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

Zehender A, Huang J, Gyoerfi AH, Matei AE, Thuong Trinh-Minh , Xu X, Li YN, Chen CW, Lin J, Dees C, Beyer C, Gelse K, Zhang ZY, Bergmann C, Ramming A, Birchmeier W, Distler O, Schett G, Distler J (2018)

Publication Type: Journal article

Publication year: 2018

Journal

Nature Communications Nature Publishing Group: Nature Communications

Book Volume: 9

Journal Issue: 1

DOI: 10.1038/s41467-018-05768-3

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.

Authors with CRIS profile

Alexandru-Emil Matei Department of Medicine 3 – Rheumatology and Immunology Clara Dees Department of Medicine 3 – Rheumatology and Immunology Christian Beyer Department of Medicine 3 – Rheumatology and Immunology Andreas Ramming Department of Medicine 3 – Rheumatology and Immunology Georg Schett Lehrstuhl für Innere Medizin III Jörg Distler Professur für Molekulare Mechanismen der Organfibrose

Additional Organisation(s)

Interdisziplinäres Zentrum für Klinische Forschung

Involved external institutions

Purdue-University US United States (USA) (US) Universitätsspital Zürich (USZ) CH Switzerland (CH) Max-Delbrück-Centrum für Molekulare Medizin / Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch DE Germany (DE)

How to cite

APA:

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

MLA:

Zehender, Ariella, et al. "The tyrosine phosphatase SHP2 controls TGFβ-induced STAT3 signaling to regulate fibroblast activation and fibrosis." Nature Communications 9.1 (2018).

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