Helmholtz Gemeinschaft

Search
Browse
Statistics
Feeds

The tyrosine phosphatase SHP2 controls TGFβ-induced STAT3 signaling to regulate fibroblast activation and fibrosis

[thumbnail of Article]
Preview
PDF (Article) - Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader
4MB
[thumbnail of Supplementary Information]
Preview
PDF (Supplementary Information) - Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader
1MB

Item Type:Article
Title:The tyrosine phosphatase SHP2 controls TGFβ-induced STAT3 signaling to regulate fibroblast activation and fibrosis
Creators Name:Zehender, A., Huang, J., Györfi, A.H., Matei, A.E., Trinh-Minh, T., Xu, X., Li, Y.N., Chen, C.W., Lin, J., Dees, C., Beyer, C., Gelse, K., Zhang, Z.Y., Bergmann, C., Ramming, A., Birchmeier, W., Distler, O., Schett, G. and Distler, J.H.W.
Abstract:Uncontrolled activation of TGFβ signaling is a common denominator of fibrotic tissue remodeling. Here we characterize the tyrosine phosphatase SHP2 as a molecular checkpoint for TGFβ-induced JAK2/STAT3 signaling and as a potential target for the treatment of fibrosis. TGFβ stimulates the phosphatase activity of SHP2, although this effect is in part counterbalanced by inhibitory effects on SHP2 expression. Stimulation with TGFβ promotes recruitment of SHP2 to JAK2 in fibroblasts with subsequent dephosphorylation of JAK2 at Y570 and activation of STAT3. The effects of SHP2 on STAT3 activation translate into major regulatory effects of SHP2 on fibroblast activation and tissue fibrosis. Genetic or pharmacologic inactivation of SHP2 promotes accumulation of JAK2 phosphorylated at Y570, reduces JAK2/STAT3 signaling, inhibits TGFβ-induced fibroblast activation and ameliorates dermal and pulmonary fibrosis. Given the availability of potent SHP2 inhibitors, SHP2 might thus be a potential target for the treatment of fibrosis.
Keywords:Cell Line, Down-Regulation, Fibroblasts, Fibrosis, Janus Kinase 2, Organ Specificity, Non-Receptor Type 11, Protein Tyrosine Phosphatase, Quinolines, Messenger, RNA, STAT3 Transcription Factor, Systemic, Scleroderma, Signal Transduction, Transforming Growth Factor beta, Animals, Mice
Source:Nature Communications
ISSN:2041-1723
Publisher:Nature Publishing Group
Volume:9
Number:1
Page Range:3259
Date:14 August 2018
Official Publication:https://doi.org/10.1038/s41467-018-05768-3
PubMed:View item in PubMed

Repository Staff Only: item control page

Downloads

Downloads per month over past year

Open Access
MDC Library