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Cited by 497Liver physiology and pathologyHepatocellular Carcinoma Treatment and PrognosisOrgan Transplantation Techniques and Outcomes

Met provides essential signals for liver regeneration

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Borowiak, Malgorzata, Garratt, Alistair N., Wüstefeld, Torsten, Strehle, Michael, Trautwein, Christian, Birchmeier, Carmen·2004·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0403412101PMC PMC490025
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Abstract

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.

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  • Whole body MET knockout animals display a marked elevation of IL-6 following PHx compared to wild type controls.

    “Borowiak et al. reported that whole body MET knockout animals do display a marked elevation of IL-6 following PHx when compared to their wild type controls [22].”

    From Synthesis of IL-6 by Hepatocytes Is a Normal Response to Common Hepatic Stimuli (2014) · cites this paper as [22]

    The Results report that circulating IL-6 remained much elevated after partial hepatectomy in conditional Met mutant mice compared with controls. But the study used an inducible mutation in the adult liver, not a whole-body Met knockout; the Abstract notes that Met−/− embryos die during gestation. (LLM, conf=0.90)

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  • Mice with hepatocellular-targeted deletion of MET have a high death rate at 48 h following PHx, whereas mice with whole body deletion of MET survive.

    “Mice with hepatocellular-targeted deletion of MET are reported to have a high death rate at 48 h following PHx whereas surprisingly, mice with a whole body deletion of the receptor have been reported to survive [21], [22].”

    From Synthesis of IL-6 by Hepatocytes Is a Normal Response to Common Hepatic Stimuli (2014) · cites this paper as [22]

    Materials and Methods reports that 95% of conditional Met mutant mice died within 2–3 days of partial hepatectomy under one surgical procedure, but 85% survived under a modified procedure; the high death rate is therefore procedure-dependent, not an unqualified outcome at 48 hours. Results reports that mice with whole-body Met deletion died during gestation, so this paper does not support their reported survival. (LLM, conf=0.90)

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Cited by

Sorted by citations

Authors
Borowiak, M., Garratt, A. N., Wüstefeld, T., Strehle, M., Trautwein, C., & Birchmeier, C.
Affiliations
Max Delbrück Center (DE)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2004-07-12
Volume
101
Issue
29
Pages
10608-10613
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0403412101
PMC
PMC490025
OpenAlex
W2061863220
Cited by
497
References
7
Citations by year
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FWCI
15.47
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
  • Health Sciences › Medicine › Surgery › Organ Transplantation Techniques and Outcomes
Keywords
MET receptor tyrosine kinase, hepatocyte growth factor, liver regeneration, partial hepatectomy, conditional mutagenesis, Akt signaling, ERK signaling, signaling crosstalk, hepatocyte cell cycle, quiescence exit, interleukin-6, liver development
MeSH terms
Glycogen Synthase Kinase 3 beta, Animals, Cell Cycle, DNA-Binding Proteins, Hepatectomy, Liver, Liver Regeneration, Mice, Transgenic, Mutation, Proto-Oncogene Proteins, Signal Transduction, Trans-Activators, Interleukin-6, Hepatocyte Growth Factor, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Transgenes, Proto-Oncogene Proteins c-met, Mitogen-Activated Protein Kinases, Glycogen Synthase Kinase 3, STAT3 Transcription Factor, Proto-Oncogene Proteins c-akt, Mice

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