Met provides essential signals for liver regeneration.
Genetic analysis in mice has demonstrated a crucial role of the Met tyrosine kinase receptor and its ligand, hepatocyte growth factor/scatter factor (HGF/SF), in development of the liver, muscle, and placenta. Here, we use conditional mutagenesis in mice to analyze the function of Met during liver regeneration, using the Mx-cre transgene to introduce the mutation in the adult. After partial hepatectomy in mice carrying the Mx-cre-induced Met mutation, regeneration of the liver is impaired. Comparison of signal transduction pathways in control and mutant livers indicates that Met and other signaling receptors cooperate to fully activate particular signaling molecules, for instance, the protein kinase Akt. However, activation of the Erk1/2 kinase during liver regeneration depends exclusively on Met. Signaling crosstalk is thus an important aspect of the regulation of liver regeneration. Analysis of cell cycle progression of hepatocytes in conditional Met mutant mice indicates a defective exit from quiescence and diminished entry into S phase. Impaired liver regeneration is accompanied by compensatory physiological responses that include prolonged up-regulation of HGF/SF and IL-6 in peripheral blood. Our data demonstrate that the HGF/SF/Met signaling system is essential not only during liver development but also for the regeneration of the organ in the adult.
Borowiak
Malgorzata
M
Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin-Buch, Germany.
Garratt
Alistair N
AN
Wüstefeld
Torsten
T
Strehle
Michael
M
Trautwein
Christian
C
Birchmeier
Carmen
C
D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006498:Hepatectomy; D017228:Hepatocyte Growth Factor / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008099:Liver / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D008115:Liver Regeneration; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism; D019076:Transgenes
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D011518:Proto-Oncogene Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D000071679:Glycogen Synthase Kinase 3 beta; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3