Journal Article Preprint Epublish
PubMed: 38979264 DOI: 10.1101/2024.06.27.600976
MAPK Phosphatase-5 is required for TGF-β signaling through a JNK-dependent pathway.
bioRxiv
Authors: Sam Dorry, Sravan Perla, Anton M Bennett
Affiliations
- 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.
Abstract
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 fibrosis.
MeSH
Dual Specificity Phosphatase 1, Fibrosis, Mitogen-Activated Protein Kinases, Phosphoric Monoester Hydrolases