The Hippo signaling pathway has been implicated in mammalian organ size regulation and tumor suppression. Specifically, the Hippo pathway plays a critical role regulating the activity of transcriptional coactivator Yes-associated protein (YAP), which modulates a proliferative transcriptional program. Recent investigations have demonstrated that while this pathway is activated in quiescent livers, its inhibition leads to liver overgrowth and tumorigenesis. However, the role of the Hippo pathway during the natural process of liver regeneration remains unknown. Here we investigated alterations in the Hippo signaling pathway and YAP activation during liver regeneration using a 70% partial hepatectomy (PH) rat model. Our results indicate an increase in YAP activation by 1 day following PH as demonstrated by increased YAP nuclear localization and increased YAP target gene expression. Investigation of the Hippo pathway revealed a decrease in the activation of core kinases Mst1/2 by 1 day as well as Lats1/2 and its adapter protein Mob1 by 3 days following PH. Evaluation of liverto-body weight ratios indicated that the liver reaches its near normal size by 7 days following PH, which correlated with a return to baseline YAP nuclear levels and target gene expression. Additionally, when liver size was restored, Mst1/2 kinase activation returned to levels observed in quiescent livers indicating reactivation of the Hippo signaling pathway. These findings illustrate the dynamic changes in the Hippo signaling pathway and YAP activation during liver regeneration, which stabilize when the liver-to-body weight ratio reaches homeostatic levels.liver; regeneration; Hippo signaling pathway; YAP; partial hepatectomy THE LIVER HAS THE REMARKABLE ability to regenerate following hepatocyte loss (8). The endpoint of regeneration is replacement of lost hepatic mass until the near original liver-to-body weight ratio is restored. In clinical practice, this regulation can be observed following liver resection or partial liver transplantation after which the liver grows to reach the optimal liverto-body weight ratio for the individual. In contrast, large size liver grafts tend to atrophy to reach the optimal liver-to-body weight ratio (4, 13). Even though numerous cytokines and growth factors have been shown to play a role in liver regeneration, the exact mechanisms that are responsible for the initiation and termination of liver regeneration are not fully understood.Recent studies have demonstrated that the Hippo signaling pathway plays a role in liver size regulation through regulation of the transcriptional coactivator Yes-associated protein (YAP) (7,20). While activation of the Hippo pathway leads to phosphorylation of YAP (p-YAP) (2, 9, 18) resulting in YAP cytoplasmic retention and degradation, attenuation of Hippo signaling leads to increased YAP nuclear localization and activation of a proliferative, antiapoptotic transcriptional program (2, 7). Deletion of Hippo pathway components in quiescent liver has been demonstrated to result in ...

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