MAPK Phosphatase-5 is required for TGF-ß signaling through a JNK-dependent pathway.
bioRxiv
; 2024 Jun 27.
Article
in En
| MEDLINE
| ID: mdl-38979264
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-ß (TGF-ß) pathway, a well-established driver of fibrosis. We show that MKP-5-deficient fibroblasts in response to TGF-ß 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-ß signaling, and that this regulation occurs through a JNK-dependent pathway. By utilizing RNA sequencing and transcriptomic analysis, we identify TGF-ß signaling activators regulated by MKP-5 in a JNK-dependent manner, providing mechanistic insight into how MKP-5 promotes TGF-ß signaling. This study elucidates a novel mechanism whereby MKP-5-mediated JNK inactivation is required for TGF-ß signaling and provides insight into the role of MKP-5 in fibrosis.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Language:
En
Journal:
BioRxiv
Year:
2024
Document type:
Article
Affiliation country:
United States