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

Ariella Zehender, Jingang Huang, Andrea Hermina Györfi, Alexandru Emil Matei, Thuong Trinh-Minh, Xiaohan Xu, Yi Nan Li, Chih Wei Chen, Jianping Lin, Clara Dees, Christian Beyer, Kolja Gelse, Zhong-Yin Zhang, Christina Bergmann, Andreas Ramming, Walter Birchmeier, Oliver Distler, Georg Schett, Jörg H.W. Distler

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article number3259
JournalNature Communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018
Externally publishedYes

Fingerprint

Non-Receptor Type 11 Protein Tyrosine Phosphatase
fibrosis
phosphatases
tyrosine
fibroblasts
Fibroblasts
Tyrosine
Fibrosis
Chemical activation
activation
Pulmonary Fibrosis
Tissue
Skin
stimulation
Phosphoric Monoester Hydrolases
deactivation
inhibitors
availability
Availability

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Zehender, A., Huang, J., Györfi, A. H., Matei, A. E., Trinh-Minh, T., Xu, X., ... Distler, J. H. W. (2018). The tyrosine phosphatase SHP2 controls TGFβ-induced STAT3 signaling to regulate fibroblast activation and fibrosis. Nature Communications, 9(1), [3259]. https://doi.org/10.1038/s41467-018-05768-3

The tyrosine phosphatase SHP2 controls TGFβ-induced STAT3 signaling to regulate fibroblast activation and fibrosis. / Zehender, Ariella; Huang, Jingang; Györfi, Andrea Hermina; Matei, Alexandru Emil; Trinh-Minh, Thuong; Xu, Xiaohan; Li, Yi Nan; Chen, Chih Wei; Lin, Jianping; Dees, Clara; Beyer, Christian; Gelse, Kolja; Zhang, Zhong-Yin; Bergmann, Christina; Ramming, Andreas; Birchmeier, Walter; Distler, Oliver; Schett, Georg; Distler, Jörg H.W.

In: Nature Communications, Vol. 9, No. 1, 3259, 01.12.2018.

Research output: Contribution to journalArticle

Zehender, A, Huang, J, Györfi, AH, Matei, AE, Trinh-Minh, T, Xu, X, Li, YN, Chen, CW, Lin, J, Dees, C, Beyer, C, Gelse, K, Zhang, Z-Y, Bergmann, C, Ramming, A, Birchmeier, W, Distler, O, Schett, G & Distler, JHW 2018, 'The tyrosine phosphatase SHP2 controls TGFβ-induced STAT3 signaling to regulate fibroblast activation and fibrosis', Nature Communications, vol. 9, no. 1, 3259. https://doi.org/10.1038/s41467-018-05768-3
Zehender, Ariella ; Huang, Jingang ; Györfi, Andrea Hermina ; Matei, Alexandru Emil ; Trinh-Minh, Thuong ; Xu, Xiaohan ; Li, Yi Nan ; Chen, Chih Wei ; Lin, Jianping ; Dees, Clara ; Beyer, Christian ; Gelse, Kolja ; Zhang, Zhong-Yin ; Bergmann, Christina ; Ramming, Andreas ; Birchmeier, Walter ; Distler, Oliver ; Schett, Georg ; Distler, Jörg H.W. / The tyrosine phosphatase SHP2 controls TGFβ-induced STAT3 signaling to regulate fibroblast activation and fibrosis. In: Nature Communications. 2018 ; Vol. 9, No. 1.
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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.",
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