SHP2 inhibition enhances Yes-associated protein–mediated liver regeneration in murine partial hepatectomy models

Abstract

Disrupted liver regeneration following hepatectomy represents an "undruggable" clinical challenge associated with poor patient outcomes. Yes-associated protein (YAP), a transcriptional co-activator which is repressed by the Hippo pathway, is instrumental in liver regeneration. We have previously described an alternative, Hippo-independent, mechanism of YAP activation mediated by tyrosine-protein phosphatase non-receptor type 11 (SHP2) inhibition. Herein, we examined the effects of YAP activation with a selective SHP1/SHP2 inhibitor, NSC-87877, on liver regeneration in murine partial hepatectomy models. In our studies, NSC-87877 led to accelerated hepatocyte proliferation, improved liver regeneration, and decreased markers of injury following partial hepatectomy. The effects of NSC-87877 were lost in mice with hepatocytespecific Yap/Taz deletion, which demonstrated dependence on these molecules for the enhanced regenerative response. Furthermore, administration of NSC-87877 to murine models of nonalcoholic steatohepatitis was associated with improved survival and decreased markers of injury post-hepatectomy. Evaluation of transcriptomic changes in the context of NSC-87877 administration revealed reduction in fibrotic signaling and augmentation of cell cycle signaling.Cytoprotective changes included downregulation of Nr4a1, an apoptosis inducer. Collectively, the data suggest that SHP2 inhibition induces a pro-proliferative and cytoprotective enhancement of liver regeneration dependent on YAP.

A small molecule MST1/2 inhibitor accelerates murine liver regeneration with improved survival in models of steatohepatitis

“…5 C). Partial hepatectomy in other murine MASH models has been shown to result in high postoperative mortality ( 4 ). Following partial hepatectomy, mice with diet-induced MASH had a 22.2% survival.…”

“…YAP activation via small molecule inhibitors has been associated with improved liver regeneration in mouse partial hepatectomy models ( 4 , 5 ). In these models the inhibitors have targeted both classic components of the Hippo pathway, which acts as a negative regulator of YAP activity, and alternative YAP activation pathways.…”

“…We have previously demonstrated the utility of targeting the YAP-interacting phosphatase SHP2 to augment liver regeneration. Mechanistically, we had demonstrated that SHP2 negatively regulates YAP activation separately from the Hippo pathway by removing an activating phosphorylation on tyrosine 357 ( 4 , 36 , 37 ). Activation of YAP via this mechanism improves regeneration and limits hepatocyte injury.…”

“…Yes-associated protein (YAP), a transcriptional coactivator, has consistently been shown to play a role in the process of liver regeneration ( 1–3 ). We, and others, have shown that activating YAP can augment or accelerate liver regeneration ( 4–6 ). The Hippo pathway is a series of serine/threonine kinases that phosphorylate and inhibit YAP, and its paralog TAZ ( 7 ).…”

YAP/TAZ: Molecular pathway and disease therapy

“…Interestingly, there is also a loop pathway in the YAP/TAZ‐induced liver regeneration. It has been shown that the binding of YAP/TAZ and TEAD can directly block NR4A1 transcription, while YAP can also stimulate NR4A1 phosphorylation and nuclear translocation under the mediation of AKT, thereby inhibiting the apoptosis‐promoting effect of NR4A1 and promoting hepatocyte proliferation, and the protein tyrosine phosphatase nonreceptor type 11 inhibition amplifies the effect of YAP on NR4A1 385 . NR4A1 can also regulate the ubiquitinated degradation of YAP through a negative feedback mechanism to prevent excessive proliferation of hepatocytes and avoid the occurrence of HCC 386 .…”