title: Large tumor suppressor homologs 1 and 2 regulate mouse liver progenitor cell proliferation and maturation through antagonism of the coactivators YAP and TAZ.
abstract: In the adult liver, the Hippo pathway mammalian STE20-like protein kinases 1 and 2 and large tumor suppressor homologs 1 and 2 (LATS1/2) control activation of the transcriptional coactivators Yes-associated protein (YAP) and WW domain containing transcription regulator 1 (TAZ) in hepatocytes and biliary epithelial cells, thereby regulating liver cell proliferation, differentiation, and malignant transformation. Less is known about the contribution of Hippo signaling to liver development. We used conditional mutagenesis to show that the Hippo signaling pathway kinases LATS1 and LATS2 are redundantly required during mouse liver development to repress YAP and TAZ in both the biliary epithelial and hepatocyte lineages. In the absence of LATS1/2, biliary epithelial cells exhibit excess proliferation while hepatoblasts fail to mature into hepatocytes, defects that result in perinatal lethality. Using an in vitro hepatocyte differentiation assay, we demonstrate that YAP activity decreases and Hippo pathway kinase activities increase upon differentiation. In addition, we show that YAP activation in vitro, resulting from either depletion of its negative regulators LATS1/2 or expression of a mutant form of YAP that is less efficiently phosphorylated by LATS1/2, results in transcriptional suppression of genes that normally accompany hepatocyte maturation. Moreover, we provide evidence that YAP activity is repressed by Hippo pathway activation upon hepatocytic maturation in vitro. Finally, we examine the localization of YAP during fetal liver development and show that higher levels of YAP are found in biliary epithelial cells, while in hepatocytes YAP levels decrease with hepatocyte maturation.
  
  
  
  Hippo signaling, mediated by the LATS1 and LATS2 kinases, is required to restrict YAP and TAZ activation during both biliary and hepatocyte differentiation. These findings suggest that dynamic regulation of the Hippo signaling pathway plays an important role in differentiation and functional maturation of the liver. (Hepatology 2016;64:1757-1772).
authors.affiliation: Department of Cancer Biology, MD Anderson Cancer Center, University of Texas, Houston, TX.
authors.forename: Jing
authors.initials: J
authors.lastname: Yi
authors.affiliation: Department of Genetics, MD Anderson Cancer Center, University of Texas, Houston, TX.
authors.forename: Li
authors.initials: L
authors.lastname: Lu
authors.affiliation: Department of Medicine, Gastroenterology Division, University of Pennsylvania School of Medicine, Philadelphia, PA.|Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA.
authors.forename: Kilangsungla
authors.initials: K
authors.lastname: Yanger
authors.affiliation: Department of Experimental Radiation Oncology, MD Anderson Cancer Center, University of Texas, Houston, TX.
authors.forename: Wenqi
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Systems Biology, MD Anderson Cancer Center, University of Texas, Houston, TX.
authors.forename: Bo Hwa
authors.initials: BH
authors.lastname: Sohn
authors.affiliation: Department of Medicine, Gastroenterology Division, University of Pennsylvania School of Medicine, Philadelphia, PA.|Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA.|Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Pennsylvania, PA.
authors.forename: Ben Z
authors.initials: BZ
authors.lastname: Stanger
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX.
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX.
authors.forename: James F
authors.initials: JF
authors.lastname: Martin
authors.affiliation: Department of GI Oncology, MD Anderson Cancer Center, University of Texas, Houston, TX.
authors.forename: Jaffer A
authors.initials: JA
authors.lastname: Ajani
authors.affiliation: Department of Experimental Radiation Oncology, MD Anderson Cancer Center, University of Texas, Houston, TX.
authors.forename: Junjie
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Systems Biology, MD Anderson Cancer Center, University of Texas, Houston, TX.
authors.forename: Ju-Seog
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Department of GI Oncology, MD Anderson Cancer Center, University of Texas, Houston, TX.
authors.forename: Shumei
authors.initials: S
authors.lastname: Song
authors.affiliation: Department of Cancer Biology, MD Anderson Cancer Center, University of Texas, Houston, TX. rljohnso@mdanderson.org.|Genes & Development Program, Graduate School of Biomedical Sciences, University of Texas Health Sciences Center, Houston, TX. rljohnso@mdanderson.org.|Developmental Biology Program, Baylor College of Medicine, Houston, TX. rljohnso@mdanderson.org.
authors.forename: Randy L
authors.initials: RL
authors.lastname: Johnson
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000818:Animals; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D049109:Cell Proliferation / Q000502:physiology*; D022781:Hepatocytes / Q000502:physiology*; D008099:Liver / Q000166:cytology*; D051379:Mice; D010750:Phosphoproteins / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D013234:Stem Cells / Q000502:physiology*; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins / Q000502:physiology*; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D010750:Phosphoproteins; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; C517794:Wwtr1 protein, mouse; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; C490501:Lats1 protein, mouse; C522633:LATS2 protein, mouse; D017346:Protein Serine-Threonine Kinases