pan-MEK1/2 antibodies in non-mouse cells. The cached review abstract does not show MEK2-specific data, and there is no mouse Map2k2 experiment for this location. The ARBA rule is not independent evidence. Undecided pending paralog-specific data. Supporting Evidence: PMID:19565474 we discuss the intracellular localizations of different components of the ERK cascade |
| GO:0005783 endoplasmic reticulum | ISO GO_REF:0000119 | UNDECIDED | Summary: ISO from human MAP2K2 (IDA in human). Reason: Based on a human localization observation not reproduced for mouse MEK2; the human review leaves this undecided. No independent mouse evidence. Supporting Evidence: PMID:19565474 we discuss the intracellular localizations of different components of the ERK cascade |
| GO:0005794 Golgi apparatus | ISO GO_REF:0000119 | UNDECIDED | Summary: ISO from human MAP2K2 (IDA in human). Reason: Golgi association of MEKs is described in pathway reviews (MEK1 and pan-MEK data predominate); no mouse MEK2-specific evidence. Undecided, consistent with the human review. Supporting Evidence: PMID:19565474 we discuss the intracellular localizations of different components of the ERK cascade |
| GO:0005794 Golgi apparatus | TAS PMID:19565474 The ERK signaling cascade--views from different subcellular ... | UNDECIDED | Summary: TAS from the Yao & Seger 2009 review. Reason: Golgi association of MEKs is described in pathway reviews (MEK1 and pan-MEK data predominate); no mouse MEK2-specific evidence. Undecided, consistent with the human review. Supporting Evidence: PMID:19565474 we discuss the intracellular localizations of different components of the ERK cascade |
| GO:0005829 cytosol | ISO GO_REF:0000119 | ACCEPT | Summary: ISO from human MAP2K2 (cytosol, IDA/TAS in human). Reason: The soluble pool of MEK2 is cytosolic, consistent with mouse cytoplasmic localization (PMID:10409742); the main compartment of MEK2 action on ERK. Supporting Evidence: file:mouse/Map2k2/Map2k2-uniprot.txt Cytoplasm {ECO:0000269|PubMed:10409742}. Membrane |
| GO:0005829 cytosol | TAS PMID:19565474 The ERK signaling cascade--views from different subcellular ... | ACCEPT | Summary: TAS from the Yao & Seger 2009 review. Reason: The soluble pool of MEK2 is cytosolic, consistent with mouse cytoplasmic localization (PMID:10409742); the main compartment of MEK2 action on ERK. Supporting Evidence: file:mouse/Map2k2/Map2k2-uniprot.txt Cytoplasm {ECO:0000269|PubMed:10409742}. Membrane PMID:19565474 we discuss the intracellular localizations of different components of the ERK cascade |
| GO:0005874 microtubule | ISO GO_REF:0000119 | UNDECIDED | Summary: ISO from human MAP2K2 (microtubule IDA in human). Reason: Microtubule association is reported for human MEK2 in one study; no mouse evidence and no clear functional context. Undecided, consistent with the human review. Supporting Evidence: PMID:19565474 we discuss the intracellular localizations of different components of the ERK cascade |
| GO:0005911 cell-cell junction | ISO GO_REF:0000119 | UNDECIDED | Summary: ISO from human MAP2K2 (cell-cell junction IDA in human). Reason: A single human localization observation without mouse corroboration; undecided, as in the human review. Supporting Evidence: PMID:19565474 we discuss the intracellular localizations of different components of the ERK cascade |
| GO:0005925 focal adhesion | IEA GO_REF:0000117 | UNDECIDED | Summary: ARBA machine-learning rule for focal adhesion. Reason: Localization of ERK-cascade components to focal adhesion is described in reviews of pathway compartmentalization, mostly from MEK1 or pan-MEK1/2 antibodies in non-mouse cells. The cached review abstract does not show MEK2-specific data, and there is no mouse Map2k2 experiment for this location. The ARBA rule is not independent evidence. Undecided pending paralog-specific data. Supporting Evidence: PMID:19565474 we discuss the intracellular localizations of different components of the ERK cascade |
| GO:0005925 focal adhesion | TAS PMID:19565474 The ERK signaling cascade--views from different subcellular ... | UNDECIDED | Summary: TAS from the Yao & Seger 2009 review for focal adhesion. Reason: Localization of ERK-cascade components to focal adhesion is described in reviews of pathway compartmentalization, mostly from MEK1 or pan-MEK1/2 antibodies in non-mouse cells. The cached review abstract does not show MEK2-specific data, and there is no mouse Map2k2 experiment for this location. The ARBA rule is not independent evidence. Undecided pending paralog-specific data. Supporting Evidence: PMID:19565474 we discuss the intracellular localizations of different components of the ERK cascade |
| GO:0005938 cell cortex | ISO GO_REF:0000096 | UNDECIDED | Summary: ISO from rat Map2k2 (cell cortex). Reason: A rat localization observation with no mouse corroboration; MEK2 is recruited to membrane-proximal scaffolds, so cortical localization is plausible but not established for the mouse protein. Supporting Evidence: PMID:10409742 this results in the appearance of MEK in membrane-associated fractions |
| GO:0006468 protein phosphorylation | IGI PMID:19047410 Phosphoinositide 3-kinase-dependent inhibition of dendritic ... | TOO GENERAL | Summary: IGI (MGI) from a study of Giardia effects on dendritic cell IL-12 that used an ERK1/2 pathway inhibitor; abstract-only in cache. Reason: MEK2 is a protein kinase, so protein phosphorylation is true, but uninformative next to the more specific peptidyl-tyrosine phosphorylation (kept) and the MAP kinase kinase activity and ERK1/ERK2 cascade terms accepted here. The cited study used a pharmacological MEK inhibitor that does not distinguish Mek1 from Mek2, so it adds no Mek2-specific information. Supporting Evidence: PMID:19047410 studies with an extracellular signal-regulated kinase 1/2 pathway inhibitor PMID:8297798 Recombinant MEK2 produced in bacteria phosphorylates a kinase-inactive Erk-1 on tyrosine and threonine, whereas a kinase-inactive mutant MEK2 does not. |
| GO:0006468 protein phosphorylation | ISO GO_REF:0000096 | TOO GENERAL | Summary: ISO from rat Map2k2. Reason: MEK2 is a protein kinase, so protein phosphorylation is true, but uninformative next to the more specific peptidyl-tyrosine phosphorylation (kept) and the MAP kinase kinase activity and ERK1/ERK2 cascade terms accepted here. The cited study used a pharmacological MEK inhibitor that does not distinguish Mek1 from Mek2, so it adds no Mek2-specific information. Supporting Evidence: PMID:8297798 Recombinant MEK2 produced in bacteria phosphorylates a kinase-inactive Erk-1 on tyrosine and threonine, whereas a kinase-inactive mutant MEK2 does not. |
| GO:0007507 heart development | IGI PMID:18952847 Mouse and human phenotypes indicate a critical conserved rol... | KEEP AS NON CORE | Summary: IGI (MGI) from Newbern et al. 2008: Wnt1-Cre neural-crest deletion of Mek1 on a Mek2-null background gives conotruncal, craniofacial and pharyngeal-derivative defects (heart development). Reason: Genetic evidence in mouse that the MEK1/MEK2 tier of the ERK cascade is required in neural crest for heart development; Mek2 acts here redundantly with Mek1 (Mek2-null mice alone are viable and morphologically normal, PMID:12832465). This is an acts-upstream, organismal consequence of ERK signalling rather than Mek2 doing a step specific to heart development. Retained as non-core context; not to be transferred as a core function. Supporting Evidence: PMID:18952847 Inactivation of upstream elements of the ERK cascade (B-Raf and C-Raf, MEK1 and MEK2) or a downstream effector, the transcription factor serum response factor resulted in analogous developmental defects. PMID:12832465 Mek2 mutant mice are viable and fertile, and they do not present flagrant morphological alteration. |
| GO:0009898 cytoplasmic side of plasma membrane | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: ISO from human MAP2K2 (IDA in human). Reason: Consistent with scaffold-mediated (KSR) recruitment of MEK to membranes shown with mouse KSR (PMID:10409742). A context-dependent pool; non-core. Supporting Evidence: PMID:10409742 this results in the appearance of MEK in membrane-associated fractions |
| GO:0010628 positive regulation of gene expression | ISO GO_REF:0000119 | MARK AS OVER ANNOTATED | Summary: ISO from human MAP2K2 (positive regulation of gene expression, IMP with MEK inhibitors in human). Reason: Changes in gene expression are downstream outputs of ERK and its transcription-factor targets; MEK2 does no part of the transcriptional work. Indirect consequence of the ERK cascade. Supporting Evidence: PMID:19219045 Mek1 and Mek2 (also known as Map2k1 and Map2k2, respectively) are evolutionarily conserved, dual-specificity kinases that mediate Erk1 and Erk2 activation during adhesion and growth factor signaling. |
| GO:0010629 negative regulation of gene expression | ISO GO_REF:0000096 | MARK AS OVER ANNOTATED | Summary: ISO from rat Map2k2 (negative regulation of gene expression). Reason: Changes in gene expression are downstream outputs of ERK and its transcription-factor targets; MEK2 does no part of the transcriptional work. Indirect consequence of the ERK cascade. Supporting Evidence: PMID:19219045 Mek1 and Mek2 (also known as Map2k1 and Map2k2, respectively) are evolutionarily conserved, dual-specificity kinases that mediate Erk1 and Erk2 activation during adhesion and growth factor signaling. |
| GO:0014044 Schwann cell development | IEA GO_REF:0000117 | UNDECIDED | Summary: ARBA rule for Schwann cell development. Reason: The ARBA rule appears to have been learned from MGI annotations such as the IMP row from PMID:10704452, which does not appear to involve Map2k2. Undecided pending resolution of that row. Supporting Evidence: PMID:10704452 we employ Cre-loxP technology to introduce erbB2 mutations late in Schwann cell development, using a Krox20-cre allele |
| GO:0014044 Schwann cell development | IMP PMID:10704452 A dual role of erbB2 in myelination and in expansion of the ... | UNDECIDED | Summary: IMP (MGI) citing Garratt et al. 2000 (Krox20-cre conditional erbB2 mutants in Schwann cells). Reason: The cited paper studies Krox20-cre conditional ablation of erbB2 in Schwann cells. The cached full text contains no mention of Mek2, Map2k2 or MEK, and the WITH/FROM field names an allele of Erbb2 (MGI:2177256), not of Map2k2, so this row does not appear to describe a Map2k2 experiment. Because MGI curators may have used information we cannot see, it is not removed; it is left undecided and flagged as a likely gene mis-attribution for MGI to check. ERK1/2 are required for Schwann cell myelination (PMID:21220101), but no mouse experiment removing Mek2 in Schwann cells is available here. Supporting Evidence: PMID:10704452 we employ Cre-loxP technology to introduce erbB2 mutations late in Schwann cell development, using a Krox20-cre allele |
| GO:0016020 membrane | EXP PMID:10409742 Kinase suppressor of Ras forms a multiprotein signaling comp... | KEEP AS NON CORE | Summary: UniProt EXP: membrane (peripheral) from Stewart et al. 1999. Reason: KSR binding shifts MEK into membrane-associated fractions (PMID:10409742); MEK2 is a peripheral membrane protein in a scaffold-dependent pool. The general term is as precise as this fractionation evidence allows. Non-core relative to the cytosolic pool. Supporting Evidence: PMID:10409742 this results in the appearance of MEK in membrane-associated fractions file:mouse/Map2k2/Map2k2-uniprot.txt Cytoplasm {ECO:0000269|PubMed:10409742}. Membrane |
| GO:0016020 membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: IEA from UniProt subcellular location (Membrane). Reason: KSR binding shifts MEK into membrane-associated fractions (PMID:10409742); MEK2 is a peripheral membrane protein in a scaffold-dependent pool. The general term is as precise as this fractionation evidence allows. Non-core relative to the cytosolic pool. Supporting Evidence: file:mouse/Map2k2/Map2k2-uniprot.txt Cytoplasm {ECO:0000269|PubMed:10409742}. Membrane |
| GO:0016020 membrane | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: ISO from human MAP2K2. Reason: KSR binding shifts MEK into membrane-associated fractions (PMID:10409742); MEK2 is a peripheral membrane protein in a scaffold-dependent pool. The general term is as precise as this fractionation evidence allows. Non-core relative to the cytosolic pool. Supporting Evidence: PMID:10409742 this results in the appearance of MEK in membrane-associated fractions |
| GO:0018108 peptidyl-tyrosine phosphorylation | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: ISO from rat Map2k2. Reason: MEK2 phosphorylates the tyrosine of the ERK TEY motif (mouse recombinant MEK2 phosphorylates Erk-1 on tyrosine, PMID:8297798). True, but the informative description is MAP kinase kinase activity within the ERK1/ERK2 cascade; non-core. Supporting Evidence: PMID:8297798 Recombinant MEK2 produced in bacteria phosphorylates a kinase-inactive Erk-1 on tyrosine and threonine, whereas a kinase-inactive mutant MEK2 does not. |
| GO:0030165 PDZ domain binding | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: ISO from human MAP2K2 (DLG1/SAP97 binds the MEK2 C-terminal PDZ-binding motif). Reason: The C-terminal RTAV motif is conserved in mouse Map2k2 (RESULTS.md shows identical C-terminal residues TPTRTAV) and absent from MEK1; no mouse experiment. A paralog-specific recruitment property; non-core. Supporting Evidence: file:mouse/Map2k2/Map2k2-bioinformatics/RESULTS.md Mouse Map2k2 (401 aa) vs human MAP2K2 P36507 (400 aa): 377 identical residues over 400 aligned pairs (identity 0.9425). |
| GO:0030878 thyroid gland development | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA rule for thyroid gland development. Reason: Same claim as the IGI row (PMID:18952847); the ARBA rule adds no independent evidence. Non-core, acts-upstream developmental context. Supporting Evidence: PMID:18952847 Inactivation of upstream elements of the ERK cascade (B-Raf and C-Raf, MEK1 and MEK2) or a downstream effector, the transcription factor serum response factor resulted in analogous developmental defects. |
| GO:0030878 thyroid gland development | IGI PMID:18952847 Mouse and human phenotypes indicate a critical conserved rol... | KEEP AS NON CORE | Summary: IGI (MGI) from Newbern et al. 2008: Wnt1-Cre neural-crest deletion of Mek1 on a Mek2-null background gives conotruncal, craniofacial and pharyngeal-derivative defects (thyroid gland development). Reason: Genetic evidence in mouse that the MEK1/MEK2 tier of the ERK cascade is required in neural crest for thyroid gland development; Mek2 acts here redundantly with Mek1 (Mek2-null mice alone are viable and morphologically normal, PMID:12832465). This is an acts-upstream, organismal consequence of ERK signalling rather than Mek2 doing a step specific to thyroid gland development. Retained as non-core context; not to be transferred as a core function. Supporting Evidence: PMID:18952847 Inactivation of upstream elements of the ERK cascade (B-Raf and C-Raf, MEK1 and MEK2) or a downstream effector, the transcription factor serum response factor resulted in analogous developmental defects. PMID:12832465 Mek2 mutant mice are viable and fertile, and they do not present flagrant morphological alteration. |
| GO:0032872 regulation of stress-activated MAPK cascade | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: ARBA rule for regulation of stress-activated MAPK cascade. Reason: MEK2 is a MAP2K of the ERK branch; it does not phosphorylate JNK or p38. Any effect on stress-activated cascades would be indirect cross-talk. Over-annotation, consistent with the human review. Supporting Evidence: PMID:19219045 Mek1 and Mek2 (also known as Map2k1 and Map2k2, respectively) are evolutionarily conserved, dual-specificity kinases that mediate Erk1 and Erk2 activation during adhesion and growth factor signaling. |
| GO:0032872 regulation of stress-activated MAPK cascade | TAS PMID:19565474 The ERK signaling cascade--views from different subcellular ... | MARK AS OVER ANNOTATED | Summary: TAS from the Yao & Seger 2009 review. Reason: MEK2 is a MAP2K of the ERK branch; it does not phosphorylate JNK or p38. Any effect on stress-activated cascades would be indirect cross-talk. Over-annotation, consistent with the human review. Supporting Evidence: PMID:19219045 Mek1 and Mek2 (also known as Map2k1 and Map2k2, respectively) are evolutionarily conserved, dual-specificity kinases that mediate Erk1 and Erk2 activation during adhesion and growth factor signaling. |
| GO:0036289 peptidyl-serine autophosphorylation | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: ISO from human MAP2K2 (peptidyl-serine autophosphorylation). Reason: UniProt records low-level autophosphorylation of mouse MEK2 (PMID:19219045). A minor biochemical property; physiological activation is by RAF trans-phosphorylation of S222/S226. Supporting Evidence: file:mouse/Map2k2/Map2k2-uniprot.txt MAP2K1/MEK1. Low levels of autophosphorylation have been observed. |
| GO:0038133 ERBB2-ERBB3 signaling pathway | IDA PMID:24493648 Activation of MAPK overrides the termination of myelin growt... | UNDECIDED | Summary: IDA (MGI) citing Sheean et al. 2014 (Mek1DD gain-of-function in Schwann cells replaces Nrg1/ErbB3 signals). Reason: The experiments use a constitutively active Mek1 allele (Mek1DD, a Map2k1 transgene); the cached full text never mentions Mek2 or Map2k2. Whether Map2k2 itself transduces ErbB2/ErbB3 signals in Schwann cells is not shown here. Not removed because the curator may have used figure data not visible to us; flagged as a possible Map2k1/Map2k2 mis-attribution. Even if correct, Mek2 acts as the generic ERK-activating kinase downstream of the receptor. Supporting Evidence: PMID:24493648 MAP kinase kinase 1 (Mek1) activates MAPK signaling by phosphorylating Erk1 and Erk2. |
| GO:0038133 ERBB2-ERBB3 signaling pathway | IEA GO_REF:0000117 | UNDECIDED | Summary: ARBA rule for ERBB2-ERBB3 signaling pathway. Reason: Same claim as the IDA row from PMID:24493648, which concerns Mek1DD rather than Mek2; ARBA adds no independent evidence. Supporting Evidence: PMID:24493648 MAP kinase kinase 1 (Mek1) activates MAPK signaling by phosphorylating Erk1 and Erk2. |
| GO:0042552 myelination | IEA GO_REF:0000117 | UNDECIDED | Summary: ARBA rule for myelination. Reason: The ARBA rule appears to be learned from MGI IMP rows (PMID:10704452, PMID:18760695) that do not appear to involve Map2k2. Undecided pending resolution of those rows. Supporting Evidence: PMID:18760695 we generated a series of conditional null mutants that completely lack NRG1 beginning at different stages of neural development |
| GO:0042552 myelination | IMP PMID:10704452 A dual role of erbB2 in myelination and in expansion of the ... | UNDECIDED | Summary: IMP (MGI) citing Garratt et al. 2000 (conditional erbB2 mutants). Reason: The cited paper studies Krox20-cre conditional ablation of erbB2 in Schwann cells. The cached full text contains no mention of Mek2, Map2k2 or MEK, and the WITH/FROM field names an allele of Erbb2 (MGI:2177256), not of Map2k2, so this row does not appear to describe a Map2k2 experiment. Because MGI curators may have used information we cannot see, it is not removed; it is left undecided and flagged as a likely gene mis-attribution for MGI to check. ERK1/2 are required for Schwann cell myelination (PMID:21220101), but no mouse experiment removing Mek2 in Schwann cells is available here. Supporting Evidence: PMID:10704452 we employ Cre-loxP technology to introduce erbB2 mutations late in Schwann cell development, using a Krox20-cre allele |
| GO:0042552 myelination | IMP PMID:18760695 Neuregulin-1/ErbB signaling serves distinct functions in mye... | UNDECIDED | Summary: IMP (MGI) citing Brinkmann et al. 2008 (Nrg1/ErbB conditional mutants), WITH Erbb3 allele. Reason: The cited paper studies conditional Nrg1, ErbB3 and ErbB4 mutants in PNS and CNS myelination. The cached full text contains no mention of Mek2, Map2k2 or MEK, and the WITH/FROM field names an allele of Erbb3 (MGI:1929598), not of Map2k2, so this row does not appear to describe a Map2k2 experiment. Because MGI curators may have used information we cannot see, it is not removed; it is left undecided and flagged as a likely gene mis-attribution for MGI to check. ERK1/2 are required for Schwann cell myelination (PMID:21220101), but no mouse experiment removing Mek2 in Schwann cells is available here. Supporting Evidence: PMID:18760695 we generated a series of conditional null mutants that completely lack NRG1 beginning at different stages of neural development |
| GO:0042552 myelination | IMP PMID:18760695 Neuregulin-1/ErbB signaling serves distinct functions in mye... | UNDECIDED | Summary: IMP (MGI) citing Brinkmann et al. 2008, WITH Nrg1 allele. Reason: The cited paper studies conditional Nrg1, ErbB3 and ErbB4 mutants in PNS and CNS myelination. The cached full text contains no mention of Mek2, Map2k2 or MEK, and the WITH/FROM field names an allele of Nrg1 (MGI:2448075), not of Map2k2, so this row does not appear to describe a Map2k2 experiment. Because MGI curators may have used information we cannot see, it is not removed; it is left undecided and flagged as a likely gene mis-attribution for MGI to check. ERK1/2 are required for Schwann cell myelination (PMID:21220101), but no mouse experiment removing Mek2 in Schwann cells is available here. Supporting Evidence: PMID:18760695 we generated a series of conditional null mutants that completely lack NRG1 beginning at different stages of neural development |
| GO:0043539 protein serine/threonine kinase activator activity | ISO GO_REF:0000119 | MODIFY | Summary: ISO from human MAP2K2 (protein serine/threonine kinase activator activity). Reason: MEK2 activates ERK by phosphorylating it, which is its catalytic MAP kinase kinase activity, not a non-catalytic activator activity. The KSR-dependent promotion of BRAF activation is handled under the MAP kinase scaffold activity row. Replace with GO:0004708, matching the human review. Proposed replacements: MAP kinase kinase activity Supporting Evidence: PMID:8297798 Recombinant MEK2 produced in bacteria phosphorylates a kinase-inactive Erk-1 on tyrosine and threonine, whereas a kinase-inactive mutant MEK2 does not. file:mouse/Map2k2/Map2k2-uniprot.txt Activates the ERK1 and ERK2 MAP kinases (PubMed:19219045). |
| GO:0045893 positive regulation of DNA-templated transcription | ISO GO_REF:0000119 | MARK AS OVER ANNOTATED | Summary: ISO from human MAP2K2 (positive regulation of DNA-templated transcription). Reason: Changes in gene expression are downstream outputs of ERK and its transcription-factor targets; MEK2 does no part of the transcriptional work. Indirect consequence of the ERK cascade. Supporting Evidence: PMID:19219045 Mek1 and Mek2 (also known as Map2k1 and Map2k2, respectively) are evolutionarily conserved, dual-specificity kinases that mediate Erk1 and Erk2 activation during adhesion and growth factor signaling. |
| GO:0048009 insulin-like growth factor receptor signaling pathway | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA rule for insulin-like growth factor receptor signaling pathway. Reason: Pharmacological MEK inhibition does not discriminate Mek1 from Mek2, so this shows that the MEK tier participates in IGF-1 receptor-driven ERK signalling rather than a Mek2-specific role. MEK2 as the ERK-activating kinase downstream of IGF1R is biologically plausible. Kept as non-core receptor-pathway context. Supporting Evidence: PMID:21699731 the combined inhibition of both MEK and PI3K ablated macrophage-mediated increases in epithelial growth |
| GO:0048009 insulin-like growth factor receptor signaling pathway | IMP PMID:21699731 Stimulation of neoplastic mouse lung cell proliferation by a... | KEEP AS NON CORE | Summary: IMP (MGI) from Fritz et al. 2011: MEK and PI3K inhibitors block IGF-1-driven proliferation of neoplastic mouse lung cells. Reason: Pharmacological MEK inhibition does not discriminate Mek1 from Mek2, so this shows that the MEK tier participates in IGF-1 receptor-driven ERK signalling rather than a Mek2-specific role. MEK2 as the ERK-activating kinase downstream of IGF1R is biologically plausible. Kept as non-core receptor-pathway context. Supporting Evidence: PMID:21699731 the combined inhibition of both MEK and PI3K ablated macrophage-mediated increases in epithelial growth |
| GO:0048471 perinuclear region of cytoplasm | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: ISO from human MAP2K2. Reason: A human localization observation consistent with the cytoplasmic distribution of MEK2; minor, non-core. Supporting Evidence: file:mouse/Map2k2/Map2k2-uniprot.txt Cytoplasm {ECO:0000269|PubMed:10409742}. Membrane |
| GO:0048538 thymus development | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA rule for thymus development. Reason: Same claim as the IGI row (PMID:18952847); the ARBA rule adds no independent evidence. Note that Mek2-null mice have normal thymocyte development (PMID:12832465); the neural-crest-derived thymus defect requires loss of both Mek genes. Supporting Evidence: PMID:18952847 Inactivation of upstream elements of the ERK cascade (B-Raf and C-Raf, MEK1 and MEK2) or a downstream effector, the transcription factor serum response factor resulted in analogous developmental defects. PMID:12832465 no such involvement was observed for MEK2, which appears to be nonessential for thymocyte differentiation and T-cell-receptor-induced proliferation and apoptosis |
| GO:0048538 thymus development | IGI PMID:18952847 Mouse and human phenotypes indicate a critical conserved rol... | KEEP AS NON CORE | Summary: IGI (MGI) from Newbern et al. 2008: Wnt1-Cre neural-crest deletion of Mek1 on a Mek2-null background gives conotruncal, craniofacial and pharyngeal-derivative defects (thymus development). Reason: Genetic evidence in mouse that the MEK1/MEK2 tier of the ERK cascade is required in neural crest for thymus development; Mek2 acts here redundantly with Mek1 (Mek2-null mice alone are viable and morphologically normal, PMID:12832465). This is an acts-upstream, organismal consequence of ERK signalling rather than Mek2 doing a step specific to thymus development. Retained as non-core context; not to be transferred as a core function. Supporting Evidence: PMID:18952847 Inactivation of upstream elements of the ERK cascade (B-Raf and C-Raf, MEK1 and MEK2) or a downstream effector, the transcription factor serum response factor resulted in analogous developmental defects. PMID:12832465 Mek2 mutant mice are viable and fertile, and they do not present flagrant morphological alteration. |
| GO:0048679 regulation of axon regeneration | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Regulation of axon regeneration: IGI (MGI) from O'Donovan et al. 2014 (kaB-RAF-driven optic nerve regeneration abolished by Mek1/Mek2 loss) or ARBA rule. Reason: In mouse, B-RAF-driven axon regeneration requires MEK1/MEK2, so Mek2 (with Mek1) acts as the obligatory downstream kinase of RAF. This is an acts-upstream genetic dependency in neurons, not a Mek2-specific regenerative function. Non-core. Supporting Evidence: PMID:24733831 Loss of MEK1 and MEK2 abolishes the regeneration driven by kaB-RAF. |
| GO:0048679 regulation of axon regeneration | IGI PMID:24733831 B-RAF kinase drives developmental axon growth and promotes a... | KEEP AS NON CORE | Summary: Regulation of axon regeneration: IGI (MGI) from O'Donovan et al. 2014 (kaB-RAF-driven optic nerve regeneration abolished by Mek1/Mek2 loss) or ARBA rule. Reason: In mouse, B-RAF-driven axon regeneration requires MEK1/MEK2, so Mek2 (with Mek1) acts as the obligatory downstream kinase of RAF. This is an acts-upstream genetic dependency in neurons, not a Mek2-specific regenerative function. Non-core. Supporting Evidence: PMID:24733831 Loss of MEK1 and MEK2 abolishes the regeneration driven by kaB-RAF. |
| GO:0048679 regulation of axon regeneration | IGI PMID:24733831 B-RAF kinase drives developmental axon growth and promotes a... | KEEP AS NON CORE | Summary: Regulation of axon regeneration: IGI (MGI) from O'Donovan et al. 2014 (kaB-RAF-driven optic nerve regeneration abolished by Mek1/Mek2 loss) or ARBA rule. Reason: In mouse, B-RAF-driven axon regeneration requires MEK1/MEK2, so Mek2 (with Mek1) acts as the obligatory downstream kinase of RAF. This is an acts-upstream genetic dependency in neurons, not a Mek2-specific regenerative function. Non-core. Supporting Evidence: PMID:24733831 Loss of MEK1 and MEK2 abolishes the regeneration driven by kaB-RAF. |
| GO:0050772 positive regulation of axonogenesis | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Positive regulation of axonogenesis: IGI (MGI) from O'Donovan et al. 2014 or ARBA rule. Reason: kaB-RAF-driven axon overgrowth in developing sensory neurons is rescued by concomitant elimination of MEK1/2, showing Mek2 (redundantly with Mek1) is the downstream effector. Acts-upstream genetic evidence; non-core. Supporting Evidence: PMID:24733831 This kaB-RAF–driven overgrowth was substantially rescued by concomitant elimination of MEK1/2, the canonical downstream kinases of RAF |
| GO:0050772 positive regulation of axonogenesis | IGI PMID:24733831 B-RAF kinase drives developmental axon growth and promotes a... | KEEP AS NON CORE | Summary: Positive regulation of axonogenesis: IGI (MGI) from O'Donovan et al. 2014 or ARBA rule. Reason: kaB-RAF-driven axon overgrowth in developing sensory neurons is rescued by concomitant elimination of MEK1/2, showing Mek2 (redundantly with Mek1) is the downstream effector. Acts-upstream genetic evidence; non-core. Supporting Evidence: PMID:24733831 This kaB-RAF–driven overgrowth was substantially rescued by concomitant elimination of MEK1/2, the canonical downstream kinases of RAF |
| GO:0050772 positive regulation of axonogenesis | IGI PMID:24733831 B-RAF kinase drives developmental axon growth and promotes a... | KEEP AS NON CORE | Summary: Positive regulation of axonogenesis: IGI (MGI) from O'Donovan et al. 2014 or ARBA rule. Reason: kaB-RAF-driven axon overgrowth in developing sensory neurons is rescued by concomitant elimination of MEK1/2, showing Mek2 (redundantly with Mek1) is the downstream effector. Acts-upstream genetic evidence; non-core. Supporting Evidence: PMID:24733831 This kaB-RAF–driven overgrowth was substantially rescued by concomitant elimination of MEK1/2, the canonical downstream kinases of RAF |
| GO:0060090 molecular adaptor activity | IDA PMID:20179103 Active Mek2 as a regulatory scaffold that promotes Pin1 bind... | KEEP AS NON CORE | Summary: IDA (BHF-UCL) from Pan et al. 2010: active Mek2 bridges Pin1 and BPGAP1. Reason: Shows a non-catalytic regulatory scaffold role of active Mek2 in an overexpression system; a single study, peripheral to MAP2K catalysis. Non-core. Supporting Evidence: PMID:20179103 only active Mek2 could bind Pin1, acting as a scaffold to bridge Pin1 and BPGAP1 |
| GO:0060324 face development | IGI PMID:18952847 Mouse and human phenotypes indicate a critical conserved rol... | KEEP AS NON CORE | Summary: IGI (MGI) from Newbern et al. 2008: Wnt1-Cre neural-crest deletion of Mek1 on a Mek2-null background gives conotruncal, craniofacial and pharyngeal-derivative defects (face development). Reason: Genetic evidence in mouse that the MEK1/MEK2 tier of the ERK cascade is required in neural crest for face development; Mek2 acts here redundantly with Mek1 (Mek2-null mice alone are viable and morphologically normal, PMID:12832465). This is an acts-upstream, organismal consequence of ERK signalling rather than Mek2 doing a step specific to face development. Retained as non-core context; not to be transferred as a core function. Supporting Evidence: PMID:18952847 Inactivation of upstream elements of the ERK cascade (B-Raf and C-Raf, MEK1 and MEK2) or a downstream effector, the transcription factor serum response factor resulted in analogous developmental defects. PMID:12832465 Mek2 mutant mice are viable and fertile, and they do not present flagrant morphological alteration. |
| GO:0060425 lung morphogenesis | IGI PMID:25100655 Crucial requirement of ERK/MAPK signaling in respiratory tra... | KEEP AS NON CORE | Summary: IGI (MGI) from Boucherat et al. 2014: Mek1 deletion on a Mek2-null background in lung mesenchyme/epithelium. Reason: Genetic evidence that the MEK1/MEK2 tier is required for respiratory tract development; Mek2 acts redundantly with Mek1 and organ-level morphogenesis is a downstream consequence of ERK signalling. Abstract-only in cache; deferred to the MGI curator. Non-core. Supporting Evidence: PMID:25100655 we performed tissue-specific deletions of Mek1 function on a Mek2 null background PMID:25100655 Mek mutation in the respiratory epithelium caused lung agenesis, a phenotype resulting from the direct impact of the ERK/MAPK pathway on cell proliferation and survival. |
| GO:0060440 trachea formation | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA rule for trachea formation. Reason: Genetic evidence that the MEK1/MEK2 tier is required for respiratory tract development; Mek2 acts redundantly with Mek1 and organ-level morphogenesis is a downstream consequence of ERK signalling. Abstract-only in cache; deferred to the MGI curator. Non-core. Supporting Evidence: PMID:25100655 we performed tissue-specific deletions of Mek1 function on a Mek2 null background |
| GO:0060440 trachea formation | IGI PMID:25100655 Crucial requirement of ERK/MAPK signaling in respiratory tra... | KEEP AS NON CORE | Summary: IGI (MGI) from Boucherat et al. 2014 (trachea formation). Reason: Genetic evidence that the MEK1/MEK2 tier is required for respiratory tract development; Mek2 acts redundantly with Mek1 and organ-level morphogenesis is a downstream consequence of ERK signalling. Abstract-only in cache; deferred to the MGI curator. Non-core. Supporting Evidence: PMID:25100655 we performed tissue-specific deletions of Mek1 function on a Mek2 null background PMID:25100655 defective tracheal cartilage |
| GO:0060502 epithelial cell proliferation involved in lung morphogenesis | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA rule for epithelial cell proliferation involved in lung morphogenesis. Reason: Genetic evidence that the MEK1/MEK2 tier is required for respiratory tract development; Mek2 acts redundantly with Mek1 and organ-level morphogenesis is a downstream consequence of ERK signalling. Abstract-only in cache; deferred to the MGI curator. Non-core. Supporting Evidence: PMID:25100655 Mek mutation in the respiratory epithelium caused lung agenesis, a phenotype resulting from the direct impact of the ERK/MAPK pathway on cell proliferation and survival. |
| GO:0060502 epithelial cell proliferation involved in lung morphogenesis | IGI PMID:25100655 Crucial requirement of ERK/MAPK signaling in respiratory tra... | KEEP AS NON CORE | Summary: IGI (MGI) from Boucherat et al. 2014 (epithelial cell proliferation involved in lung morphogenesis). Reason: Genetic evidence that the MEK1/MEK2 tier is required for respiratory tract development; Mek2 acts redundantly with Mek1 and organ-level morphogenesis is a downstream consequence of ERK signalling. Abstract-only in cache; deferred to the MGI curator. Non-core. Supporting Evidence: PMID:25100655 Mek mutation in the respiratory epithelium caused lung agenesis, a phenotype resulting from the direct impact of the ERK/MAPK pathway on cell proliferation and survival. |
| GO:0070371 ERK1 and ERK2 cascade | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA rule for ERK1 and ERK2 cascade. Reason: Consistent with direct mouse evidence that Mek2 phosphorylates and activates Erk1/Erk2 (PMID:8297798, PMID:19219045). Core process. Supporting Evidence: PMID:19219045 Mek1 and Mek2 (also known as Map2k1 and Map2k2, respectively) are evolutionarily conserved, dual-specificity kinases that mediate Erk1 and Erk2 activation during adhesion and growth factor signaling. PMID:8297798 Recombinant MEK2 produced in bacteria phosphorylates a kinase-inactive Erk-1 on tyrosine and threonine, whereas a kinase-inactive mutant MEK2 does not. |
| GO:0070371 ERK1 and ERK2 cascade | IGI PMID:25100655 Crucial requirement of ERK/MAPK signaling in respiratory tra... | ACCEPT | Summary: IGI (MGI) from Boucherat et al. 2014 (Mek1/Mek2 compound mutants lose ERK signalling). Reason: Mouse genetic evidence that Mek2 (with Mek1) is required for ERK1/2 activation in vivo; Mek2 is the MAP2K tier of this cascade. Core process. Supporting Evidence: PMID:25100655 we performed tissue-specific deletions of Mek1 function on a Mek2 null background PMID:19219045 Disabling this Erk-proximal negative-feedback step stabilizes the phosphorylation of both Mek2 and Erk in cultured cells and in vivo in Mek1 knockout embryos and mice. |
| GO:0070371 ERK1 and ERK2 cascade | ISO GO_REF:0000119 | ACCEPT | Summary: ISO from human MAP2K2. Reason: Consistent with direct mouse evidence (PMID:19219045). Core process. Supporting Evidence: PMID:19219045 Mek1 and Mek2 (also known as Map2k1 and Map2k2, respectively) are evolutionarily conserved, dual-specificity kinases that mediate Erk1 and Erk2 activation during adhesion and growth factor signaling. file:mouse/Map2k2/Map2k2-uniprot.txt Activates the ERK1 and ERK2 MAP kinases (PubMed:19219045). |
| GO:0071902 positive regulation of protein serine/threonine kinase activity | ISO GO_REF:0000119 | MODIFY | Summary: ISO from human MAP2K2 (positive regulation of protein serine/threonine kinase activity). Reason: Correct but general; the kinase whose activity MEK2 raises is a MAP kinase (ERK1/ERK2). Refine to positive regulation of MAP kinase activity (GO:0043406), an is_a descendant, as in the human review. Proposed replacements: positive regulation of MAP kinase activity Supporting Evidence: file:mouse/Map2k2/Map2k2-uniprot.txt Activates the ERK1 and ERK2 MAP kinases (PubMed:19219045). PMID:8297798 Recombinant MEK2 produced in bacteria phosphorylates a kinase-inactive Erk-1 on tyrosine and threonine, whereas a kinase-inactive mutant MEK2 does not. |
| GO:0090170 regulation of Golgi inheritance | IEA GO_REF:0000117 | UNDECIDED | Summary: Regulation of Golgi inheritance: ARBA rule or TAS from the Yao & Seger 2009 review. Reason: MEK-dependent Golgi fragmentation during mitosis was described mainly for MEK1 and pan-MEK inhibition in non-mouse cells; the cached review abstract gives no MEK2-specific evidence. Undecided, consistent with the human review. Supporting Evidence: PMID:19565474 we discuss the intracellular localizations of different components of the ERK cascade |
| GO:0090170 regulation of Golgi inheritance | TAS PMID:19565474 The ERK signaling cascade--views from different subcellular ... | UNDECIDED | Summary: Regulation of Golgi inheritance: ARBA rule or TAS from the Yao & Seger 2009 review. Reason: MEK-dependent Golgi fragmentation during mitosis was described mainly for MEK1 and pan-MEK inhibition in non-mouse cells; the cached review abstract gives no MEK2-specific evidence. Undecided, consistent with the human review. Supporting Evidence: PMID:19565474 we discuss the intracellular localizations of different components of the ERK cascade |
| GO:0097110 scaffold protein binding | ISO GO_REF:0000119 | ACCEPT | Summary: ISO from human MAP2K2 (scaffold protein binding; KSR1 and other ERK-module scaffolds). Reason: Mammalian KSR binds MEK1 and MEK2 and recruits them into a large membrane-associated complex (PMID:10409742, using murine KSR); RGS12 and MORG1 scaffolds also associate with MEK2/MEK (PMID:17380122, PMID:15118098). Binding to ERK-module scaffolds is integral to how MEK2 is positioned in the cascade. Supporting Evidence: PMID:10409742 Both nematode and mammalian KSRs are capable of binding to MEKs PMID:17380122 RGS12 associates with the nerve growth factor (NGF) receptor tyrosine kinase TrkA, activated H-Ras, B-Raf, and MEK2 and facilitates their coordinated signaling to prolonged ERK activation. |
| GO:0097225 sperm midpiece | ISO GO_REF:0000119 | UNDECIDED | Summary: ISO from human MAP2K2 (sperm midpiece). Reason: Based on a human sperm localization observation; no mouse evidence and no established function of MEK2 in the sperm midpiece. Left undecided. Supporting Evidence: PMID:19565474 we discuss the intracellular localizations of different components of the ERK cascade |
| GO:0097228 sperm principal piece | ISO GO_REF:0000119 | UNDECIDED | Summary: ISO from human MAP2K2 (sperm principal piece). Reason: Based on a human sperm localization observation; no mouse evidence and no established function of MEK2 in the sperm principal piece. Left undecided. Supporting Evidence: PMID:19565474 we discuss the intracellular localizations of different components of the ERK cascade |
| GO:0097229 sperm end piece | ISO GO_REF:0000119 | UNDECIDED | Summary: ISO from human MAP2K2 (sperm end piece). Reason: Based on a human sperm localization observation; no mouse evidence and no established function of MEK2 in the sperm end piece. Left undecided. Supporting Evidence: PMID:19565474 we discuss the intracellular localizations of different components of the ERK cascade |
| GO:0106310 protein serine kinase activity | EXP PMID:10409742 Kinase suppressor of Ras forms a multiprotein signaling comp... | MODIFY | Summary: UniProt EXP from the Rhea-split EC 2.7.12.2 reaction (serine phosphorylation), citing Stewart et al. 1999. Reason: The serine reaction is an artefact of splitting EC 2.7.12.2 by residue type; the physiological substrate residues of MEK2 are the Thr and Tyr of the ERK TEY motif. Represent with MAP kinase kinase activity (GO:0004708), as in the human review (lateral refinement in current GO). Proposed replacements: MAP kinase kinase activity Supporting Evidence: file:mouse/Map2k2/Map2k2-uniprot.txt a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases. PMID:8297798 Recombinant MEK2 produced in bacteria phosphorylates a kinase-inactive Erk-1 on tyrosine and threonine, whereas a kinase-inactive mutant MEK2 does not. |
| GO:0106310 protein serine kinase activity | IEA GO_REF:0000116 | MODIFY | Summary: IEA from Rhea mapping (RHEA:17989, serine phosphorylation). Reason: The serine reaction is an artefact of splitting EC 2.7.12.2 by residue type; the physiological substrate residues of MEK2 are the Thr and Tyr of the ERK TEY motif. Represent with MAP kinase kinase activity (GO:0004708), as in the human review (lateral refinement in current GO). Proposed replacements: MAP kinase kinase activity Supporting Evidence: file:mouse/Map2k2/Map2k2-uniprot.txt a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases. |
| GO:0106310 protein serine kinase activity | ISO GO_REF:0000119 | MODIFY | Summary: ISO from human MAP2K2 (protein serine kinase activity). Reason: The serine reaction is an artefact of splitting EC 2.7.12.2 by residue type; the physiological substrate residues of MEK2 are the Thr and Tyr of the ERK TEY motif. Represent with MAP kinase kinase activity (GO:0004708), as in the human review (lateral refinement in current GO). Proposed replacements: MAP kinase kinase activity Supporting Evidence: file:mouse/Map2k2/Map2k2-uniprot.txt a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases. |
| GO:2000147 positive regulation of cell motility | IDA PMID:20179103 Active Mek2 as a regulatory scaffold that promotes Pin1 bind... | KEEP AS NON CORE | Summary: IDA (BHF-UCL) from Pan et al. 2010: coexpression of BPGAP1 and active Mek2 induces cell migration. Reason: Overexpression-based evidence that active Mek2 promotes BPGAP1-induced migration; a downstream cellular output of ERK/Rho cross-talk. Non-core. Supporting Evidence: PMID:20179103 inhibited cell migration induced by coexpression of BPGAP1 and active Mek2 |
| GO:2000641 regulation of early endosome to late endosome transport | IEA GO_REF:0000117 | UNDECIDED | Summary: Regulation of early endosome to late endosome transport: ARBA rule or TAS from the Yao & Seger 2009 review. Reason: Endosomal ERK-module function (e.g. via the MP1/LAMTOR3 scaffold) has been described mostly for MEK1; no MEK2-specific mouse data. Undecided, consistent with the human review. Supporting Evidence: PMID:19565474 we discuss the intracellular localizations of different components of the ERK cascade |
| GO:2000641 regulation of early endosome to late endosome transport | TAS PMID:19565474 The ERK signaling cascade--views from different subcellular ... | UNDECIDED | Summary: Regulation of early endosome to late endosome transport: ARBA rule or TAS from the Yao & Seger 2009 review. Reason: Endosomal ERK-module function (e.g. via the MP1/LAMTOR3 scaffold) has been described mostly for MEK1; no MEK2-specific mouse data. Undecided, consistent with the human review. Supporting Evidence: PMID:19565474 we discuss the intracellular localizations of different components of the ERK cascade |
Loading supporting content…
Download this section (compressed HTML)Q: MGI IMP rows annotate Map2k2 to myelination and Schwann cell development from PMID:10704452 (erbB2 conditional mutants) and PMID:18760695 (Nrg1/ErbB mutants), with WITH/FROM naming Erbb2, Erbb3 and Nrg1 alleles; neither paper mentions Mek2. Are these gene mis-attributions, and is the ERBB2-ERBB3 signaling IDA from PMID:24493648 (Mek1DD) intended for Map2k1?
Q: Which MEK2 subcellular localizations (endosomes, Golgi, mitochondria, focal adhesions) rest on MEK2-specific data rather than MEK1 or pan-MEK antibodies?
Experiment: Schwann-cell-specific deletion of Mek1 on a Mek2-null background (e.g. Dhh-Cre or P0-Cre), with Mek2 re-expression rescue, to test directly whether the MEK tier, and Mek2 specifically, is required for myelination.
Experiment: Endogenous epitope tagging of Mek2 versus Mek1 in mouse cells, with organelle markers, to establish paralog-specific localization and the role of the Mek2-specific C-terminal PDZ-binding motif.
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)