“The tyrosine phosphatase SHP2 is a molecular checkpoint for TGFβ signalling and a potential target for the treatment of fibrosis,” says Jörg Distler, corresponding author of a new study published in Nature Communications.

Fibrotic diseases such as systemic sclerosis (SSc) are characterized by persistent and excessive activation of fibroblasts by transforming growth factor-β (TGFβ), resulting in aberrant deposition of extracellular matrix proteins and consequent scarring and organ dysfunction. However, why pro-fibrotic signalling pathways are unable to turn off is not clear.

Credit: Springer Nature Limited

“Previous studies from our group and others have demonstrated that transcription factors JAK2 and STAT3 are important downstream mediators of the pro-fibrotic effects of TGFβ on fibroblasts,” says Distler.

In the new work, the researchers identify that SHP2 has a regulatory function in JAK2–STAT3 signalling. The researchers describe this control as a checkpoint, akin to those that enable cancer cells to avoid the immune system, only here the checkpoint controls persistence of fibrosis.

SHP2 has been shown previously to affect various signalling pathways, and some confusion exists as to whether it activates or deactivates signalling proteins. Importantly, Distler and colleagues now show that TGFβ has opposing effects on SHP2 expression and activity. In vivo data from patients with SSc, TSK1 mice (which model dermal fibrosis) and a bleomycin-induced mouse pulmonary fibrosis model, as well as in vitro stimulation of fibroblasts all show that TGFβ inhibits expression of SHP2. However, the researchers also show that TGFβ induces rapid SHP2 phosphatase activity in fibroblasts in vitro. This phosphatase activity is responsible for dephosphorylation of the inhibitory Y570 site in JAK2, resulting in enhanced activation of STAT3 and associated downstream pro-fibrotic signalling.

“The latest results on SHP2 may have direct translational implications as several potent SHP2 inhibitors are available, some of which already showed promising results in first clinical trials in cancer,” notes Distler.

…TGFβ induces rapid SHP2 phosphatase activity in fibroblasts

Indeed, this new study shows that either fibroblast-specific SHP2 knockout or what might be called checkpoint inhibitors of SHP2 can prevent TGFβ-induced JAK2–STAT3 signalling, fibroblast activation and fibrotic disease in the TSK1 and bleomycin-induced mouse models.