ArticleScience signaling2020
An allosteric site on MKP5 reveals a strategy for small-molecule inhibition.
Article in Science signaling, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 22 citations in OpenAlex.
- MAP kinase phosphatases in metabolic diseases.Trends in endocrinology and metabolism: TEM · 2026Review
- Structural analysis of dual specificity phosphatases, the only type of protein tyrosine phosphatases found in humans and across diverse microorganisms.Journal of microbiology (Seoul, Korea) · 2025Review
- Dynamic and structural insights into allosteric regulation on MKP5 a dual-specificity phosphatase.Nature communications · 2025Article
- Mitogen-Activated Protein Kinase Phosphatase-5 is Required for TGF-β Signaling Through a JNK-Dependent Pathway.Molecular and cellular biology · 2025Article
- MAPK Phosphatase-5 is required for TGF-β signaling through a JNK-dependent pathway.bioRxiv : the preprint server for biology · 2024Article
- MKP1 promotes nonalcoholic steatohepatitis by suppressing AMPK activity through LKB1 nuclear retention.Nature communications · 2023Article
- Targeting protein phosphatases in cancer immunotherapy and autoimmune disorders.Nature reviews. Drug discovery · 2023Review
- Mitogen-Activated Protein Kinase Phosphatases: No Longer Undruggable?Annual review of pharmacology and toxicology · 2023Review
- Defining the structure-activity relationship for a novel class of allosteric MKP5 inhibitors.European journal of medicinal chemistry · 2022Article
- Functional interrogation and therapeutic targeting of protein tyrosine phosphatases.Biochemical Society transactions · 2021Review
- Structural Insights into the Active Site Formation of DUSP22 in N-loop-containing Protein Tyrosine Phosphatases.International journal of molecular sciences · 2020Article
- Improving Obesity and Insulin Resistance by Targeting Skeletal Muscle MKP-1.Journal of cellular signaling · 2020Article
Corrections and comments
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Authors and funding
17 authors at 3 institutions in 2 countries.
Funding
Abstract
The mitogen-activated protein kinase (MAPK) phosphatases (MKPs) have been considered "undruggable," but their position as regulators of the MAPKs makes them promising therapeutic targets. MKP5 has been suggested as a potential target for the treatment of dystrophic muscle disease. Here, we identified an inhibitor of MKP5 using a p38α MAPK-derived, phosphopeptide-based small-molecule screen. We solved the structure of MKP5 in complex with this inhibitor, which revealed a previously undescribed allosteric binding pocket. Binding of the inhibitor to this pocket collapsed the MKP5 active site and was predicted to limit MAPK binding. Treatment with the inhibitor recapitulated the phenotype of MKP5 deficiency, resulting in activation of p38 MAPK and JNK. We demonstrated that MKP5 was required for TGF-β1 signaling in muscle and that the inhibitor blocked TGF-β1-mediated Smad2 phosphorylation. TGF-β1 pathway antagonism has been proposed for the treatment of dystrophic muscle disease. Thus, allosteric inhibition of MKP5 represents a therapeutic strategy against dystrophic muscle disease.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.