title: Dynamic alterations in Hippo signaling pathway and YAP activation during liver regeneration.
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.
authors.affiliation: Department of Surgery, Boston Children's Hospital, Boston, Massachusetts;
authors.forename: James L
authors.initials: JL
authors.lastname: Grijalva
authors.affiliation: MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Boston, Massachusetts; and.
authors.forename: Megan
authors.initials: M
authors.lastname: Huizenga
authors.affiliation: Department of Surgery, Boston Children's Hospital, Boston, Massachusetts;
authors.forename: Kaly
authors.initials: K
authors.lastname: Mueller
authors.affiliation: MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Boston, Massachusetts; and.
authors.forename: Steven
authors.initials: S
authors.lastname: Rodriguez
authors.affiliation: Department of Surgery, Boston Children's Hospital, Boston, Massachusetts;
authors.forename: Joseph
authors.initials: J
authors.lastname: Brazzo
authors.affiliation: Department of Stem Cell and Regenerative Biology, Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Fernando
authors.initials: F
authors.lastname: Camargo
authors.affiliation: MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Boston, Massachusetts; and.
authors.forename: Ghazaleh
authors.initials: G
authors.lastname: Sadri-Vakili
authors.affiliation: Department of Surgery, Boston Children's Hospital, Boston, Massachusetts; Khashayar.Vakili@childrens.harvard.edu.
authors.forename: Khashayar
authors.initials: K
authors.lastname: Vakili
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D049109:Cell Proliferation; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D006498:Hepatectomy; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D008099:Liver / Q000201:enzymology* / Q000473:pathology / Q000601:surgery; D008115:Liver Regeneration; D008297:Male; D023421:Models, Animal; D009929:Organ Size; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051381:Rats; D011917:Rats, Inbred Lew; D000090742:Serine-Threonine Kinase 3; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic; D000091102:YAP-Signaling Proteins; D000099317:Hippo Kinases
chemical_list: D051017:Apoptosis Regulatory Proteins; D017228:Hepatocyte Growth Factor; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000090742:Serine-Threonine Kinase 3; D000091102:YAP-Signaling Proteins; C509425:Yap1 protein, rat; C082332:macrophage stimulating protein; C490817:Stk3 protein, rat; D000099317:Hippo Kinases; C511957:Stk4 protein, rat; C000591484:Lats1 protein, rat; C000591485:Lats2 protein, rat
keywords: Hippo signaling pathway; YAP; liver; partial hepatectomy; regeneration