Affinage

DUSP26

Dual specificity protein phosphatase 26 · UniProt Q9BV47

Length
211 aa
Mass
23.9 kDa
Annotated
2026-06-09
25 papers in source corpus 17 papers cited in narrative 17 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DUSP26 is an atypical dual-specificity phosphatase that dephosphorylates a broad panel of substrates to control cell survival, proliferation, apoptosis, and mitochondrial and neuronal homeostasis across diverse tissues (PMID:16924234, PMID:24548998, PMID:35313355, PMID:41748589). In its best-defined survival role, DUSP26 forms a complex with and dephosphorylates p38 MAPK to suppress p38-mediated apoptosis in anaplastic thyroid cancer cells (PMID:16924234), and its activity is potentiated by adenylate kinase 2 (AK2), which binds DUSP26 and stimulates dephosphorylation of FADD at Ser194 to restrain proliferation (PMID:24548998). DUSP26 directly binds and dephosphorylates p53 at Ser312 to dampen p53-driven cell-death transcription and protect renal tubular cells (PMID:41748589), and it inactivates HDAC1, HDAC2, and HDAC8 to maintain chondrocyte integrity (PMID:41789628). The enzyme also acts on receptor and cytoskeletal substrates, dephosphorylating TrkA and FGFR1 with consequences for retinal and motor-neuron development (PMID:28701747), the KIF3 motor subunit Kap3 to promote N-cadherin/beta-catenin junctional localization and cell-cell adhesion (PMID:19043453), and FAK to negatively regulate FAK-ERK signaling (PMID:39510451). DUSP26 is targeted to the mitochondrial outer membrane via an N-terminal targeting sequence, where its loss elevates ROS, reduces ATP and mitochondrial motility, and triggers dopaminergic neuronal death (PMID:35313355); its abundance is controlled by PRMT9-mediated arginine methylation at R29 that licenses Trim32-dependent polyubiquitination and proteasomal degradation (PMID:42261762). The small molecule NSC-87877 competitively inhibits its catalytic activity (PMID:19233143). Substrate selectivity is context-dependent: in epithelial cells DUSP26 does not dephosphorylate ERK, JNK, or p38, yet still suppresses growth in a phosphatase-activity-dependent manner (PMID:20347885).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2006 High

    Established the first DUSP26 substrate and a pro-survival function, answering whether this atypical phosphatase had a defined MAPK target relevant to cancer.

    Evidence Reciprocal Co-IP and in vitro phosphatase assay with overexpression/knockdown across anaplastic thyroid cancer lines and primary tumors

    PMID:16924234

    Open questions at the time
    • Did not define the structural basis of p38 recognition
    • Substrate specificity later found to be cell-context dependent
  2. 2006 Medium

    Identified a transcription-factor-linked interaction, showing DUSP26 can influence ERK activity and HSF4b DNA-binding.

    Evidence Yeast two-hybrid, Co-IP, in vitro kinase/phosphatase assays

    PMID:16581800

    Open questions at the time
    • Direct phosphatase target within the HSF4b axis not pinpointed
    • Single-lab finding without in vivo validation
  3. 2008 High

    Extended DUSP26 substrates beyond signaling kinases to cytoskeletal transport and to transcriptional control of EGFR, broadening its functional scope.

    Evidence Y2H, Co-IP, colocalization, in vitro dephosphorylation of Kap3, catalytic-mutant analysis; separately EGFR promoter reporter and C152S mutant in PC12 cells

    PMID:19014381 PMID:19043453

    Open questions at the time
    • Phospho-sites on Kap3 not mapped
    • Mechanistic link between phosphatase activity and WT1/EGFR promoter regulation indirect
  4. 2009 Medium

    Provided a pharmacological tool, establishing that NSC-87877 competitively inhibits DUSP26 and blocks p38 dephosphorylation.

    Evidence In vitro phosphatase assay with kinetic inhibition analysis

    PMID:19233143

    Open questions at the time
    • Selectivity against other phosphatases not established
    • No cellular potency or off-target profile in this study
  5. 2010 Medium

    Challenged the universality of MAPK targeting by showing DUSP26 does not dephosphorylate ERK/JNK/p38 in epithelial cells yet still suppresses growth, establishing context-dependent substrate selection.

    Evidence In vitro phosphatase assay, overexpression/knockdown, and 3D culture in epithelial lines

    PMID:20347885

    Open questions at the time
    • The relevant epithelial substrate driving growth suppression not identified
    • Contradicts MAPK-dependent models without reconciling mechanism
  6. 2014 High

    Revealed allosteric regulation of DUSP26, showing AK2 stimulates its phosphatase activity independent of kinase function and redirects it to FADD-Ser194.

    Evidence Co-IP, in vitro reconstitution, xenograft, AK2-deficient MEFs

    PMID:24548998

    Open questions at the time
    • Structural basis of AK2-induced activation not resolved
    • How AK2 dictates substrate choice unclear
  7. 2015 Medium

    Defined a DUSP26-p53/p38 survival axis in neuroblastoma, linking enzyme inhibition to apoptosis induction.

    Evidence shRNA, NSC-87877 and SB203580 epistasis, Western blot, intrarenal mouse model

    PMID:26247726

    Open questions at the time
    • Whether p53 effects were direct not addressed here
    • p53/p38 contributions only partially separable
  8. 2016 Medium

    Connected DUSP26 catalytic activity to amyloidogenic axonal transport, implicating it in JNK-driven C99 vesicle trafficking under hypoxia.

    Evidence Genome-wide cDNA screen, live-cell trafficking assay, JNK inhibitor and catalytic-dead mutant

    PMID:26924229

    Open questions at the time
    • Direct phosphatase substrate in the JNK/transport pathway not identified
    • Mechanism of anterograde bias unresolved
  9. 2017 Medium

    Demonstrated direct receptor tyrosine kinase substrates (TrkA, FGFR1) and an in vivo developmental requirement.

    Evidence In vitro dephosphorylation, PC12 RNAi, zebrafish morpholino knockdown

    PMID:28701747

    Open questions at the time
    • Specific phospho-tyrosines on TrkA/FGFR1 not mapped
    • Morpholino specificity not genetically confirmed
  10. 2021 Medium

    Uncovered a non-canonical, phosphatase-independent stabilizing role, with DUSP26 antagonizing MDM2-mediated DPP4 degradation to drive valve calcification.

    Evidence Co-IP, LC-MS/MS, calcification assays, AAV-shRNA in ApoE-/- mice

    PMID:34179958

    Open questions at the time
    • Whether catalytic activity contributes not resolved
    • Mechanism of MDM2 antagonism unclear
  11. 2022 High

    Localized DUSP26 to the mitochondrial outer membrane via an N-terminal targeting sequence and tied its loss to mitochondrial dysfunction and dopaminergic neurodegeneration.

    Evidence Subcellular fractionation, live imaging, Dusp26 knockout mouse, ROS/ATP assays

    PMID:35313355

    Open questions at the time
    • Direct mitochondrial substrate not defined
    • HtrA2 release mechanism downstream of DUSP26 loss unresolved
  12. 2024 Medium

    Added FAK and TAK1-p38-JNK axes as functional targets, linking DUSP26 to cardiac mitochondrial fusion and prostate cancer suppression.

    Evidence In vivo overexpression in db/db mice with FAK-activator rescue; PC3 overexpression/siRNA, xenograft, RNA-seq, TAK1 inhibitor rescue

    PMID:39222869 PMID:39510451

    Open questions at the time
    • Direct vs indirect dephosphorylation of TAK1 not distinguished
    • Single-lab in vivo models
  13. 2026 High

    Provided direct, site-specific substrate definitions (p53-Ser312 and HDAC1/2/8) with cell-type-specific genetic models, anchoring DUSP26's protective roles in kidney and cartilage.

    Evidence Co-IP, site-specific in vitro dephosphorylation, proximal-tubule knock-in mouse; MS proteomics with adenoviral gain/loss in chondrocytes

    PMID:41748589 PMID:41789628

    Open questions at the time
    • Structural recognition of these substrates not solved
    • HDAC substrate work is single-lab
  14. 2026 Medium

    Established post-translational control of DUSP26 abundance via PRMT9 methylation at R29 driving Trim32-dependent degradation in a Parkinson's model.

    Evidence Co-IP, methylation and ubiquitination assays, PRMT9 OE/KO in MPTP mice

    PMID:42261762

    Open questions at the time
    • How R29 methylation recruits Trim32 mechanistically unclear
    • Single-lab biochemical model

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how DUSP26 selects among its many reported substrates in different cell types and which determinants (localization, AK2 binding, methylation state) govern this specificity.
  • No structural model of substrate recognition
  • Substrate repertoire varies by tissue without a unifying selectivity rule
  • Catalytic vs scaffolding contributions not separated across functions

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 7 GO:0016787 hydrolase activity 4
Localization
GO:0005739 mitochondrion 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-5357801 Programmed Cell Death 3 R-HSA-1852241 Organelle biogenesis and maintenance 1
Partners
AK2FADDKAP3KIF3AMAPK14PRMT9TP53TRIM32

Evidence

Reading pass · 17 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 DUSP26 forms a physical complex with p38 MAPK and effectively dephosphorylates p38, promoting survival of anaplastic thyroid cancer cells by inhibiting p38-mediated apoptosis. Co-immunoprecipitation, in vitro phosphatase assay, overexpression/knockdown in ATC cell lines Oncogene High 16924234
2006 DUSP26 interacts with HSF4b (identified by yeast two-hybrid) and controls ERK activity, leading to phosphorylation/dephosphorylation of HSF4b and altering its DNA-binding ability. Yeast two-hybrid screen, co-immunoprecipitation, in vitro kinase/phosphatase assays Molecular and cellular biology Medium 16581800
2008 DUSP26 associates with KIF3 motor subunit Kif3a (identified by yeast two-hybrid) and also with Kap3; DUSP26 dephosphorylates Kap3, promoting N-cadherin/beta-catenin distribution to cell-cell junctions and increased cell-cell adhesiveness; this requires catalytic activity. Yeast two-hybrid, co-immunoprecipitation, colocalization, in vitro dephosphorylation assay, catalytically inactive mutant analysis Oncogene High 19043453
2009 NSC-87877 competitively inhibits DUSP26 phosphatase activity in vitro and blocks DUSP26-mediated dephosphorylation of p38. In vitro phosphatase assay, kinetic inhibition analysis Biochemical and biophysical research communications Medium 19233143
2010 DUSP26 does not dephosphorylate ERK, JNK, or p38 MAPKs in epithelial cells as measured by in vitro phosphatase assays and overexpression; its growth-suppressive effects on MCF10A cells depend on phosphatase activity but not MAPK dephosphorylation. In vitro phosphatase assay, overexpression and knockdown in epithelial cell lines, 3D culture Biochimica et biophysica acta Medium 20347885
2014 Adenylate kinase 2 (AK2) forms a complex with DUSP26, stimulates DUSP26 phosphatase activity independently of AK enzymatic activity, and the AK2/DUSP26 complex dephosphorylates FADD at Ser194, suppressing cell proliferation. Co-immunoprecipitation, in vitro phosphatase reconstitution, xenograft assay, AK2-deficient MEFs Nature communications High 24548998
2015 DUSP26 inhibition by NSC-87877 or shRNA knockdown in neuroblastoma cells increases p53 phosphorylation (Ser37, Ser46) and activates p38 downstream effectors (HSP27, MAPKAPK2), inducing apoptosis; p53 knockdown or p38 inhibition partially reverses this cytotoxicity. shRNA knockdown, pharmacological inhibition (NSC-87877, SB203580), Western blot, intrarenal mouse model Cell death & disease Medium 26247726
2016 DUSP26 phosphatase activity is required for increased Aβ42 generation; DUSP26 induces JNK activation and stimulates anterograde axonal transport of C99-positive vesicles, shifting γ-secretase/C99 localization from cell body to axons under hypoxia. Genome-wide functional cDNA screen, live-cell vesicle trafficking assay, JNK inhibitor (SP600125), NSC-87877, catalytically inactive mutant Journal of neurochemistry Medium 26924229
2008 NEAP/DUSP26 (phosphatase-competent form) suppresses EGFR expression in PC12 cells by decreasing EGFR promoter activity through downregulation of the Akt pathway and Wilms' tumor gene product (WT1); catalytic activity is required. Overexpression of WT and C152S mutant, EGFR promoter reporter assay, RNAi knockdown, EGFR inhibitor rescue Journal of neurochemistry Medium 19014381
2017 NEAP/DUSP26 directly dephosphorylates TrkA and FGFR1 in vitro; morpholino knockdown of NEAP in zebrafish causes hyper-phosphorylation of TrkA and FGFR1 and defects in retinal differentiation and cranial motor neurons. In vitro dephosphorylation assay, RNAi knockdown in PC12 cells, zebrafish morpholino knockdown Scientific reports Medium 28701747
2021 DUSP26 antagonizes MDM2-mediated ubiquitination and degradation of DPP4 in human valvular interstitial cells, thereby stabilizing DPP4 and promoting aortic valve calcification. Immunoprecipitation, LC-MS/MS, functional calcification assays, adeno-associated virus shRNA in ApoE-/- mice European heart journal Medium 34179958
2022 DUSP26 is targeted to the mitochondrial outer membrane via its NH2-terminal mitochondrial targeting sequence; loss of DUSP26 increases ROS, reduces ATP production and mitochondrial motility, releases HtrA2 into cytoplasm, and activates p38 MAPK, leading to dopaminergic neuronal death in mouse substantia nigra. Subcellular fractionation, live imaging for mitochondrial targeting, Dusp26 knockout mouse model, ROS/ATP measurements Cellular and molecular life sciences High 35313355
2024 DUSP26 dephosphorylates FAK and negatively regulates the FAK-ERK signaling pathway in cardiomyocytes; DUSP26 overexpression improves mitochondrial fusion and cardiac function in diabetic db/db mice, and pharmacological FAK activation partially offsets these benefits. Overexpression in db/db mouse model, echocardiography, mitochondrial function assays, FAK activator rescue experiment Free radical biology & medicine Medium 39510451
2026 DUSP26 directly binds p53 and dephosphorylates it at serine 312, dampening p53 transcriptional activity toward cell death genes and protecting kidney tubular cells from acute kidney injury. Co-immunoprecipitation, in vitro dephosphorylation assay with site-specific p53 antibodies, proximal tubule-specific knock-in mouse, pharmacological inhibition Nature communications High 41748589
2026 DUSP26 dephosphorylates HDAC1, HDAC2, and HDAC8 (identified by mass spectrometry-based proteomics), inactivating them and maintaining chondrocyte integrity; DUSP26 overexpression protects against IL-1β-induced cartilage degradation. Mass spectrometry proteomics, adenovirus-mediated overexpression and shRNA silencing, in vitro chondrocyte inflammatory model International journal of molecular medicine Medium 41789628
2026 PRMT9 directly interacts with DUSP26 and methylates it at arginine R29, promoting its polyubiquitination by Trim32 and proteasomal degradation, thereby reducing DUSP26 levels and exacerbating mitochondrial dysfunction in dopaminergic neurons. Co-immunoprecipitation, arginine methylation assay, ubiquitination assay, Trim32 identification, PRMT9 overexpression/KO in MPTP mouse model Advanced science Medium 42261762
2024 DUSP26 overexpression in prostate cancer PC3 cells impairs TAK1, p38, and JNK phosphorylation, suppressing proliferation, migration, and invasion; TAK1 inhibitor treatment attenuates the effect of DUSP26. Overexpression and siRNA knockdown, Western blot, subcutaneous xenograft, RNA-seq, pharmacological TAK1 inhibition rescue Experimental cell research Medium 39222869

Source papers

Stage 0 corpus · 25 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 A novel amplification target, DUSP26, promotes anaplastic thyroid cancer cell growth by inhibiting p38 MAPK activity. Oncogene 84 16924234
2014 The DUSP26 phosphatase activator adenylate kinase 2 regulates FADD phosphorylation and cell growth. Nature communications 65 24548998
2006 Association and regulation of heat shock transcription factor 4b with both extracellular signal-regulated kinase mitogen-activated protein kinase and dual-specificity tyrosine phosphatase DUSP26. Molecular and cellular biology 64 16581800
2021 DUSP26 induces aortic valve calcification by antagonizing MDM2-mediated ubiquitination of DPP4 in human valvular interstitial cells. European heart journal 57 34179958
2009 NSC-87877, inhibitor of SHP-1/2 PTPs, inhibits dual-specificity phosphatase 26 (DUSP26). Biochemical and biophysical research communications 50 19233143
2008 Protein phosphatase Dusp26 associates with KIF3 motor and promotes N-cadherin-mediated cell-cell adhesion. Oncogene 43 19043453
2015 NSC-87877 inhibits DUSP26 function in neuroblastoma resulting in p53-mediated apoptosis. Cell death & disease 32 26247726
2010 DUSP26 negatively affects the proliferation of epithelial cells, an effect not mediated by dephosphorylation of MAPKs. Biochimica et biophysica acta 26 20347885
2022 Falnidamol and cisplatin combinational treatment inhibits non-small cell lung cancer (NSCLC) by targeting DUSP26-mediated signal pathways. Free radical biology & medicine 25 35278641
2021 A Review of DUSP26: Structure, Regulation and Relevance in Human Disease. International journal of molecular sciences 24 33466673
2019 DUSP26 regulates podocyte oxidative stress and fibrosis in a mouse model with diabetic nephropathy through the mediation of ROS. Biochemical and biophysical research communications 21 31155289
2016 Dual-specificity phosphatase 26 (DUSP26) stimulates Aβ42 generation by promoting amyloid precursor protein axonal transport during hypoxia. Journal of neurochemistry 20 26924229
2008 NEAP causes down-regulation of EGFR, subsequently induces the suppression of NGF-induced differentiation in PC12 cells. Journal of neurochemistry 17 19014381
2017 NEAP/DUSP26 suppresses receptor tyrosine kinases and regulates neuronal development in zebrafish. Scientific reports 15 28701747
2012 Higher estimates of daily dietary net endogenous acid production (NEAP) in the elderly as compared to the young in a healthy, free-living elderly population of Pakistan. Clinical interventions in aging 12 23271903
2024 Targeting DUSP26 to drive cardiac mitochondrial dynamics via FAK-ERK signaling in diabetic cardiomyopathy. Free radical biology & medicine 10 39510451
2022 Dusp26 phosphatase regulates mitochondrial respiration and oxidative stress and protects neuronal cell death. Cellular and molecular life sciences : CMLS 9 35313355
2022 Phytoplankton habitats and size distribution during a neap-spring transition in the highly turbid macrotidal Chikugo River estuary. The Science of the total environment 6 35932862
2021 Decreased DUSP26 Expression Promotes Malignant Behavior in Glioblastoma Cells via Deregulation of MAPK and Akt Signaling Pathway. Frontiers in oncology 4 33718185
2001 Feeding rhythms of the green-lipped mussel, Perna viridis (Linnaeus, 1758) (Bivalvia: Mytilidae) during spring and neap tidal cycles. Journal of experimental marine biology and ecology 2 11165297
2026 DUSP26 protects against acute kidney injury by dephosphorylating p53 at serine 312. Nature communications 1 41748589
2024 Overexpression of DUSP26 gene suppressed the proliferation, migration, and invasion of human prostate cancer cells. Experimental cell research 1 39222869
2021 Corrigendum: Decreased DUSP26 Expression Promotes Malignant Behavior in Glioblastoma Cells via Deregulation of MAPK and Akt Signaling Pathway. Frontiers in oncology 1 33928040
2026 DUSP26: Unveiling a critical molecular mediator and therapeutic target in developmental dysplasia of the hip‑associated secondary osteoarthritis. International journal of molecular medicine 0 41789628
2026 PRMT9 Aggravated Dopaminergic Neurodegeneration in Parkinson's Disease Model by Facilitating the Degradation of DUSP26 and Inducing Mitochondrial Dysfunction. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 0 42261762

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