Dynamic alterations in Hippo signaling pathway and YAP activation during liver regeneration

Am J Physiol Gastrointest Liver Physiol. 2014 Jul 15;307(2):G196-204. doi: 10.1152/ajpgi.00077.2014. Epub 2014 May 29.

Abstract

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 liver-to-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.

Keywords: Hippo signaling pathway; YAP; liver; partial hepatectomy; regeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / metabolism*
  • Cell Proliferation*
  • Enzyme Activation
  • Gene Expression Regulation
  • Hepatectomy
  • Hepatocyte Growth Factor / metabolism*
  • Liver / enzymology*
  • Liver / pathology
  • Liver / surgery
  • Liver Regeneration*
  • Male
  • Models, Animal
  • Organ Size
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / metabolism*
  • Rats
  • Rats, Inbred Lew
  • Signal Transduction*
  • Time Factors
  • Transcription, Genetic

Substances

  • Apoptosis Regulatory Proteins
  • Proto-Oncogene Proteins
  • Yap protein, rat
  • macrophage stimulating protein
  • Hepatocyte Growth Factor
  • Stk3 protein, rat
  • Stk4 protein, rat
  • Lats1 protein, rat
  • Lats2 protein, rat
  • Protein-Serine-Threonine Kinases