Molecular Mechanisms of Tissue Regeneration through the Conversion of HGF Receptor Signaling in Response of Injury

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(1) Regulation of HGF/c-Met activation through tyrosine dephosphrylation by LAR:Inhibition of cell proliferation regulated by cell-cell contact is a fundamental characteristic of normal cells. In hepatocytes cultured at a confluent cell density, HGF stimulation induced transient c-Met tyrosine phosphorylation and failed to induce mitogenic response. We found that LAR plays a definitive role in inactivation, i.e. tyrosine dephosphorylation of c-Met through their physical interaction, which specifically occurs in hepatocytes under confluent condition. We published these results in J-Biol-Chem 281 : 8765 (2006).(2) Physiological significance of HGF/c-Met activation in cholestatic injury:We used a surgical technique of bile duct ligation (BDL) to induce cholestatic conditions in mice. After the BDL surgery, HGF and c-Met mRNA levels transiently increased in livers. Furthmore, we obtained evidence that endogenous HGF is involved in the physiological protection of hepatocyte cell death including necrosis and apoptosis. We published these results in Am-J-Physiol 292 : G639 (2007).(3) Generation of knock-in mice expressing only mutated c-Met (ΔJxt-Met):The phosphorylation status of juxtamembrane Ser-985 of c-Met plays functional regulatory role in activation of c-Met. c-Met has a splice variant that lacks a cytoplasmic juxtamembrane region (ΔJxt-Met). To analyze the function of ΔJxt-Met, we generated knock-in mice expressing only ΔJxt form of c-Met. Homozygous mutant mice died during neonatal period. Pathological analysis is now in progress.