DUSP23

DUSP23 (VHZ/DUSP25) is a catalytically active, structurally minimal dual-specificity phosphatase that acts on phospho-tyrosine and phospho-threonine residues and regulates cell adhesion, cell cycle progression, differentiation, and disease-associated signaling through dephosphorylation of specific substrates (PMID:15147733, PMID:18245086). It is the smallest active protein-tyrosine phosphatase characterized, and its 1.93 Å crystal structure reveals a typical αβα PTP fold with a shallow active-site cleft, with active-site residues Phe66, Leu97, and Phe99 shaping substrate binding and catalysis (PMID:15201283, PMID:18245086). Functionally, DUSP23 dephosphorylates GCM1 at Ser322 to reverse GSK-3β-mediated phosphodegradation, stabilizing GCM1 and driving its target gene expression and placental cell fusion (PMID:20855292); it dephosphorylates β-catenin at Tyr142 to strengthen α-catenin/β-catenin interaction and E-cadherin-based cell-cell adhesion and coordinated collective migration (PMID:27255161); and it dephosphorylates pSMAD3 at Ser423/425 to attenuate macrophage-to-myofibroblast transition and renal fibrosis (PMID:39987296). Its catalytic activity, localized in part to the centrosome, is required for G1/S cell cycle progression and proliferation (PMID:20509867), and it supports neuronal differentiation (PMID:26704437) and, in cisplatin-resistant lung cancer, sustains STAT3 phosphorylation and SOX2-driven cancer stem cell-like properties (PMID:41257937). DUSP23 expression is itself silenced by EZH2-mediated H3K27me3 deposition on its promoter (PMID:39987296).

1. 2004 Medium

   Established that DUSP23 is a genuinely active dual-specificity phosphatase and defined its substrate selectivity, answering whether this orphan DSP had catalytic function.

   Evidence In vitro phosphatase assays on pNPP, oligopeptides, and recombinant MAPKs, with localization in transfected cells

   PMID:15147733 PMID:15201283

   Open questions at the time

   • Physiological substrates not identified
   • MAPK relevance ambiguous between studies
   • Localization reported variably (cytoplasm vs. cytosol/nucleoli)
2. 2008 High

   Determined the atomic structure of DUSP23, defining the minimal PTP fold and the active-site residues governing substrate binding and catalysis.

   Evidence X-ray crystallography at 1.93 Å with an enzyme-substrate/product complex and site-directed mutagenesis of Phe66, Leu97, Phe99

   PMID:18245086

   Open questions at the time

   • Crystallographic TY-motif mimic does not establish a physiological MAPK substrate
   • No structure with a validated cellular substrate
3. 2010 High

   Connected DUSP23 catalytic activity to control of cell proliferation and identified its centrosomal localization, placing it in cell cycle regulation.

   Evidence Immunofluorescence localization, retroviral overexpression of wild-type vs. C95S phosphatase-dead mutant, shRNA knockdown, and FACS cell cycle analysis in MCF-7 cells

   PMID:20509867

   Open questions at the time

   • Centrosomal substrate driving G1/S transition unidentified
   • Mechanism of centrosome targeting unknown
4. 2010 High

   Identified the first physiological substrate, GCM1-pSer322, showing DUSP23 antagonizes GSK-3β to stabilize a transcription factor and drive placental cell fusion.

   Evidence Reciprocal Co-IP, in vitro dephosphorylation, phospho-site mutagenesis, and shRNA knockdown with target gene and cell fusion readouts

   PMID:20855292

   Open questions at the time

   • How PKA-dependent priming gates DUSP23-GCM1 binding mechanistically unresolved
   • In vivo placental requirement not tested
5. 2015 Medium

   Extended DUSP23 function to differentiation, showing it is required for neuronal differentiation of embryonic stem cells.

   Evidence shRNA/siRNA knockdown in mouse J1 ESC neuronal differentiation model with marker and morphology readouts

   PMID:26704437

   Open questions at the time

   • No substrate or pathway identified in this context
   • Single model system
6. 2016 High

   Identified β-catenin-pTyr142 as a substrate, mechanistically linking DUSP23 to α/β-catenin interaction and E-cadherin-based adhesion and collective migration.

   Evidence AP-MS interaction mapping, Co-IP, phospho-specific detection, and siRNA knockdown with adhesion, polarization, and migration assays

   PMID:27255161

   Open questions at the time

   • In vivo relevance of adhesion phenotype not established
   • Selectivity for E-cadherin vs. other adhesion routes not fully explained
7. 2025 Medium

   Placed DUSP23 in disease signaling: it sustains STAT3/SOX2 to maintain cancer stem cell properties, while EZH2-mediated H3K27me3 silences DUSP23 to permit pSMAD3-driven fibrosis.

   Evidence siRNA knockdown with pSTAT3/SOX2, sphere, invasion, apoptosis and in vivo tumor assays; and ChIP-seq, Co-IP, EZH2 knockout/inhibition with pSMAD3 and fibrosis readouts

   PMID:39987296 PMID:41257937

   Open questions at the time

   • Mechanism by which DUSP23 promotes (rather than removes) STAT3 phosphorylation unresolved
   • Direct vs. indirect action on pSMAD3 needs reconstitution
   • Single-study findings per disease context

• It remains unresolved how DUSP23 substrate selectivity and subcellular targeting are coordinated across its diverse contexts (centrosome/cell cycle, adhesion, differentiation, fibrosis, cancer stemness).
• No unifying recruitment/scaffolding mechanism identified
• Regulation of DUSP23 activity beyond EZH2-mediated promoter silencing unknown
• Paradoxical positive effect on STAT3 phosphorylation unexplained