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.
Highlights
Uncontrolled activation of Transforming growth factor-β (TGFβ) signaling is a common denominator of fibrotic tissue remodeling
Double staining with the fibroblast marker prolyl-4-hydroxylase-β (P4Hβ), the endothelial marker CD31 and the leukocyte marker CD45 demonstrated that fibroblasts account for most of the SHP2 expression in the dermis and that Systemic sclerosis (SSc) fibroblasts express reduced levels of SHP2 compared to fibroblasts in healthy skin (Fig. 1c)
Our data characterize SHP2 as an important regulator of TGFβ signaling in fibroblasts
Summary
Uncontrolled activation of TGFβ signaling is a common denominator of fibrotic tissue remodeling. 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. SHP2 directly interacts with cytokine and growth factor receptors, and binds to a variety of signaling intermediates such as GRB2, FRS2, JAK2, the p85 subunit of PI3 kinase, IRS1 and GAB proteins to further modulate the signaling outcome[14,15] This regulation at multiple levels enables SHP2 to generate a wide range of diverse effects in different cellular contexts. Inactivation of SHP2 prevents TGFβ-induced JAK2/ STAT3 signaling, reduces fibroblast activation and ameliorates experimental fibrosis. These findings might have translational implications as potent inhibitors of SHP2 currently undergo clinical evaluation in cancer
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