Demonstration of cooperative contribution of MET- and EGFR-mediated STAT3 phosphorylation to liver regeneration by exogenous suppressor of cytokine signalings.
OBJECTIVE
As conditional knockout mice for stat3 are impaired in liver regeneration after partial hepatectomy while those for gp130 have defects in early STAT3 phosphorylation but have normal DNA synthesis, late STAT3 phosphorylation induced independently of gp130 seems to be essential for liver regeneration. Since HGF and EGF can activate STAT3 via gp130-independent MET and EGFR, respectively, we assumed that these factors account for STAT3-dependent liver regeneration. Here, we investigated this hypothesis by introducing suppressor of cytokine signaling (SOCS)-1 and SOCS3, potent negative regulators of STAT3 signaling, selectively in hepatocytes.


METHODS
We generated recombinant adenoviruses expressing socs1 and socs3.


RESULTS
Hepatocytes infected with socs1-virus lacked STAT3 phosphorylation in response to IL-6 and HGF, while cells infected with socs3-virus lacked the response to all of IL-6, HGF and EGF, indicating that those SOCS proteins differently regulate EGFR signaling. Mice infected with socs3-virus exhibited severe and persistent impairment while those with socs1-virus showed only delayed regeneration, indicating requirement of both MET and EGFR signalings.


CONCLUSIONS
These results clearly demonstrated that MET- and EGFR-mediated STAT3 signalings cooperatively contribute to liver regeneration and could provide new insights into tissue homeostasis.
Seki
Ekihiro
E
Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan.
Kondo
Yuichi
Y
Iimuro
Yuji
Y
Naka
Tetsuji
T
Son
Gakuhei
G
Kishimoto
Tadamitsu
T
Fujimoto
Jiro
J
Tsutsui
Hiroko
H
Nakanishi
Kenji
K
D000818:Animals; D002453:Cell Cycle; D004247:DNA / Q000096:biosynthesis; D066246:ErbB Receptors / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D008115:Liver Regeneration; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D019859:Proto-Oncogene Proteins c-met / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000502:physiology*
D050796:STAT3 Transcription Factor; C491590:Socs1 protein, mouse; C491411:Socs3 protein, mouse; C494087:Stat3 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D004247:DNA; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met; D048049:Extracellular Signal-Regulated MAP Kinases