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

Beitrag in einer Fachzeitschrift


Details zur Publikation

Autor(en): 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
Zeitschrift: Nature Communications
Jahr der Veröffentlichung: 2018
Band: 9
Heftnummer: 1
ISSN: 2041-1723


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.


FAU-Autoren / FAU-Herausgeber

Beyer, Christian PD Dr.
Medizinische Klinik 3 - Rheumatologie und Immunologie
Dees, Clara Dr. rer. nat.
Medizinische Klinik 3 - Rheumatologie und Immunologie
Distler, Jörg PD Dr.
Heisenberg-Professur für Molekulare Mechanismen der Organfibrose
Matei, Alexandru-Emil Dr.
Medizinische Klinik 3 - Rheumatologie und Immunologie
Schett, Georg Prof. Dr. med.
Lehrstuhl für Innere Medizin III


Autor(en) der externen Einrichtung(en)
Max-Delbrück-Centrum für Molekulare Medizin (MDC) Berlin-Buch
Purdue-University
Universitätsspital Zürich (USZ)


Zitierweisen

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).

BibTeX: 

Zuletzt aktualisiert 2018-11-10 um 13:53