DUSP26 Human
Description
Gene Overview
Symbol: DUSP26
HGNC ID: 28161
NCBI Gene ID: 78986
UniProt ID: Q9BV47
Genomic Location: Chromosome 8p12 .
Aliases:
-
DUSP24
-
NEAP (Neuroendocrine-Associated Phosphatase)
-
MKP8 (Mitogen-Activated Protein Kinase Phosphatase 8)
Expression:
-
Tissue Distribution: Predominantly expressed in the brain, particularly in neurons and neuropil. Lower expression observed in glioblastoma (GBM) and other cancers .
Protein Structure and Function
Protein Characteristics:
-
Catalytic Activity: Dual-specificity phosphatase targeting phosphorylated tyrosine, serine, and threonine residues.
-
Substrates:
Mechanism:
-
Inactivates MAPKs (e.g., p38) via dephosphorylation, modulating stress responses, apoptosis, and proliferation .
-
Binds transforming growth factor-β activated kinase 1 (TAK1), suppressing TAK1-p38/JNK signaling in cardiac hypertrophy .
Role in Cancer
DUSP26 exhibits context-dependent roles in tumorigenesis:
Tumor-Suppressive Roles
-
Glioblastoma (GBM):
Table 1: DUSP26 Expression and Survival in Glioma Patients
| DUSP26 Expression | 5-Year Survival Rate | 10-Year Survival Rate |
|---|---|---|
| Low | 57.8% | 54.4% |
| High | 83.3% | 80.0% |
Oncogenic Roles
-
Anaplastic Thyroid Cancer (ATC):
-
Neuroblastoma:
Regulatory Mechanisms
Transcriptional Regulation:
Binding Partners:
-
SCRIB: Enhances DUSP26-mediated dephosphorylation of ERK in neuronal cells .
-
AK2 (Adenylate Kinase 2): Activates DUSP26, suppressing FADD phosphorylation and apoptosis in cancer cells .
Pathway Modulation:
-
Inhibits MAPK and Akt pathways, reducing cell proliferation and metastasis .
-
Suppresses TAK1-p38/JNK axis in cardiomyocytes, attenuating pathological hypertrophy .
Therapeutic Potential
Targeted Inhibition:
-
NSC-87877: Inhibits DUSP26 activity, reducing neuroblastoma cell viability .
-
Ethyl-3,4-dephostatin: Suppresses DUSP26 in thyroid cancer models .
Clinical Implications:
Data Tables
Table 2: Key Substrates and Pathways Regulated by DUSP26
| Substrate | Pathway Affected | Biological Outcome |
|---|---|---|
| p38 MAPK | MAPK signaling | Reduced apoptosis in ATC |
| ERK | Proliferation | Inhibited GBM growth |
| TAK1 | Cardiac hypertrophy | Attenuated heart remodeling |
| p53 | DNA damage response | Enhanced neuroblastoma survival |
Product Specs
Q&A
What are the primary molecular functions of DUSP26 in human cells?
DUSP26 (Dual Specificity Phosphatase 26) regulates intracellular signaling by dephosphoryating key substrates in the MAPK (mitogen-activated protein kinase) and Akt pathways. It exhibits phosphatase activity toward ERK1/2, JNK, and p38 MAPKs , while also modulating Akt phosphorylation states to influence cell proliferation and apoptosis . Structurally, its catalytic activity depends on a conserved PTP-loop conformation stabilized by N-terminal residues . Methodologically, its function is validated via in vitro phosphatase assays, co-immunoprecipitation (Co-IP), and CRISPR-mediated knockdown/overexpression models .
Table 1: Validated DUSP26 Substrates and Functional Outcomes
How is DUSP26 expression quantified in human tissues?
DUSP26 expression is measured using:
-
qRT-PCR for mRNA levels (primer sequences targeting exons 2–4) .
-
Western blotting with antibodies against residues 61–211 (e.g., Abcam ab154867) .
-
Immunohistochemistry (IHC) on tissue microarrays, showing reduced expression in high-grade gliomas vs. normal brain .
Critical controls include normalizing to housekeeping genes (e.g., GAPDH) and validating antibody specificity using CRISPR-KO cell lines .
What structural features enable DUSP26’s catalytic activity?
The N-terminal α1-helix (residues 39–60) stabilizes the PTP-loop via hydrogen bonding with the α7-α8 loop, enabling substrate binding . Crystal structures (PDB: 5GJ7) reveal a monomeric fold distinct from other DUSPs, with a substrate-binding pocket accommodating phosphorylated tyrosine and serine/threonine residues . Mutagenesis studies show that C152S mutations abolish activity by disrupting the catalytic cysteine .
How do contradictory reports on DUSP26’s role in cancer arise?
DUSP26 exhibits context-dependent oncogenic or tumor-suppressive roles:
-
Tumor-Suppressive: Downregulation in glioblastoma correlates with poor survival, and overexpression reduces proliferation via MAPK/Akt inhibition .
-
Oncogenic: In neuroblastoma, DUSP26 stabilizes mitochondrial ROS-p38 signaling, promoting survival .
These contradictions arise from tissue-specific binding partners (e.g., DPP4 in aortic valves vs. p53 in neuroblastoma) and differential substrate targeting . Researchers must validate substrate interactions using phosphoproteomics and kinase activity assays in disease-specific models.
What experimental models are optimal for studying DUSP26 in vivo?
For genetic manipulation, CRISPR-Cas9 gRNAs (e.g., 5′-GCTCAGCTCTACCTGCACCATG-3′) achieve >80% KO efficiency in U87 cells .
How can researchers resolve ambiguities in DUSP26’s substrate specificity?
-
Structural-guided mutagenesis: Swap residues in the PTP-loop (e.g., R156A) to assess phosphatase activity toward phosphopeptide libraries .
-
Crosslinking-MS: Identify proximal interactors in mitochondrial fractions (e.g., Pink1 in neurons) .
-
Phos-tag gels: Resolve phosphorylation shifts in MAPKs/Akt after DUSP26 overexpression .
A 2021 study combining cryo-EM and molecular dynamics simulations revealed that DUSP26’s substrate selectivity is dynamically regulated by its N-terminal membrane-anchoring domain .
What methodologies address DUSP26’s dual role in apoptosis and survival?
-
Live-cell imaging: Track real-time caspase activation (e.g., FLICA assays) in DUSP26-KO neuroblastoma cells .
-
Metabolic profiling: Measure OCR (oxygen consumption rate) and ROS levels via Seahorse assays to link mitochondrial dysfunction to apoptosis .
-
Single-cell RNA-seq: Stratify patient gliomas by DUSP26 expression to correlate MAPK/Akt activity with survival .
Why is achieving crystallographic resolution of active DUSP26 challenging?
DUSP26’s N-terminal region (residues 1–38) is intrinsically disordered, complicating crystallization . A 2016 study overcame this by:
-
Using C152S mutants to stabilize the protein without altering catalytic loops .
-
Employing SEC-MALS (size-exclusion chromatography with multi-angle light scattering) to confirm monodispersity .
How do post-translational modifications regulate DUSP26 activity?
Methodologically, methylation-specific PCR and ubiquitin pulldowns are used to profile these modifications .
What strategies improve DUSP26-targeted therapeutic design?
-
Allosteric inhibitors: Target the α7-α8 loop (e.g., compound 23a, IC50 = 120 nM) .
-
PROTACs: Degrade oncogenic DUSP26 variants using VHL-based recruiters .
-
AAV-mediated delivery: Restore DUSP26 in Dusp26−/− mice, reducing aortic valve calcification by 60% .
Current inhibitors lack specificity due to homology among DUSPs; cryo-EM-guided drug design is addressing this .
Product Science Overview
Dual Specificity Phosphatase 26 (DUSP26) is a member of the tyrosine phosphatase family of proteins. It exhibits dual specificity by dephosphorylating tyrosine as well as serine and threonine residues . This enzyme plays a crucial role in the regulation of intracellular signaling pathways, which in turn influence a broad range of physiological processes .
DUSP26 is an atypical dual specificity phosphatase with a range of physiological substrates, including the Mitogen-Activated Protein Kinases (MAPKs) . The protein is known to inactivate MAPK1 and MAPK3, leading to the dephosphorylation of heat shock factor protein 4 and a reduction in its DNA-binding activity . Additionally, DUSP26 inhibits MAP kinase p38 by dephosphorylating it and inhibits p38-mediated apoptosis in anaplastic thyroid cancer cells .
DUSP26 is heavily implicated in cancer, where it displays both tumor-suppressive and tumor-promoting properties . The residues that govern DUSP26 substrate specificity are yet to be determined; however, recent evidence suggests that interactions with a binding partner may be required for DUSP26 catalytic activity .
