DUSP5 is an inducible, nuclear dual-specificity MAP kinase phosphatase (MKP) of the non-receptor dual-specificity subfamily of protein-tyrosine phosphatases. It has an N-terminal rhodanese-like noncatalytic domain that carries a kinase interaction motif (KIM) for ERK binding and an independent nuclear localization signal, and a C-terminal dual-specificity phosphatase domain whose active-site cysteine forms a phosphocysteine intermediate. DUSP5 dephosphorylates the activation-loop phosphothreonine and phosphotyrosine of ERK1/2, inactivating them, and binds and retains inactive ERK2 in the nucleus, so that it acts as an ERK-selective negative feedback regulator of the ERK1/ERK2 MAP kinase cascade; it does not inactivate JNK or p38. Its expression is induced by mitogenic stimulation and heat shock. The donkey protein (384 aa) is a full-length product of the DUSP5 ortholog (PANTHER subfamily PTHR10159:SF40, shared with human and rat DUSP5), 94.8% identical to human DUSP5, with the catalytic Cys263, the N-terminal domain and the nuclear localization signal conserved.
Summary: Endoderm formation, transferred by TreeGrafter from a DUSP family PANTHER node.
Reason: The corresponding human IBA (PAINT node PTN000017039) is grounded in a zebrafish DUSP-family developmental annotation. Endoderm formation is an organismal developmental outcome; an MKP could influence it only indirectly, by attenuating FGF/ERK signalling, which is the regulatory role already captured by negative regulation of the ERK1 and ERK2 cascade. No experiment in mammals places DUSP5 in germ-layer formation, and the characterised mammalian function is nuclear ERK inactivation. The term is therefore retained only as an over-annotation of the donkey protein rather than as a demonstrated process; this judgment does not dispute the PAINT node placement for the donor gene.
We conclude that DUSP5 is an inducible nuclear ERK-specific MAP kinase phosphatase that functions as both an inactivator of and a nuclear anchor for ERK2 in mammalian cells.
Summary: Phosphoprotein phosphatase activity: correct but generic description of the catalytic activity.
Reason: DUSP5 is a phosphoprotein phosphatase (conserved Cys263), but the evidence supports the specific MAP kinase dual-specificity activity GO:0017017, a descendant of this term that the gene already carries.
Dual specificity protein phosphatase; active with phosphotyrosine, phosphoserine and phosphothreonine residues. The highest relative activity is toward ERK1.
This binding determines the substrate specificity of DUSP5 in vivo, as it inactivates ERK2 but not Jun N-terminal protein kinase or p38 MAP kinase.
file:EQUAS/DUSP5/DUSP5-bioinformatics/RESULTS.md
ACT_SITE Phosphocysteine intermediate: human [263] C -> donkey [263] C
GO:0004722 protein serine/threonine phosphatase activity
IEA GO_REF:0000003
MODIFY
Summary: Protein serine/threonine phosphatase activity from the EC 3.1.3.16 mapping.
Reason: DUSP5 does hydrolyse protein phosphothreonine/phosphoserine, but only as part of a dual-specificity reaction on the ERK activation loop; the EC-mapped single-specificity term misrepresents the enzyme class (it is a PTP-family cysteine phosphatase, not a PPP/PPM Ser/Thr phosphatase). GO:0017017 captures both halves of the reaction and the MAP kinase substrate class; it is a lateral rather than descendant replacement.
Dual specificity protein phosphatase; active with phosphotyrosine, phosphoserine and phosphothreonine residues. The highest relative activity is toward ERK1.
Summary: Protein tyrosine phosphatase activity from the EC 3.1.3.48 mapping and UniRule.
Reason: Correct as the phosphotyrosine half of the reaction (conserved PTP-family active-site cysteine), but the enzyme is a dual-specificity MKP; GO:0017017 represents the actual activity, including the phosphothreonine half and the ERK substrate class. Lateral replacement, as GO:0017017 is not a descendant of this term.
Dual specificity protein phosphatase; active with phosphotyrosine, phosphoserine and phosphothreonine residues. The highest relative activity is toward ERK1.
Reason: DUSP5 is an inducible nuclear MKP with a functional NLS in its N-terminal domain; the 22-residue human NLS is fully conserved in the donkey protein, and nuclear residence is required for its ERK2-anchoring function.
We conclude that DUSP5 is an inducible nuclear ERK-specific MAP kinase phosphatase that functions as both an inactivator of and a nuclear anchor for ERK2 in mammalian cells.
file:EQUAS/DUSP5/DUSP5-bioinformatics/RESULTS.md
MOTIF Nuclear localization signal: human [53, 74] RR -> donkey [53, 74] RR; 22 of 22 human residues in this span are identical
Summary: Cytoplasm, transferred by TreeGrafter from a deep MKP-family PANTHER node.
Reason: The cytoplasm assertion comes from a deep PAINT node (human IBA from PTN001605855) whose experimental donors are largely cytoplasmic or nucleocytoplasmic MKPs and yeast/plant/fly relatives. DUSP5 is the clearest case in the family of a lineage-specific nuclear phosphatase: it carries a dedicated NLS, it is described as the nuclear counterpart of the cytoplasmic ERK-specific DUSP6, and human UniProt lists nucleus only. Transient cytoplasmic presence (e.g. after synthesis) is not excluded, so the row is over-annotation rather than demonstrably false.
We conclude that DUSP5 is an inducible nuclear ERK-specific MAP kinase phosphatase that functions as both an inactivator of and a nuclear anchor for ERK2 in mammalian cells.
DUSP5 can thus be regarded as a nuclear equivalent of the cytoplasmic ERK-specific phosphatase MKP-3/DUSP6.
GO:0008138 protein tyrosine/serine/threonine phosphatase activity
IEA GO_REF:0000120
MODIFY
Summary: Protein tyrosine/serine/threonine phosphatase activity (dual-specificity phosphatase).
Reason: Correct and supported by direct assay of human DUSP5 (conserved catalytic domain and Cys263 in donkey), but the substrate class is known: DUSP5 acts on the MAP kinases ERK1/2, so the descendant GO:0017017, which the gene already carries, is the warranted term.
Dual specificity protein phosphatase; active with phosphotyrosine, phosphoserine and phosphothreonine residues. The highest relative activity is toward ERK1.
Dual specificity protein phosphatase; active with phosphotyrosine, phosphoserine and phosphothreonine residues. The highest relative activity is toward ERK1.
file:EQUAS/DUSP5/DUSP5-bioinformatics/RESULTS.md
ACT_SITE Phosphocysteine intermediate: human [263] C -> donkey [263] C
Dual specificity protein phosphatase; active with phosphotyrosine, phosphoserine and phosphothreonine residues. The highest relative activity is toward ERK1.
file:EQUAS/DUSP5/DUSP5-bioinformatics/RESULTS.md
ACT_SITE Phosphocysteine intermediate: human [263] C -> donkey [263] C
Reason: Core activity. Human DUSP5, in the same PANTHER subfamily (PTHR10159:SF40) as the donkey protein, has highest in vitro activity on phospho-ERK1 and selectively inactivates ERK2 (not JNK or p38) in cells through KIM-mediated binding. The donkey protein is a full-length ortholog with the catalytic Cys263 and the N-terminal ERK-binding domain conserved.
Dual specificity protein phosphatase; active with phosphotyrosine, phosphoserine and phosphothreonine residues. The highest relative activity is toward ERK1.
file:EQUAS/DUSP5/DUSP5-bioinformatics/RESULTS.md
ACT_SITE Phosphocysteine intermediate: human [263] C -> donkey [263] C
file:EQUAS/DUSP5/DUSP5-bioinformatics/RESULTS.md
DOMAIN Rhodanese: human [19, 141] AV -> donkey [19, 141] AV; 122 of 123 human residues in this span are identical
Summary: Negative regulation of MAPK cascade (TreeGrafter).
Reason: Correct in essence: DUSP5 terminates MAP kinase signalling by dephosphorylating the kinase. But DUSP5 is ERK-selective (it inactivates ERK2 but not JNK or p38), so the warranted term is the descendant GO:0070373 negative regulation of ERK1 and ERK2 cascade.
We conclude that DUSP5 is an inducible nuclear ERK-specific MAP kinase phosphatase that functions as both an inactivator of and a nuclear anchor for ERK2 in mammalian cells.
GO:0051019 mitogen-activated protein kinase binding
ISS PMID:15713638 Specific inactivation and nuclear anchoring of extracellular...
NEW
Summary: DUSP5 binds ERK2 through the KIM in its N-terminal noncatalytic domain; this binding is a separable, non-catalytic function that anchors inactive ERK2 in the nucleus.
Reason: KIM-mediated ERK binding determines DUSP5 substrate specificity and, independently of catalysis (a catalytically inactive mutant still tethers ERK2), retains ERK2 in the nucleus, so it is a molecular function in its own right and not merely substrate binding. Comparator check: the cytoplasmic ERK-specific paralog DUSP6 is curated to GO:0051019 in this repository for the same KIM-mediated ERK binding. The donkey N-terminal domain is 122/123 identical to human, and the protein lies in the DUSP5 PANTHER subfamily, so the transfer is by orthology.
Here we demonstrate that DUSP5, an inducible nuclear phosphatase, interacts specifically with ERK2 via a kinase interaction motif (KIM) within its amino-terminal noncatalytic domain.
Finally, the use of a catalytically inactive mutant to anchor ERK2 in the nucleus reveals that MEK function is not restricted to the cytoplasmic compartment
file:EQUAS/DUSP5/DUSP5-bioinformatics/RESULTS.md
DOMAIN Rhodanese: human [19, 141] AV -> donkey [19, 141] AV; 122 of 123 human residues in this span are identical
Core Functions
Nuclear dual-specificity phosphatase that dephosphorylates the activation-loop phosphothreonine and phosphotyrosine of ERK1/2, inactivating them, providing ERK-selective negative feedback on the ERK1/ERK2 cascade.
We conclude that DUSP5 is an inducible nuclear ERK-specific MAP kinase phosphatase that functions as both an inactivator of and a nuclear anchor for ERK2 in mammalian cells.
Here we demonstrate that DUSP5, an inducible nuclear phosphatase, interacts specifically with ERK2 via a kinase interaction motif (KIM) within its amino-terminal noncatalytic domain.
Finally, the use of a catalytically inactive mutant to anchor ERK2 in the nucleus reveals that MEK function is not restricted to the cytoplasmic compartment
file:EQUAS/DUSP5/DUSP5-bioinformatics/RESULTS.md
DOMAIN Rhodanese: human [19, 141] AV -> donkey [19, 141] AV; 122 of 123 human residues in this span are identical
Q: Is donkey DUSP5 transcriptionally induced by ERK signalling (as an immediate-early negative feedback gene) in equine cells, as in other mammals?
Q: Should the endoderm formation and cytoplasm assertions at the DUSP-family PAINT nodes be excluded from the DUSP5 subfamily (PTHR10159:SF40), given that DUSP5 is a lineage-specific nuclear MKP?
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 the single ProtNLM2 GO prediction for donkey DUSP5 (A0A8C4MED2), a nuclear dual-specificity MAP kinase phosphatase 94.8% identical to human DUSP5. The prediction, myosin phosphatase activity, is refuted (NPI). ProtNLM2 emitted no function text or subcellular-location output for this accession in the frozen snapshot.
Prediction method: ProtNLM2 · Version: UniProt API snapshot 2026-10-14
Review rationale: GO:0017018 is defined as catalysis of phosphomyosin + H2O = myosin + phosphate, an activity carried out by the PP1c-MYPT1 myosin phosphatase holoenzyme of the PPP family. DUSP5 is a cysteine-based dual-specificity phosphatase of the PTP superfamily whose characterized substrate is ERK; human DUSP5 inactivates ERK2 but not JNK or p38, and its activity is highest toward ERK1. The donkey protein conserves the catalytic Cys263 and is 94.8% identical to human over its full length, so it is expected to share this ERK-directed specificity. No evidence links DUSP5 to myosin dephosphorylation, and the donkey GOA already records the correct MAP kinase tyrosine/serine/threonine phosphatase activity. The one study a PubMed search finds linking DUSP5 to myosin places it upstream, reporting that DUSP5 lowers myosin IIB activation indirectly by inhibiting ERK, which acts through MLCK, rather than by dephosphorylating myosin itself. The prediction assigns a substrate-specific phosphatase activity that belongs to an unrelated enzyme family (PPP-type myosin phosphatase), not to a paralog. No error-type value fits a training-data origin that cannot be shown here, so none is set.
PMID:15713638: "This binding determines the substrate specificity of DUSP5 in vivo, as it inactivates ERK2 but not Jun N-terminal protein kinase or p38 MAP kinase."