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 and Jörg H. W. Distler ()
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Ariella Zehender: Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen
Jingang Huang: Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen
Andrea-Hermina Györfi: Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen
Alexandru-Emil Matei: Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen
Thuong Trinh-Minh: Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen
Xiaohan Xu: Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen
Yi-Nan Li: Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen
Chih-Wei Chen: Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen
Jianping Lin: Purdue University
Clara Dees: Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen
Christian Beyer: Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen
Kolja Gelse: Friedrich-Alexander-University Erlangen-Nürnberg (FAU)
Zhong-Yin Zhang: Purdue University
Christina Bergmann: Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen
Andreas Ramming: Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen
Walter Birchmeier: Max Delbrück Center for Molecular Medicine (MDC)
Oliver Distler: University Hospital Zurich
Georg Schett: Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen
Jörg H. W. Distler: Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen

Nature Communications, 2018, vol. 9, issue 1, 1-17

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05768-3

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