Affinage

DUSP12

Dual specificity protein phosphatase 12 · UniProt Q9UNI6

Length
340 aa
Mass
37.7 kDa
Annotated
2026-06-09
20 papers in source corpus 15 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DUSP12 (YVH1) is an evolutionarily conserved dual-specificity phosphatase that operates through a C-terminal cysteine-rich zinc-binding domain to coordinate ribosome biogenesis, cell cycle progression, and stress survival (PMID:19797078, PMID:19797079, PMID:10446167, PMID:41851086, PMID:39868293). Its catalytic domain dephosphorylates both phosphoserine and phosphotyrosine residues in vitro, and the C-terminal zinc finger coordinates 2 mol zinc/mol protein in an arrangement where zinc plays an allosteric role in catalysis and is essential for in vivo function (PMID:10446167, PMID:14698441). In ribosome assembly, the yeast ortholog Yvh1 binds late pre-60S subunits and displaces the placeholder protein Mrt4, an obligatory step that licenses subsequent loading of the P0 (Rpp0) stalk complex; loss of Yvh1 traps Mrt4 on pre-60S particles, delays rRNA processing, blocks subunit export, and impairs nascent protein production, with this function residing in the zinc-binding (RING-finger) domain rather than the phosphatase domain (PMID:19797078, PMID:19797079, PMID:19114459, PMID:36009873). In cell cycle control, the zinc-binding domain is necessary and sufficient to drive G2/M accumulation and protect against senescence, and DUSP12 binds the zinc finger protein ZNF622 (ZPR9) and dephosphorylates it at Ser143 to safeguard cells against ZNF622-mediated, stress-induced apoptosis (PMID:21521943, PMID:41851086, PMID:39868293). In injury and inflammatory contexts, DUSP12 acts as a negative regulator of the ASK1 (MAP3K5)–JNK/p38 cascade, binding ASK1 directly to suppress JNK and p38 activation during hepatic ischemia-reperfusion, endothelial LPS stimulation, and ox-LDL exposure, where its expression is driven by the transcription factor FOXP1; it also engages HSPB8 to promote mitophagy and limit oxidative apoptosis (PMID:32803262, PMID:33811209, PMID:36644958, PMID:37614418).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 1999 High

    Established that human DUSP12/YVH1 is a functional ortholog of yeast Yvh1 and defined its defining structural feature—a novel zinc finger domain essential for activity—making it the first protein-tyrosine phosphatase shown to be regulated by a zinc finger.

    Evidence Yeast complementation, zinc-binding stoichiometry, and domain deletion analysis

    PMID:10446167

    Open questions at the time
    • Did not define the physiological substrate
    • Did not localize the cellular process the zinc finger supports
  2. 2004 Medium

    Demonstrated the enzyme is a genuine dual-specificity phosphatase whose catalysis depends allosterically on zinc, linking the zinc finger directly to catalytic competence in a reconstituted system.

    Evidence Recombinant PfYVH1 in vitro phosphatase assay on phosphoserine/phosphotyrosine, cysteine mutagenesis, zinc stoichiometry, and Co-IP with pescadillo (PfPES)

    PMID:14698441

    Open questions at the time
    • Used Plasmodium ortholog, not human DUSP12
    • Physiological substrate in cells unidentified
    • PfPES interaction not validated in human cells
  3. 2008 Medium

    Placed Yvh1 mechanistically as a 60S ribosome assembly factor and showed the zinc-binding RING domain, not the phosphatase domain, carries this function—decoupling the conserved cellular role from catalytic activity.

    Evidence Polysome profiling, sucrose gradient sedimentation, and domain deletion in yvh1Δ yeast

    PMID:19114459

    Open questions at the time
    • Molecular target on the pre-60S not yet identified at this stage
    • Did not show order of assembly events
  4. 2009 High

    Resolved the step Yvh1 performs in 60S maturation: it displaces the placeholder Mrt4 to permit P0 stalk loading, an obligatory ordered step whose loss delays rRNA processing and blocks subunit export.

    Evidence Two independent labs using co-sedimentation of pre-60S particles, genetic epistasis with Mrt4 bypass alleles, rRNA processing and export assays

    PMID:19797078 PMID:19797079

    Open questions at the time
    • Structural basis of Mrt4 displacement not determined
    • Trigger for Yvh1 release after P0 loading unknown
  5. 2011 Medium

    Extended Yvh1 function beyond ribosome assembly to downstream cellular outputs (glycogen accumulation, mRNA decay, sporulation gene induction) and, in human cells, established a zinc-domain-dependent role in G2/M progression and senescence protection.

    Evidence Mrt4(G68D) suppressor epistasis with phenotypic readouts in yeast; siRNA, overexpression, flow cytometry, and MS phosphosite mapping (Ser335) in human cells

    PMID:21474464 PMID:21521943

    Open questions at the time
    • Mechanism connecting ribosome function to cell cycle phenotypes unclear
    • Ser335 phospho-regulation of localization not mapped to a kinase
  6. 2022 Medium

    Linked the Mrt4-displacement step to translational competency and identified specific zinc-domain variants that abolish function, including a dominant-negative allele.

    Evidence Unbiased genetic screen, BONCAT nascent protein labeling, and dominant-negative analysis in yeast

    PMID:36009873

    Open questions at the time
    • Variant effects not mapped onto a structure
    • Human disease relevance of these variants untested
  7. 2023 Medium

    Defined DUSP12 as a negative regulator of the ASK1/JNK/p38 stress axis with direct ASK1 binding, an HSPB8-mediated mitophagy arm, and FOXP1-driven transcriptional control, providing a coherent protective mechanism across injury models.

    Evidence Direct binding assay and siRNA/inhibitor epistasis in endothelial cells; Co-IP with HSPB8 and mitophagy markers in cardiomyocytes; luciferase reporter and ChIP for FOXP1 regulation

    PMID:33811209 PMID:36644958 PMID:37614418

    Open questions at the time
    • Whether ASK1, HSPB8, and ribosome roles share a common biochemical mechanism unknown
    • ASK1 dephosphorylation by DUSP12 not directly demonstrated
    • Single-lab findings per model
  8. 2025 Medium

    Identified ZNF622 (ZPR9) as a zinc-domain-binding substrate dephosphorylated at Ser143, mechanistically connecting DUSP12 to mitotic fidelity and protection from ZNF622-mediated apoptosis.

    Evidence AP/proximity MS, in-cell and in-vitro IP validation, phosphomimetic/phospho-deficient Ser143 mutants, siRNA, and overexpression

    PMID:39868293 PMID:41851086

    Open questions at the time
    • Structural basis of ZNF622 recognition by the zinc domain not solved
    • Single lab
    • How Ser143 phosphorylation drives mitotic defects mechanistically unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown whether the ribosome-assembly, cell-cycle/ZNF622, and ASK1-stress functions of DUSP12 reflect one unified biochemical activity or independent roles, and whether its dual-specificity catalytic activity acts on defined substrates in human cells.
  • No human-cell substrate of the phosphatase domain confirmed beyond ZNF622
  • No structure of DUSP12 bound to any partner
  • Relationship between conserved ribosome role and vertebrate stress signaling untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0016787 hydrolase activity 2 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-1640170 Cell Cycle 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-8953854 Metabolism of RNA 2
Partners
ASK1HSPB8MRT4ZNF622

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 Yeast Yvh1 (ortholog of DUSP12) is required for displacement of Mrt4 from pre-60S ribosomal subunits in the cytoplasm. Yvh1 binds pre-60S subunits that contain Rpl12 but lack both Mrt4 and P0, suggesting a linear sequence: Yvh1 binding displaces Mrt4, then P0 loads to assemble the mature stalk, then Yvh1 is released. A mutation in Mrt4 at the protein-RNA interface bypasses the requirement for Yvh1. Genetic deletion (yvh1Δ), co-sedimentation/sucrose gradient analysis, epistasis with Mrt4 gain-of-function mutation, biochemical fractionation of pre-60S particles The Journal of cell biology High 19797078 19797079
2009 In yvh1Δ yeast cells, Mrt4 fails to dissociate from late pre-60S particles, inducing a delay in nuclear pre-ribosomal RNA processing and a pre-60S export defect. Gain-of-function alleles of Mrt4 specifically bypass the requirement for Yvh1 and rescue all yvh1Δ-associated phenotypes, establishing that Yvh1-mediated Mrt4 release is an obligatory step before cytoplasmic loading of Rpp0 (P0). Genetic deletion, gain-of-function suppressor allele isolation, rRNA processing analysis, pre-60S export assay The Journal of cell biology High 19797078 19797079
1999 Human YVH1/DUSP12 can rescue the slow-growth defect of S. cerevisiae YVH1 deletion. The C-terminal cysteine-rich domain coordinates 2 mol zinc/mol protein, defining a novel zinc finger domain that is essential for in vivo function. This is the first protein-tyrosine phosphatase shown to contain and be regulated by a zinc finger domain. Yeast complementation assay, zinc-binding stoichiometry determination, domain deletion analysis The Journal of biological chemistry High 10446167
2008 In yvh1Δ yeast, free 60S and 80S ribosomal subunits are decreased, free 40S subunits are increased, and half-mer polysomes accumulate, confirming Yvh1 as a ribosome assembly factor. The RING finger (zinc-binding) domain of Yvh1, but not its phosphatase domain, is required for its cellular function in this context. Polysome profiling, sucrose gradient sedimentation, domain deletion analysis Genetics Medium 19114459
2011 Overexpression of human hYVH1/DUSP12 causes increased polyploidy and G2/M accumulation, while siRNA-mediated knockdown increases the G0/G1 population and susceptibility to cellular senescence. The zinc-binding domain is necessary and sufficient for these cell cycle effects, while phosphatase activity is dispensable. Phosphorylation at Ser335 in the zinc-binding domain regulates subcellular targeting of hYVH1 and augments the G2/M phenotype. siRNA knockdown, overexpression, flow cytometry cell cycle analysis, mass spectrometry phosphosite identification, domain deletion and phosphomimetic mutants Cell cycle (Georgetown, Tex.) Medium 21521943
2020 DUSP12 inhibits JNK and p38 activity (but not ERK1/2) during hepatic ischemia-reperfusion injury in vivo. Hepatocyte-specific DUSP12 knockout exacerbated injury while DUSP12 transgenic mice were protected. ASK1 was required for DUSP12 function, placing DUSP12 as a negative regulator upstream of the ASK1-JNK/p38 pathway. Hepatocyte-specific knockout mice, transgenic overexpression mice, in vitro H/R cell model, western blot for pathway kinases, ASK1 inhibition epistasis Clinical science (London, England : 1979) Medium 32803262
2021 DUSP12 directly binds to ASK1 (apoptosis signal-regulating kinase 1) to inhibit JNK activation in lung vascular endothelial cells. JNK1/2 inhibitor and ASK1 siRNA both rescued the exacerbating effects of DUSP12 knockdown, confirming DUSP12 acts through the ASK1/JNK pathway. Direct binding assay (reported as direct binding), siRNA knockdown, JNK inhibitor epistasis, ASK1 siRNA epistasis, in vitro LPS-stimulated endothelial cell model Medical science monitor : international medical journal of experimental and clinical research Medium 33811209
2023 DUSP12 physically interacts with HSPB8 (heat-shock protein beta-8) as demonstrated by co-immunoprecipitation. DUSP12 overexpression upregulates HSPB8 expression to promote mitophagy, and HSPB8 knockdown abolishes the protective effects of DUSP12 overexpression against hypoxia/reoxygenation-induced apoptosis and oxidative stress. Co-immunoprecipitation, siRNA knockdown of HSPB8, mitophagy marker western blot, H9c2 cell hypoxia/reoxygenation model Journal of biochemical and molecular toxicology Medium 36644958
2023 FOXP1 transcription factor promotes DUSP12 transcription as shown by luciferase reporter and chromatin immunoprecipitation assays. DUSP12 downstream protective effects in ox-LDL-treated endothelial cells are mediated through the MAP3K5 (ASK1) signaling pathway. Luciferase reporter assay, chromatin immunoprecipitation (ChIP), western blot for MAP3K5 pathway components, dual overexpression/knockdown epistasis Experimental and therapeutic medicine Medium 37614418
2025 ZPR9/ZNF622 is identified as a novel DUSP12 interactor binding specifically to the zinc-binding domain of DUSP12. Validated by in-cell and in-vitro IP assays. DUSP12 overexpression promotes dephosphorylation of ZNF622 at Ser143. Knockdown of DUSP12 causes mitotic defects in metaphase; overexpression of ZNF622 (but not phosphomimetic or phosphorylation-deficient Ser143 mutants) causes pre-metaphase mitotic defects. Knockdown of DUSP12 promotes stress-induced apoptosis while knockdown of ZNF622 suppresses it, establishing that DUSP12 protects cells from ZNF622-mediated apoptosis. Affinity- and proximity-based biochemical purification coupled to mass spectrometry, in-cell and in-vitro IP validation, phosphomimetic/phosphorylation-deficient mutant analysis, siRNA knockdown, overexpression Cell death & disease / bioRxiv Medium 39868293 41851086
2022 Unbiased genetic screen identified Yvh1 cysteine-rich domain (CRD) variants that fail to displace Mrt4 from pre-60S ribosomes. One loss-of-function variant, Yvh1F283L, acts as an expression-dependent dominant-negative, interfering with endogenous Yvh1 function. BONCAT (bioorthogonal non-canonical amino acid tagging) showed these loss-of-function variants also display defects in nascent protein production, linking Mrt4 displacement to translational competency. Unbiased genetic screen, BONCAT nascent protein labeling, dominant-negative analysis, ribosome fractionation Biology Medium 36009873
2011 Genetic interaction between Mrt4 and Yvh1 is essential for normal glycogen accumulation, mRNA decay, and induction of sporulation genes (IME2, SPO13, HOP1) in S. cerevisiae. The Mrt4(G68D) suppressor allele restores these phenotypes in yvh1Δ cells. Yvh1 is not essential for wild-type induction of the IME1 transcriptional regulator, suggesting Yvh1 affects translation or post-translational modification of Ime1. Genetic epistasis using dominant suppressor allele Mrt4(G68D), glycogen accumulation assay, mRNA decay analysis, sporulation gene expression analysis Journal of biochemistry Medium 21474464
2015 Yeast Yvh1 phosphatase is required for pre-autophagosomal structure (PAS) formation after TORC1 inactivation, but is not required for autophagy induction per se. Genetic deletion (yvh1Δ), fluorescence microscopy of PAS markers, rapamycin treatment to inactivate TORC1 Bioscience, biotechnology, and biochemistry Low 26125457
2004 P. falciparum PfYVH1 (ortholog of DUSP12) dephosphorylates both phosphoserine and phosphotyrosine residues in vitro (dual-specificity phosphatase activity). Mutation of specific Cys residues in the zinc finger region abolished zinc binding and drastically reduced phosphatase activity, demonstrating an allosteric role of zinc in catalysis. Recombinant PfYVH1 coordinates 2 mol zinc/mol protein. PfYVH1 interacts with the Plasmodium pescadillo nuclear protein (PfPES). Recombinant protein expression, in vitro phosphatase assay with phosphoserine and phosphotyrosine substrates, cysteine mutagenesis, zinc stoichiometry measurement, co-immunoprecipitation with PfPES Molecular and biochemical parasitology Medium 14698441

Source papers

Stage 0 corpus · 20 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Ribosome stalk assembly requires the dual-specificity phosphatase Yvh1 for the exchange of Mrt4 with P0. The Journal of cell biology 97 19797078
2009 Yvh1 is required for a late maturation step in the 60S biogenesis pathway. The Journal of cell biology 91 19797079
1999 Identification of the human YVH1 protein-tyrosine phosphatase orthologue reveals a novel zinc binding domain essential for in vivo function. The Journal of biological chemistry 45 10446167
2005 A putative dual-specific protein phosphatase encoded by YVH1 controls growth, filamentation and virulence in Candida albicans. Microbiology (Reading, England) 28 16000712
2004 A zinc-binding dual-specificity YVH1 phosphatase in the malaria parasite, Plasmodium falciparum, and its interaction with the nuclear protein, pescadillo. Molecular and biochemical parasitology 27 14698441
2011 The dual-specificity phosphatase hYVH1 (DUSP12) is a novel modulator of cellular DNA content. Cell cycle (Georgetown, Tex.) 26 21521943
2006 Polymorphisms in the glucokinase-associated, dual-specificity phosphatase 12 (DUSP12) gene under chromosome 1q21 linkage peak are associated with type 2 diabetes. Diabetes 25 16936214
2008 A mutant plasma membrane protein is stabilized upon loss of Yvh1, a novel ribosome assembly factor. Genetics 17 19114459
2023 DUSP12 ameliorates myocardial ischemia-reperfusion injury through HSPB8-induced mitophagy. Journal of biochemical and molecular toxicology 15 36644958
2020 DUSP12 protects against hepatic ischemia-reperfusion injury dependent on ASK1-JNK/p38 pathway in vitro and in vivo. Clinical science (London, England : 1979) 15 32803262
2011 Lack of association between genetic polymorphisms within DUSP12 - ATF6 locus and glucose metabolism related traits in a Chinese population. BMC medical genetics 13 21211013
2021 DUSP12 acts as a novel endogenous protective signal against hepatic ischemia-reperfusion damage by inhibiting ASK1 pathway. Clinical science (London, England : 1979) 12 33416082
2021 Expression of DUSP12 Reduces Lung Vascular Endothelial Cell Damage in a Murine Model of Lipopolysaccharide-Induced Acute Lung Injury via the Apoptosis Signal-Regulating Kinase 1 (ASK1)-Jun N-Terminal Kinase Activation (JNK) Pathway. Medical science monitor : international medical journal of experimental and clinical research 9 33811209
2011 Genetic interactions of ribosome maturation factors Yvh1 and Mrt4 influence mRNA decay, glycogen accumulation, and the expression of early meiotic genes in Saccharomyces cerevisiae. Journal of biochemistry 9 21474464
2023 FOXP1‑induced DUSP12 alleviates vascular endothelial cell inflammation and oxidative stress injury induced by ox‑LDL via MAP3K5 signaling pathway. Experimental and therapeutic medicine 7 37614418
2015 Yvh1 protein phosphatase is required for pre-autophagosomal structure formation after TORC1 inactivation. Bioscience, biotechnology, and biochemistry 7 26125457
2020 Characterization of Single Gene Deletion Mutants Affecting Alternative Oxidase Production in Neurospora crassa: Role of the yvh1 Gene. Microorganisms 2 32759834
2026 DUSP12 promotes cell cycle progression and protects cells from ZNF622 mediated apoptosis. Cell death & disease 1 41851086
2025 DUSP12 promotes cell cycle progression and protects cells from cell death by regulating ZPR9. bioRxiv : the preprint server for biology 1 39868293
2022 Mutational Analyses of the Cysteine-Rich Domain of Yvh1, a Protein Required for Translational Competency in Yeast. Biology 0 36009873

Missed literature

Know a paper Affinage missed for DUSP12? Flag it for the maintainers and the community.

No submissions yet.