title: Combined systemic elimination of MET and epidermal growth factor receptor signaling completely abolishes liver regeneration and leads to liver decompensation.
abstract: Receptor tyrosine kinases MET and epidermal growth factor receptor (EGFR) are critically involved in initiation of liver regeneration. Other cytokines and signaling molecules also participate in the early part of the process. Regeneration employs effective redundancy schemes to compensate for the missing signals. Elimination of any single extracellular signaling pathway only delays but does not abolish the process. Our present study, however, shows that combined systemic elimination of MET and EGFR signaling (MET knockout + EGFR-inhibited mice) abolishes liver regeneration, prevents restoration of liver mass, and leads to liver decompensation. MET knockout or simply EGFR-inhibited mice had distinct and signaling-specific alterations in Ser/Thr phosphorylation of mammalian target of rapamycin, AKT, extracellular signal-regulated kinases 1/2, phosphatase and tensin homolog, adenosine monophosphate-activated protein kinase α, etc. In the combined MET and EGFR signaling elimination of MET knockout + EGFR-inhibited mice, however, alterations dependent on either MET or EGFR combined to create shutdown of many programs vital to hepatocytes. These included decrease in expression of enzymes related to fatty acid metabolism, urea cycle, cell replication, and mitochondrial functions and increase in expression of glycolysis enzymes. There was, however, increased expression of genes of plasma proteins. Hepatocyte average volume decreased to 35% of control, with a proportional decrease in the dimensions of the hepatic lobules. Mice died at 15-18 days after hepatectomy with ascites, increased plasma ammonia, and very small livers.
  
  
  
  MET and EGFR separately control many nonoverlapping signaling endpoints, allowing for compensation when only one of the signals is blocked, though the combined elimination of the signals is not tolerated; the results provide critical new information on interactive MET and EGFR signaling and the contribution of their combined absence to regeneration arrest and liver decompensation. (Hepatology 2016;64:1711-1724).
authors.affiliation: Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA.
authors.forename: Shirish
authors.initials: S
authors.lastname: Paranjpe
authors.affiliation: Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA.
authors.forename: William C
authors.initials: WC
authors.lastname: Bowen
authors.affiliation: Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA.
authors.forename: Wendy M
authors.initials: WM
authors.lastname: Mars
authors.affiliation: Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA.
authors.forename: Anne
authors.initials: A
authors.lastname: Orr
authors.affiliation: Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA.
authors.forename: Meagan M
authors.initials: MM
authors.lastname: Haynes
authors.affiliation: Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA.
authors.forename: Marie C
authors.initials: MC
authors.lastname: DeFrances
authors.affiliation: Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA.
authors.forename: Silvia
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA.
authors.forename: George C
authors.initials: GC
authors.lastname: Tseng
authors.affiliation: Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Tsagianni
authors.affiliation: Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA. michalopoulosgk@upmc.edu.
authors.forename: George K
authors.initials: GK
authors.lastname: Michalopoulos
mesh_terms: D000818:Animals; D066246:ErbB Receptors / Q000502:physiology*; D017093:Liver Failure / Q000209:etiology*; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D051379:Mice; D019859:Proto-Oncogene Proteins c-met / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met