Article ; Online: Discoidin domain receptor 2 signaling through PIK3C2α in fibroblasts promotes lung fibrosis.
2024 Volume 262, Issue 4, Page(s) 505–516
Abstract: Pulmonary fibrosis, especially idiopathic pulmonary fibrosis (IPF), portends significant morbidity and mortality, and current therapeutic options are suboptimal. We have previously shown that type I collagen signaling through discoidin domain receptor 2 ( ...
| Abstract | Pulmonary fibrosis, especially idiopathic pulmonary fibrosis (IPF), portends significant morbidity and mortality, and current therapeutic options are suboptimal. We have previously shown that type I collagen signaling through discoidin domain receptor 2 (DDR2), a receptor tyrosine kinase expressed by fibroblasts, is critical for the regulation of fibroblast apoptosis and progressive fibrosis. However, the downstream signaling pathways for DDR2 remain poorly defined and could also be attractive potential targets for therapy. A recent phosphoproteomic approach indicated that PIK3C2α, a poorly studied member of the PI3 kinase family, could be a downstream mediator of DDR2 signaling. We hypothesized that collagen I/DDR2 signaling through PIK3C2α regulates fibroblast activity during progressive fibrosis. To test this hypothesis, we found that primary murine fibroblasts and IPF-derived fibroblasts stimulated with endogenous or exogenous type I collagen led to the formation of a DDR2/PIK3C2α complex, resulting in phosphorylation of PIK3C2α. Fibroblasts treated with an inhibitor of PIK3C2α or with deletion of PIK3C2α had fewer markers of activation after stimulation with TGFβ and more apoptosis after stimulation with a Fas-activating antibody. Finally, mice with fibroblast-specific deletion of PIK3C2α had less fibrosis after bleomycin treatment than did littermate control mice with intact expression of PIK3Cα. Collectively, these data support the notion that collagen/DDR2/PIK3C2α signaling is critical for fibroblast function during progressive fibrosis, making this pathway a potential target for antifibrotic therapy. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. |
|---|---|
| MeSH term(s) | Mice ; Animals ; Discoidin Domain Receptor 2/genetics ; Discoidin Domain Receptor 2/metabolism ; Collagen Type I/metabolism ; Fibroblasts/pathology ; Collagen/metabolism ; Idiopathic Pulmonary Fibrosis/metabolism ; Discoidin Domain Receptors/metabolism ; Lung/pathology |
| Chemical Substances | Discoidin Domain Receptor 2 (EC 2.7.10.1) ; Collagen Type I ; Collagen (9007-34-5) ; Discoidin Domain Receptors (EC 2.7.10.1) |
| Language | English |
| Publishing date | 2024-02-09 |
| Publishing country | England |
| Document type | Journal Article ; Research Support, N.I.H., Extramural |
| ZDB-ID | 3119-7 |
| ISSN | 1096-9896 ; 0022-3417 |
| ISSN (online) | 1096-9896 |
| ISSN | 0022-3417 |
| DOI | 10.1002/path.6253 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
More links
Kategorien
In stock of ZB MED Cologne/Königswinter
| Ud II Zs.12: Show issues | Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG) |
Order via subito
This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.