DUSP6 (MKP-3, PYST1; UniProt Q16828) curation notes

2026-10-01 initial review

Context: reviewed as the representative ERK-specific DUSP for the DUSP/MKP
negative-feedback step (mapk_negative_regulation / dusp_role) in
modules/erk_cascade.yaml (module not edited).

Core biology

• ERK-selective dual-specificity MKP. PMID:8670865
  and PMID:8670865.
• ERK2 docking activates the enzyme. PMID:11239467
• Cytoplasmic via CRM1-dependent NES; shuttles; anchors ERK2 in cytoplasm.
  PMID:15269220;
  PMID:15269220.
• ERK-driven feedback: FGF/ERK/Ets induce transcription.
  PMID:18321244;
  mouse knockout PMID:17164422.
• Endogenous human knockdown (IMP): PMID:18771677.
• ERK phosphorylates DUSP6 (Ser159/Ser197) promoting degradation:
  PMID:15632084.
• Deep research (falcon) also notes 2024 HER2 Y877 dephosphorylation in PDAC models
  (Bulle et al. 2024, not cached, not used for annotation) and BCI inhibitor non-selectivity.

New PMIDs fetched (all resolved from DOIs given in the deep-research report via NCBI
esearch, not guessed): 11239467, 15269220, 17164422, 18321244, 15632084.

Decisions

• Core MF: GO:0017017 MAP kinase tyrosine/serine/threonine phosphatase activity
  (ACCEPT for IBA/IEA/IDA). Generic phosphatase MFs (GO:0004721, GO:0004722,
  GO:0004725, GO:0008138; EXP/IEA/TAS) MODIFY -> GO:0017017. IBA GO:0033550 and
  GO:0008330 ACCEPT (accurate partial descriptions).
• Core BP: GO:0070373 negative regulation of ERK1 and ERK2 cascade (ACCEPT IBA/IEA/IMP).
  GO:0043409 (IDA/IEA) MODIFY -> GO:0070373 (ERK-selective, does not block JNK/p38).
  GO:0000165, GO:0070371 (TAS/IEA) and GO:0007165 (IBA) MODIFY -> GO:0070373:
  DUSP6 terminates rather than propagates the cascade.
• Protein binding IPIs: ERK1/ERK2 partners MODIFY -> GO:0051019 MAP kinase binding
  (docking is functional: specificity, activation, anchoring). APP, PHB2, TXK
  (high-throughput screens) REMOVE as uninformative.
  PMID:18060821 cached abstract is on SpvC lyase and does not mention DUSP6; did not
  REMOVE, deferred to curator (MODIFY to MAPK binding, interaction well established).
• CC: cytoplasm/cytosol ACCEPT; nucleoplasm (Reactome TAS) MARK_AS_OVER_ANNOTATED
  (shuttles but excluded from nucleus at steady state).
• Non-core: positive regulation of apoptotic process (IDA, IBA), regulation of heart
  growth (IBA from mouse Dusp6 MGI:1914853, verified via UniProt Q9DBB1), cell
  differentiation and response to growth factor (IEA from rat).
• response to nitrosative stress (IEP, PMID:10846176): MARK_AS_OVER_ANNOTATED;
  expression/mRNA-stability readout, NO used as survival factor, phosphatase activity
  unaffected. response to xenobiotic stimulus (IEA from rat): REMOVE.
• No NOT (negated) annotations exist in GOA for DUSP6. A possible MF-shaped NOT
  (p38/JNK phosphatase) is raised as a suggested question only.

Module-relevant summary

• Best MF for the erk_cascade DUSP step: GO:0017017.
• PANTHER: PTHR10159 "DUAL SPECIFICITY PROTEIN PHOSPHATASE"; subfamily PTHR10159:SF45
  "DUAL SPECIFICITY PROTEIN PHOSPHATASE 6" (UniProt DR line; names verified in
  interpro/panther/panther.obo; Q16828 not yet in panther-members.tsv index).