Affinage

DUSP23

Dual specificity protein phosphatase 23 · UniProt Q9BVJ7

Round 2 corrected
Length
150 aa
Mass
16.6 kDa
Annotated
2026-04-28
48 papers in source corpus 9 papers cited in narrative 9 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DUSP23 (VHZ) is the smallest known catalytically active cysteine-based protein tyrosine phosphatase (150 residues), functioning as a dual-specificity phosphatase that dephosphorylates both phospho-Tyr and phospho-Ser/Thr residues on a growing list of substrates including ERK1, GCM1 (Ser322), β-catenin (Tyr142), and pSMAD3 (Ser423/425) (PMID:15147733, PMID:20855292, PMID:27255161, PMID:39987296). Its crystal structure reveals an αβα PTP fold with a characteristically shallow active-site cleft that accommodates both pTyr and pSer/pThr substrates (PMID:18245086). DUSP23 localizes to the cytoplasm and centrosome, promotes G1/S cell-cycle progression in a catalytic-activity-dependent manner, maintains E-cadherin-based adherens junctions through β-catenin Tyr142 dephosphorylation, coordinates GCM1 stabilization and placental cell fusion by counteracting GSK-3β phosphorylation, and supports neuronal differentiation (PMID:20509867, PMID:27255161, PMID:20855292, PMID:26704437). In non-small cell lung cancer, DUSP23 promotes cancer stem cell-like properties and chemoresistance via positive regulation of STAT3 phosphorylation and SOX2 transcription (PMID:41257937).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2004 High

    Identification of DUSP23 as the smallest active dual-specificity phosphatase established it as a bona fide enzyme capable of dephosphorylating pTyr and pThr substrates, including ERK1 but not p38 or SAPK, and placed it in the cytoplasm.

    Evidence In vitro phosphatase assays with pNPP, oligopeptide substrates, and recombinant p44ERK1; subcellular localization in transfected HEK293 cells; independent characterization confirming dual-specificity and noting cytosol/nucleolar localization

    PMID:15147733 PMID:15201283

    Open questions at the time
    • In vivo substrates beyond ERK1 not yet identified
    • Physiological relevance of nucleolar localization not addressed
    • No structural data to explain substrate selectivity
  2. 2008 High

    The crystal structure at 1.93 Å resolution revealed how DUSP23's shallow active site cleft accommodates both pTyr and pSer/pThr substrates, resolving the structural basis for its dual specificity and identifying key catalytic residues (Phe66, Leu97, Phe99).

    Evidence X-ray crystallography with enzyme-substrate/product complex mimicked by Thr135-Tyr136 dipeptide and malate ion; functional mutagenesis of active-site residues

    PMID:18245086

    Open questions at the time
    • No co-crystal with a physiological substrate
    • Structural basis for selectivity against p38/SAPK not fully resolved
  3. 2010 High

    Discovery of centrosomal localization and catalytic-activity-dependent promotion of G1/S transition answered how DUSP23 participates in cell proliferation and revealed a centrosome-associated function, while identification of GCM1 Ser322 as a substrate linked DUSP23 to placental cell fusion through antagonism of GSK-3β.

    Evidence Indirect immunofluorescence of endogenous/exogenous protein; catalytically dead C95S mutant control; shRNA knockdown with cell-cycle and cell-fusion phenotypes; Co-IP and dephosphorylation assays for GCM1

    PMID:20509867 PMID:20855292

    Open questions at the time
    • Centrosomal substrate(s) not identified
    • Mechanism linking DUSP23 to G1/S regulators not defined
    • Whether GCM1 dephosphorylation is direct at physiological stoichiometry not fully confirmed
  4. 2015 Medium

    Demonstration that DUSP23 is upregulated during and required for neuronal differentiation of mouse embryonic stem cells extended its functional scope beyond proliferation to a developmental lineage commitment role.

    Evidence shRNA knockdown during mESC neuronal differentiation; neuronal outgrowth and marker expression quantification

    PMID:26704437

    Open questions at the time
    • Downstream substrate(s) mediating the differentiation phenotype not identified
    • Not independently replicated
    • Limited mechanistic pathway placement
  5. 2016 High

    Identification of β-catenin Tyr142 as a direct DUSP23 substrate explained how it maintains E-cadherin-based adherens junctions and coordinates collective cell migration, establishing a cell-adhesion function.

    Evidence Affinity purification–mass spectrometry interaction mapping; pTyr142-specific phosphorylation assays; DUSP23 knockdown with E-cadherin adhesion, polarity, and migration phenotypes

    PMID:27255161

    Open questions at the time
    • Whether DUSP23 regulates β-catenin transcriptional (Wnt) signaling in addition to adhesion not tested
    • Tissue-specific relevance of this function not explored
  6. 2025 Medium

    Two studies expanded DUSP23's substrate repertoire and disease-context roles: DUSP23 promotes cancer stemness and chemoresistance in NSCLC via STAT3/SOX2 signaling, and DUSP23 dephosphorylates pSMAD3 (Ser423/425) to attenuate macrophage-to-myofibroblast transition in kidney fibrosis, with its expression regulated by EZH2-mediated H3K27me3.

    Evidence shRNA knockdown in cisplatin-resistant NSCLC cells with in vivo xenograft; Co-IP and molecular docking for pSMAD3; ChIP-seq for EZH2-mediated promoter silencing; nephrocalcinosis model

    PMID:39987296 PMID:41257937

    Open questions at the time
    • Paradoxical promotion of STAT3 phosphorylation by a phosphatase requires mechanistic explanation — indirect mechanism not delineated
    • pSMAD3 as substrate validated by Co-IP and docking but not by in vitro reconstitution with purified proteins
    • Both studies from single laboratories, awaiting independent replication

Open questions

Synthesis pass · forward-looking unresolved questions
  • How DUSP23 achieves substrate selectivity across its diverse substrates (ERK1, GCM1, β-catenin, SMAD3, STAT3 pathway), what its centrosomal substrate(s) are, and whether its apparently contradictory pro-phosphorylation effect on STAT3 is indirect remain unresolved.
  • No systematic substrate profiling or phospho-proteomics performed
  • Centrosomal interactors and substrates unknown
  • No in vivo genetic model (knockout mouse) reported

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6
Localization
GO:0005829 cytosol 2 GO:0005730 nucleolus 1 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-1500931 Cell-Cell communication 1 R-HSA-1640170 Cell Cycle 1
Partners
CTNNB1GCM1MAPK3SMAD3

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 DUSP23 (VHZ) was identified as the smallest active protein-tyrosine phosphatase known (150 residues), containing a DSPc domain but lacking a CH2 domain. It was shown to be enzymatically active, dephosphorylating phospho-tyrosine and phospho-threonine substrates including p-nitrophenyl phosphate and p44ERK1 (but not p38 or p54SAPKbeta) in vitro. In transfected HEK293 cells, DUSP23 localizes to the cytoplasm. In vitro phosphatase assay with pNPP and oligopeptides; in vitro dephosphorylation of p44ERK1; RT-PCR expression analysis; transient transfection with subcellular localization The international journal of biochemistry & cell biology High 15147733
2004 DUSP23 (VHZ) was independently characterized as the smallest active cysteine-based PTP, bearing the HCXXGXXRS(T) active site motif. It was shown to dephosphorylate phospho-Tyr and phospho-Ser/Thr residues and, unlike the related VHR, is unlikely to dephosphorylate MAP kinases based on surface charge distribution modeling. VHZ was found in cytosol and nucleoli of transfected cells. In vitro phosphatase assay; computer modeling of structure; subcellular localization in transfected cells The Journal of biological chemistry Medium 15201283
2008 Crystal structure of DUSP23 (VHZ) was solved at 1.93 Å resolution, revealing a typical αβα PTP fold with a shallow active site cleft that supports dual-specificity. The Thr135-Tyr136 dipeptide from a symmetry-related molecule, together with a malate ion, occupied the active site mimicking the phosphorylated TY motif of the MAPK activation loop. Functional analysis of Phe66, Leu97, and Phe99 provided mechanistic insight into substrate binding and catalysis. X-ray crystallography (1.93 Å); enzyme-substrate/product complex analysis; functional mutagenesis of active site residues The Journal of biological chemistry High 18245086
2010 DUSP23 (VHZ) was shown to localize to the centrosome in addition to the cytoplasm, as demonstrated by indirect immunofluorescence of both exogenous and endogenous VHZ. Overexpression of VHZ (but not the catalytically inactive VHZ-C95S mutant) in MCF-7 cells promoted cell proliferation; shRNA-mediated knockdown increased G1 and decreased S phase cell populations, indicating that VHZ facilitates G1/S cell cycle transition in a phosphatase-activity-dependent manner. Indirect immunofluorescence; retroviral overexpression and shRNA knockdown; cell proliferation assay; cell cycle analysis by flow cytometry Molecular cancer High 20509867
2010 DUSP23 was identified as a phosphatase for GCM1, a transcription factor essential for placental development. DUSP23 interaction with GCM1 is enhanced by PKA-dependent phosphorylation of GCM1 on Ser269 and Ser275. Recruited DUSP23 reverses GSK-3β-mediated phosphorylation of GCM1 Ser322, which promotes GCM1 acetylation, stabilization, and transcriptional activation. Knockdown of DUSP23 suppressed GCM1 target gene expression and placental cell fusion. Co-immunoprecipitation; phosphorylation/dephosphorylation assays; shRNA knockdown; placental cell fusion assay; reporter gene assays Nucleic acids research High 20855292
2015 DUSP23 expression increases during neuronal differentiation of mouse embryonic stem cells. Knockdown of DUSP23 decreased neuronal differentiation as measured by reduced neuronal outgrowth and decreased expression of neuronal marker proteins and mRNAs. Expression profiling (RT-PCR/Western blot); shRNA knockdown; neuronal outgrowth assay; neuronal marker protein/mRNA quantification during differentiation Neuroscience letters Medium 26704437
2016 DUSP23 was identified as a phosphatase for β-catenin at Tyr142, promoting dephosphorylation of this residue and enhancing the interaction between α- and β-catenin. DUSP23 knockdown specifically diminished adhesion to E-cadherin (without altering fibronectin adhesion), produced 'zipper-like' cell-cell adhesions, caused defects in transmission of polarization cues, and reduced coordination during collective cell migration. Protein interaction mapping (affinity purification-MS); DUSP23 knockdown; β-catenin pTyr142 phosphorylation assay; E-cadherin adhesion assay; live-cell imaging of collective migration Scientific reports High 27255161
2025 DUSP23 promotes cancer stem cell-like properties and chemoresistance in non-small cell lung cancer by positively regulating STAT3 phosphorylation, thereby enhancing SOX2 transcription. DUSP23 knockdown impaired cell cluster formation under ultra-low adhesion conditions, suppressed SOX2 expression, decreased invasive behavior in cisplatin-resistant cells, and induced apoptosis. DUSP23 knockdown also suppressed lung tumorigenesis in vivo. shRNA knockdown; STAT3 phosphorylation assay; SOX2 transcription/protein assay; cluster formation assay; invasion assay; apoptosis assay; in vivo xenograft Scientific reports Medium 41257937
2025 EZH2-mediated H3K27me3 enrichment on the DUSP23 promoter suppresses DUSP23 expression. When EZH2 is inhibited, DUSP23 expression is elevated. DUSP23 was shown by Co-IP and molecular docking to mediate dephosphorylation of pSMAD3 (Ser423/425), thereby attenuating macrophage-to-myofibroblast transition and kidney fibrosis in a nephrocalcinosis model. ChIP-seq; Co-immunoprecipitation; molecular docking; EZH2 knockout/inhibition (GSK-126); transcriptomic sequencing; immunofluorescence; flow cytometry Communications biology Medium 39987296

Source papers

Stage 0 corpus · 48 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2021 Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV. Nature 532 33845483
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
1996 Normalization and subtraction: two approaches to facilitate gene discovery. Genome research 401 8889548
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2010 Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. Cell 318 21145461
2019 Mitochondrial ClpP-Mediated Proteolysis Induces Selective Cancer Cell Lethality. Cancer cell 298 31056398
2016 The cell proliferation antigen Ki-67 organises heterochromatin. eLife 265 26949251
2011 A directed protein interaction network for investigating intracellular signal transduction. Science signaling 258 21900206
2021 Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context. Cell metabolism 239 34800366
2007 hORFeome v3.1: a resource of human open reading frames representing over 10,000 human genes. Genomics 222 17207965
2016 Mitochondrial Protein Interaction Mapping Identifies Regulators of Respiratory Chain Function. Molecular cell 220 27499296
2011 Next-generation sequencing to generate interactome datasets. Nature methods 200 21516116
2020 UFMylation maintains tumour suppressor p53 stability by antagonizing its ubiquitination. Nature cell biology 168 32807901
2020 A High-Density Human Mitochondrial Proximity Interaction Network. Cell metabolism 148 32877691
2019 Mapping the proximity interaction network of the Rho-family GTPases reveals signalling pathways and regulatory mechanisms. Nature cell biology 137 31871319
2011 Proteomic characterization of the human sperm nucleus. Proteomics 116 21630459
2021 FBW7 suppresses ovarian cancer development by targeting the N6-methyladenosine binding protein YTHDF2. Molecular cancer 106 33658012
2020 Receptor-mediated clustering of FIP200 bypasses the role of LC3 lipidation in autophagy. The EMBO journal 100 33226137
2018 SRSF1 modulates PTPMT1 alternative splicing to regulate lung cancer cell radioresistance. EBioMedicine 93 30429088
2020 Kinase Interaction Network Expands Functional and Disease Roles of Human Kinases. Molecular cell 88 32707033
2019 MAP4K Family Kinases and DUSP Family Phosphatases in T-Cell Signaling and Systemic Lupus Erythematosus. Cells 78 31766293
2011 Identification of epigenetically regulated genes that predict patient outcome in neuroblastoma. BMC cancer 60 21314941
2010 Dual-specificity phosphatase 23 mediates GCM1 dephosphorylation and activation. Nucleic acids research 32 20855292
2004 The minimal essential core of a cysteine-based protein-tyrosine phosphatase revealed by a novel 16-kDa VH1-like phosphatase, VHZ. The Journal of biological chemistry 30 15201283
2004 Molecular cloning and characterization of a novel dual-specificity phosphatase 23 gene from human fetal brain. The international journal of biochemistry & cell biology 25 15147733
2018 Integration of Murine and Human Studies for Mapping Periodontitis Susceptibility. Journal of dental research 23 29294296
2008 Structure of human dual specificity protein phosphatase 23, VHZ, enzyme-substrate/product complex. The Journal of biological chemistry 22 18245086
2010 VHZ is a novel centrosomal phosphatase associated with cell growth and human primary cancers. Molecular cancer 19 20509867
2016 A protein interaction map for cell-cell adhesion regulators identifies DUSP23 as a novel phosphatase for β-catenin. Scientific reports 17 27255161
2016 DUSP23 is over-expressed and linked to the expression of DNMTs in CD4+ T cells from systemic lupus erythematosus patients. Clinical and experimental immunology 13 27737517
2023 The genomic signature of resistance to platinum-containing neoadjuvant therapy based on single-cell data. Cell & bioscience 12 37291676
2015 Profiling analysis of protein tyrosine phosphatases during neuronal differentiation. Neuroscience letters 9 26704437
2025 EZH2-mediated macrophage-to-myofibroblast transition contributes to calcium oxalate crystal-induced kidney fibrosis. Communications biology 6 39987296
2023 Evidence for Extensive Duplication and Subfunctionalization of FCRL6 in Armadillo (Dasypus novemcinctus). International journal of molecular sciences 3 36901962
2024 ACSL1 positively regulates adipogenic differentiation. Biochemical and biophysical research communications 2 39442449
2026 Common variation at 1q23.3, 2p23.3, 2q33.3, and 2p21 influences the risk of acute myeloid leukemia. Blood 1 41610418
2025 Candidate Transcript Panel in Semen Extracellular Vesicles Can Improve Prediction of Aggressiveness of Prostate Cancer. International journal of molecular sciences 0 41096831
2025 Targeting dual-specificity phosphatase 23 to overcome chemoresistance and stem cell-like behavior in non-small cell lung cancer cells. Scientific reports 0 41257937