MAP2K2 (MEK2) is a cytoplasmic dual-specificity protein kinase of the MAP kinase kinase family that acts in the RAF-MEK-ERK cascade. Once activated by RAF phosphorylation of its activation loop, it phosphorylates the threonine and tyrosine of the Thr-Glu-Tyr motif in the activation loop of the ERK1 and ERK2 MAP kinases, relaying growth-factor and mitogen signals to ERK-dependent control of proliferation and differentiation. The horse entry A0A9L0SHX8 is one of several gene-model products of the horse MAP2K2 locus; it retains the N-terminal ERK-docking region and the catalytic core (human residues 1-363) but carries an unrelated 27-residue C-terminal tail in place of the final part of the kinase domain and the C-terminal DVD docking region.
Summary: MEK2 is an ERK1/ERK2-specific MAP2K; MAPK cascade is correct but less specific than the ERK1 and ERK2 cascade.
Reason: PAINT node PTN000684494 (eukaryote-level, human P36507 among the seeds) asserts MAPK cascade, and horse MAP2K2 (PANTHER PTHR47448:SF3, MAP2K2 subfamily) descends from it, so the claim holds. Within the MAP2K family, MEK1/MEK2 activate only ERK1/ERK2 (human MEK2 phosphorylates and activates ERK1, PMID:8388392), so the precise process is GO:0070371 ERK1 and ERK2 cascade, an is_a descendant of GO:0000165, which the human MAP2K2 review accepts. A0A9L0SHX8 is an alternative horse MAP2K2 gene model that retains human MEK2 residues 1-363 (Lys101, Asp194, Ser222/Ser226 conserved) but replaces human 364-400, including the DVD docking region, with an unrelated tail; the row is judged as a claim about the horse MAP2K2 gene product, and the activity of this particular splice form is untested.
Both MEK1 and MEK2 were expressed in Escherichia coli and shown to be able to activate recombinant human ERK1 in vitro. The purified MEK2 protein stimulated threonine and tyrosine phosphorylation on ERK1 and concomitantly activated ERK1 kinase activity more than 100-fold.
file:human/MAP2K2/MAP2K2-uniprot.txt
CC -!- FUNCTION: Catalyzes the concomitant phosphorylation of a threonine and CC a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases. CC Activates the ERK1 and ERK2 MAP kinases (By similarity). Activates BRAF CC in a KSR1 or KSR2-dependent manner; by binding to KSR1 or KSR2 releases CC the inhibitory intramolecular interaction between KSR1 or KSR2 protein CC kinase and N-terminal domains which promotes KSR1 or KSR2-BRAF CC dimerization and BRAF activation (PubMed:29433126). CC {ECO:0000250|UniProtKB:Q63932, ECO:0000269|PubMed:29433126}.
Summary: Nucleotide binding is correct but general; the kinase binds ATP as phosphate donor.
Reason: The conserved glycine-rich loop and Lys101 ATP-binding residue are retained in this model; ATP binding (GO:0005524, also annotated to this entry) is the specific supported term.
Summary: Protein kinase activity is correct but general; the specific activity is MAP kinase kinase activity.
Reason: MAP kinase kinase activity (GO:0004708, is_a descendant of protein kinase activity) is asserted at PAINT node PTN000684494 from which horse MAP2K2 descends, and is directly shown for human MEK2 (PMID:8388392). A0A9L0SHX8 is an alternative horse MAP2K2 gene model that retains human MEK2 residues 1-363 (Lys101, Asp194, Ser222/Ser226 conserved) but replaces human 364-400, including the DVD docking region, with an unrelated tail; the row is judged as a claim about the horse MAP2K2 gene product, and the activity of this particular splice form is untested.
Both MEK1 and MEK2 were expressed in Escherichia coli and shown to be able to activate recombinant human ERK1 in vitro. The purified MEK2 protein stimulated threonine and tyrosine phosphorylation on ERK1 and concomitantly activated ERK1 kinase activity more than 100-fold.
| A0A9L0SHX8 (target) | 390 | ENSECAT00000136538 | False | 11 | 90.26 | 97.5 | 363 | K D S S L S | 2/8 | 2/31 |
GO:0004674 protein serine/threonine kinase activity
IEA GO_REF:0000120
MODIFY
Summary: Serine/threonine kinase activity captures only half of the dual-specificity MEK2 reaction.
Reason: MEK2 phosphorylates both the threonine and the tyrosine of the ERK activation loop (PMID:8388392). GO:0004708 MAP kinase kinase activity (a child of protein serine/threonine/tyrosine kinase activity, not of GO:0004674) is the accurate term; this is a lateral correction rather than a refinement. A0A9L0SHX8 is an alternative horse MAP2K2 gene model that retains human MEK2 residues 1-363 (Lys101, Asp194, Ser222/Ser226 conserved) but replaces human 364-400, including the DVD docking region, with an unrelated tail; the row is judged as a claim about the horse MAP2K2 gene product, and the activity of this particular splice form is untested.
Both MEK1 and MEK2 were expressed in Escherichia coli and shown to be able to activate recombinant human ERK1 in vitro. The purified MEK2 protein stimulated threonine and tyrosine phosphorylation on ERK1 and concomitantly activated ERK1 kinase activity more than 100-fold.
node PTN000684494 asserts GO:0004708 (F, IBD, negated=false), taxon taxon:2759; 29 seeds; human P36507 among seeds: True
file:human/MAP2K2/MAP2K2-uniprot.txt
CC -!- FUNCTION: Catalyzes the concomitant phosphorylation of a threonine and CC a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases. CC Activates the ERK1 and ERK2 MAP kinases (By similarity). Activates BRAF CC in a KSR1 or KSR2-dependent manner; by binding to KSR1 or KSR2 releases CC the inhibitory intramolecular interaction between KSR1 or KSR2 protein CC kinase and N-terminal domains which promotes KSR1 or KSR2-BRAF CC dimerization and BRAF activation (PubMed:29433126). CC {ECO:0000250|UniProtKB:Q63932, ECO:0000269|PubMed:29433126}.
Summary: Core function: dual-specificity phosphorylation and activation of ERK1/ERK2.
Reason: Horse MAP2K2 is in PANTHER subfamily PTHR47448:SF3 (MAP2K2) and descends from PAINT node PTN000684494, which asserts MAP kinase kinase activity by IBD with human MEK2 among its seeds. Recombinant human MEK2 phosphorylated ERK1 on threonine and tyrosine and activated it >100-fold (PMID:8388392). The catalytic machinery (Lys101, HRD Asp194, activation-loop Ser222/Ser226) and the N-terminal ERK-docking region are conserved in this model. A0A9L0SHX8 is an alternative horse MAP2K2 gene model that retains human MEK2 residues 1-363 (Lys101, Asp194, Ser222/Ser226 conserved) but replaces human 364-400, including the DVD docking region, with an unrelated tail; the row is judged as a claim about the horse MAP2K2 gene product, and the activity of this particular splice form is untested.
Both MEK1 and MEK2 were expressed in Escherichia coli and shown to be able to activate recombinant human ERK1 in vitro. The purified MEK2 protein stimulated threonine and tyrosine phosphorylation on ERK1 and concomitantly activated ERK1 kinase activity more than 100-fold.
| A0A9L0SHX8 (target) | 390 | ENSECAT00000136538 | False | 11 | 90.26 | 97.5 | 363 | K D S S L S | 2/8 | 2/31 |
file:human/MAP2K2/MAP2K2-uniprot.txt
CC -!- FUNCTION: Catalyzes the concomitant phosphorylation of a threonine and CC a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases. CC Activates the ERK1 and ERK2 MAP kinases (By similarity). Activates BRAF CC in a KSR1 or KSR2-dependent manner; by binding to KSR1 or KSR2 releases CC the inhibitory intramolecular interaction between KSR1 or KSR2 protein CC kinase and N-terminal domains which promotes KSR1 or KSR2-BRAF CC dimerization and BRAF activation (PubMed:29433126). CC {ECO:0000250|UniProtKB:Q63932, ECO:0000269|PubMed:29433126}.
Summary: Localization of MEK2 to the mitochondrion is not established for MAP2K2 specifically.
Reason: No PAINT node asserts this term for the MAP2K lineage; the electronic row derives from an ARBA rule whose human training annotations cite a review of compartmentalized ERK signaling (PMID:19565474, abstract only in cache) that does not specify MEK2. I cannot verify whether this is a MEK2 property rather than a MEK1- or ERK-specific one, so the row is left UNDECIDED, consistent with the human MAP2K2 review. Experimentally, human MEK2 is cytoplasmic and peripherally membrane-associated via KSR1.
Supporting Evidence:
file:human/MAP2K2/MAP2K2-uniprot.txt
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:10409742}. Membrane CC {ECO:0000269|PubMed:10409742}; Peripheral membrane protein CC {ECO:0000269|PubMed:10409742}. Note=Membrane localization is probably CC regulated by its interaction with KSR1. {ECO:0000269|PubMed:10409742}.
Summary: Localization of MEK2 to the early endosome is not established for MAP2K2 specifically.
Reason: No PAINT node asserts this term for the MAP2K lineage; the electronic row derives from an ARBA rule whose human training annotations cite a review of compartmentalized ERK signaling (PMID:19565474, abstract only in cache) that does not specify MEK2. I cannot verify whether this is a MEK2 property rather than a MEK1- or ERK-specific one, so the row is left UNDECIDED, consistent with the human MAP2K2 review. Experimentally, human MEK2 is cytoplasmic and peripherally membrane-associated via KSR1.
Supporting Evidence:
file:human/MAP2K2/MAP2K2-uniprot.txt
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:10409742}. Membrane CC {ECO:0000269|PubMed:10409742}; Peripheral membrane protein CC {ECO:0000269|PubMed:10409742}. Note=Membrane localization is probably CC regulated by its interaction with KSR1. {ECO:0000269|PubMed:10409742}.
Summary: Localization of MEK2 to the late endosome is not established for MAP2K2 specifically.
Reason: No PAINT node asserts this term for the MAP2K lineage; the electronic row derives from an ARBA rule whose human training annotations cite a review of compartmentalized ERK signaling (PMID:19565474, abstract only in cache) that does not specify MEK2. I cannot verify whether this is a MEK2 property rather than a MEK1- or ERK-specific one, so the row is left UNDECIDED, consistent with the human MAP2K2 review. Experimentally, human MEK2 is cytoplasmic and peripherally membrane-associated via KSR1.
Supporting Evidence:
file:human/MAP2K2/MAP2K2-uniprot.txt
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:10409742}. Membrane CC {ECO:0000269|PubMed:10409742}; Peripheral membrane protein CC {ECO:0000269|PubMed:10409742}. Note=Membrane localization is probably CC regulated by its interaction with KSR1. {ECO:0000269|PubMed:10409742}.
Summary: Localization of MEK2 to the focal adhesion is not established for MAP2K2 specifically.
Reason: No PAINT node asserts this term for the MAP2K lineage; the electronic row derives from an ARBA rule whose human training annotations cite a review of compartmentalized ERK signaling (PMID:19565474, abstract only in cache) that does not specify MEK2. I cannot verify whether this is a MEK2 property rather than a MEK1- or ERK-specific one, so the row is left UNDECIDED, consistent with the human MAP2K2 review. Experimentally, human MEK2 is cytoplasmic and peripherally membrane-associated via KSR1.
Supporting Evidence:
file:human/MAP2K2/MAP2K2-uniprot.txt
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:10409742}. Membrane CC {ECO:0000269|PubMed:10409742}; Peripheral membrane protein CC {ECO:0000269|PubMed:10409742}. Note=Membrane localization is probably CC regulated by its interaction with KSR1. {ECO:0000269|PubMed:10409742}.
Both MEK1 and MEK2 were expressed in Escherichia coli and shown to be able to activate recombinant human ERK1 in vitro. The purified MEK2 protein stimulated threonine and tyrosine phosphorylation on ERK1 and concomitantly activated ERK1 kinase activity more than 100-fold.
Both MEK1 and MEK2 were expressed in Escherichia coli and shown to be able to activate recombinant human ERK1 in vitro. The purified MEK2 protein stimulated threonine and tyrosine phosphorylation on ERK1 and concomitantly activated ERK1 kinase activity more than 100-fold.
GO:0032872 regulation of stress-activated MAPK cascade
IEA GO_REF:0000117
UNDECIDED
Summary: A role in regulation of a stress-activated MAPK cascade (JNK/p38 branches, whose MAP2Ks are MKK3/4/6/7, not MEK2) is not established for MAP2K2 specifically.
Reason: No PAINT node asserts this term for the MAP2K lineage; the electronic row derives from an ARBA rule whose human training annotations cite a review of compartmentalized ERK signaling (PMID:19565474, abstract only in cache) that does not specify MEK2. I cannot verify whether this is a MEK2 property rather than a MEK1- or ERK-specific one, so the row is left UNDECIDED, consistent with the human MAP2K2 review.
the cascade exhibits versatile and dynamic subcellular distribution
file:human/MAP2K2/MAP2K2-uniprot.txt
CC -!- FUNCTION: Catalyzes the concomitant phosphorylation of a threonine and CC a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases. CC Activates the ERK1 and ERK2 MAP kinases (By similarity). Activates BRAF CC in a KSR1 or KSR2-dependent manner; by binding to KSR1 or KSR2 releases CC the inhibitory intramolecular interaction between KSR1 or KSR2 protein CC kinase and N-terminal domains which promotes KSR1 or KSR2-BRAF CC dimerization and BRAF activation (PubMed:29433126). CC {ECO:0000250|UniProtKB:Q63932, ECO:0000269|PubMed:29433126}.
Summary: A role in regulation of Golgi inheritance is not established for MAP2K2 specifically.
Reason: No PAINT node asserts this term for the MAP2K lineage; the electronic row derives from an ARBA rule whose human training annotations cite a review of compartmentalized ERK signaling (PMID:19565474, abstract only in cache) that does not specify MEK2. I cannot verify whether this is a MEK2 property rather than a MEK1- or ERK-specific one, so the row is left UNDECIDED, consistent with the human MAP2K2 review.
the cascade exhibits versatile and dynamic subcellular distribution
file:human/MAP2K2/MAP2K2-uniprot.txt
CC -!- FUNCTION: Catalyzes the concomitant phosphorylation of a threonine and CC a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases. CC Activates the ERK1 and ERK2 MAP kinases (By similarity). Activates BRAF CC in a KSR1 or KSR2-dependent manner; by binding to KSR1 or KSR2 releases CC the inhibitory intramolecular interaction between KSR1 or KSR2 protein CC kinase and N-terminal domains which promotes KSR1 or KSR2-BRAF CC dimerization and BRAF activation (PubMed:29433126). CC {ECO:0000250|UniProtKB:Q63932, ECO:0000269|PubMed:29433126}.
GO:2000641 regulation of early endosome to late endosome transport
IEA GO_REF:0000117
UNDECIDED
Summary: A role in regulation of early endosome to late endosome transport is not established for MAP2K2 specifically.
Reason: No PAINT node asserts this term for the MAP2K lineage; the electronic row derives from an ARBA rule whose human training annotations cite a review of compartmentalized ERK signaling (PMID:19565474, abstract only in cache) that does not specify MEK2. I cannot verify whether this is a MEK2 property rather than a MEK1- or ERK-specific one, so the row is left UNDECIDED, consistent with the human MAP2K2 review.
the cascade exhibits versatile and dynamic subcellular distribution
file:human/MAP2K2/MAP2K2-uniprot.txt
CC -!- FUNCTION: Catalyzes the concomitant phosphorylation of a threonine and CC a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases. CC Activates the ERK1 and ERK2 MAP kinases (By similarity). Activates BRAF CC in a KSR1 or KSR2-dependent manner; by binding to KSR1 or KSR2 releases CC the inhibitory intramolecular interaction between KSR1 or KSR2 protein CC kinase and N-terminal domains which promotes KSR1 or KSR2-BRAF CC dimerization and BRAF activation (PubMed:29433126). CC {ECO:0000250|UniProtKB:Q63932, ECO:0000269|PubMed:29433126}.
Core Functions
Dual-specificity MAP kinase kinase that phosphorylates the activation-loop threonine and tyrosine of ERK1/ERK2 in the RAF-MEK-ERK cascade. Inferred for the horse MAP2K2 gene product from PAINT node PTN000684494 and human MEK2 biochemistry; the A0A9L0SHX8 model lacks the C-terminal DVD region and its own activity is untested.
Both MEK1 and MEK2 were expressed in Escherichia coli and shown to be able to activate recombinant human ERK1 in vitro. The purified MEK2 protein stimulated threonine and tyrosine phosphorylation on ERK1 and concomitantly activated ERK1 kinase activity more than 100-fold.
Q: Is the horse MAP2K2 transcript ENSECAT00000136538 (A0A9L0SHX8), whose final exon replaces human MEK2 residues 364-400, supported by RNA-seq junction reads, or is it a gene-build artefact? Which horse transcript encodes the human-like 400-residue MEK2?
Q: Should horse MAP2K2 GO annotation be anchored on a corrected full-length gene model (A0A9L0SHX8 residues 1-363 joined to the F6YUU0 C-terminal exon) rather than on the current defective models?
Q: Are the ARBA-propagated endosome, Golgi-inheritance and mitochondrial terms MEK2 properties, or MEK1/ERK properties transferred to MEK2 through review-based TAS annotations?
Suggested Experiments
Experiment: Express full-length horse MEK2 (reconstructed human-like model) and the A0A9L0SHX8 product, co-express with BRAF or RAF1, and compare activation-loop Ser222/Ser226 phosphorylation and phosphorylation of kinase-dead ERK2 in vitro.
Hypothesis: Loss of the end of the kinase domain and the DVD docking site in the A0A9L0SHX8 product abolishes RAF-dependent activation of horse MEK2.
External Prediction Reviews
These computational predictions are reviewed separately from the GOA annotation set used for this review. The assessments below are from this project and do not constitute official GO annotations or endorsement by GO/UniProt. They are not included in the existing annotation review above.
Assessment of 1 ProtNLM GO predictions for the selected horse MAP2K2 protein, using mammalian experimental findings and an explicit comparison of the horse sequence.
Prediction method: ProtNLM2 · Version: UniProt API snapshot 2026-09-08
Review rationale: MAP2K2 (MEK2) is a dual-specificity MAP kinase kinase that itself phosphorylates the threonine and tyrosine of the ERK1/ERK2 activation loop, so the gene product performs protein phosphorylation rather than merely being required for it. Human MEK2 phosphorylates and activates ERK1 in vitro (PMID:8388392), and horse MAP2K2 descends from PAINT node PTN000684494, which asserts MAP kinase kinase activity with human MEK2 among its seeds. A0A9L0SHX8 is an alternative horse MAP2K2 gene model that retains human residues 1-363 with Lys101, Asp194 and Ser222/Ser226 conserved, but carries an unrelated C-terminal tail; the prediction is judged as a claim about the horse MAP2K2 gene product, and the catalytic competence of this particular model is untested. Neither this entry nor any other horse MAP2K2 product (A0A9L0SF07, F6YUU0, A0A9L0R4J0, A0A9L0SD26) carries GO:0006468 or a descendant in GOA; MAPK cascade and ERK1 and ERK2 cascade are signal-transduction terms, not is_a descendants of protein phosphorylation, and the kinase MF terms are in a different aspect. The broad BP is therefore correct and novel. Training-set membership is unknown.
Supporting Evidence:
file:human/MAP2K2/MAP2K2-uniprot.txt: "CC -!- FUNCTION: Catalyzes the concomitant phosphorylation of a threonine and CC a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases. CC Activates the ERK1 and ERK2 MAP kinases (By similarity). Activates BRAF CC in a KSR1 or KSR2-dependent manner; by binding to KSR1 or KSR2 releases CC the inhibitory intramolecular interaction between KSR1 or KSR2 protein CC kinase and N-terminal domains which promotes KSR1 or KSR2-BRAF CC dimerization and BRAF activation (PubMed:29433126). CC {ECO:0000250|UniProtKB:Q63932, ECO:0000269|PubMed:29433126}."
file:HORSE/MAP2K2/MAP2K2-bioinformatics/RESULTS.md: "The horse sequence A0A9L0SHX8 (390 residues) aligns to human P36507 (400 residues) with 90.26% identity across 390 paired residues. Paired coverage is 97.5% of the human sequence and 100.0% of the horse sequence."
PMID:8388392: "Both MEK1 and MEK2 were expressed in Escherichia coli and shown to be able to activate recombinant human ERK1 in vitro. The purified MEK2 protein stimulated threonine and tyrosine phosphorylation on ERK1 and concomitantly activated ERK1 kinase activity more than 100-fold."