| Autor: |
Dorry S; Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA., Perla S; Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA., Bennett AM; Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA.; Yale Center for Molecular and Systems Metabolism, Yale University School of Medicine, New Haven, Connecticut, USA. |
| Jazyk: |
angličtina |
| Zdroj: |
Molecular and cellular biology [Mol Cell Biol] 2025 Jan; Vol. 45 (1), pp. 17-31. Date of Electronic Publication: 2024 Nov 28. |
| DOI: |
10.1080/10985549.2024.2426665 |
| Abstrakt: |
Mitogen-activated protein kinase (MAPK) phosphatases (MKPs) constitute members of the dual-specificity family of protein phosphatases that dephosphorylate the MAPKs. MKP-5 dephosphorylates the stress-responsive MAPKs, p38 MAPK and JNK, and has been shown to promote tissue fibrosis. Here, we provide insight into how MKP-5 regulates the transforming growth factor-β (TGF-β) pathway, a well-established driver of fibrosis. We show that MKP-5-deficient fibroblasts in response to TGF-β are impaired in SMAD2 phosphorylation at canonical and non-canonical sites, nuclear translocation, and transcriptional activation of fibrogenic genes. Consistent with this, pharmacological inhibition of MKP-5 is sufficient to block TGF-β signaling, and that this regulation occurs through a JNK-dependent pathway. By utilizing RNA sequencing and transcriptomic analysis, we identify TGF-β signaling activators regulated by MKP-5 in a JNK-dependent manner, providing mechanistic insight into how MKP-5 promotes TGF-β signaling. This study elucidates a novel mechanism whereby MKP-5-mediated JNK inactivation is required for TGF-β signaling and provides insight into the role of MKP-5 in tissue fibrosis. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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