The tyrosine phosphatase SHP2 controls TGFβ-induced STAT3 signaling to regulate fibroblast activation and fibrosis
| Autor: | Andreas Ramming, Xiaohan Xu, Walter Birchmeier, Clara Dees, Jingang Huang, Chih-Wei Chen, Ariella Zehender, Yi Nan Li, Kolja Gelse, Christian Beyer, Jörg H W Distler, Georg Schett, Jian-Ping Lin, Andrea Hermina Györfi, Alexandru-Emil Matei, Christina Bergmann, Oliver Distler, Zhong Yin Zhang, Thuong Trinh-Minh |
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| Přispěvatelé: | University of Zurich, Huang, Jingang |
| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Cancer Research General Physics and Astronomy Protein Tyrosine Phosphatase Non-Receptor Type 11 Protein tyrosine phosphatase Transforming Growth Factor beta Fibrosis Pulmonary fibrosis lcsh:Science Mice Knockout Multidisciplinary biology Chemistry 10051 Rheumatology Clinic and Institute of Physical Medicine Middle Aged 3100 General Physics and Astronomy 3. Good health Cell biology medicine.anatomical_structure Organ Specificity Quinolines Phosphorylation Female Signal Transduction Adult STAT3 Transcription Factor Science Phosphatase Down-Regulation 610 Medicine & health 1600 General Chemistry Article General Biochemistry Genetics and Molecular Biology Cell Line Dephosphorylation Young Adult 03 medical and health sciences 1300 General Biochemistry Genetics and Molecular Biology medicine Animals Humans RNA Messenger Fibroblast Aged Scleroderma Systemic General Chemistry Transforming growth factor beta Fibroblasts Janus Kinase 2 medicine.disease Phosphoric Monoester Hydrolases 030104 developmental biology biology.protein Tyrosine lcsh:Q |
| Zdroj: | Nature Communications Nature Communications, Vol 9, Iss 1, Pp 1-17 (2018) |
| ISSN: | 2041-1723 |
| Popis: | 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. Hyperactivation of TGFβ signaling is a common feature of fibrotic diseases. Here the authors show that genetic or pharmacologic inactivation of the tyrosine phosphatase SHP2 prevents TGFβ-induced JAK2/STAT3 signaling, inhibits fibroblast activation and exerts potent anti-fibrotic effects. |
| Databáze: | OpenAIRE |
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