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

(1)LAR通过酪氨酸去磷酸化调节HGF/c-Met活化：通过细胞-细胞接触调节的细胞增殖抑制是正常细胞的基本特征。在以汇合细胞密度培养的肝细胞中，HGF刺激诱导瞬时c-Met酪氨酸磷酸化，但未能诱导促有丝分裂反应。我们发现LAR在失活中起决定性作用，即通过它们的物理相互作用使c-Met的酪氨酸去磷酸化，这特别发生在汇合条件下的肝细胞中。我们将这些结果发表在J-Biol-Chem 281：8765（2006）中。(2)HGF/c-Met激活在胆汁淤积性损伤中的生理学意义：我们使用胆管结扎（BDL）的手术技术在小鼠中诱导胆汁淤积状况。BDL手术后，肝脏中HGF和c-Met mRNA水平短暂升高。此外，我们还获得了证据表明，内源性HGF参与了肝细胞死亡的生理保护，包括坏死和凋亡。我们在Am-J-Physiol 292：G639（2007）中发表了这些结果。(3)仅表达突变c-Met（ΔJxt-Met）的敲入小鼠的产生：c-Met的胞膜Ser-985磷酸化状态在c-Met的活化中起功能性调节作用。c-Met有一个剪接变体，缺少胞质质膜区（ΔJxt-Met）。为了分析ΔJxt-Met的功能，我们产生了仅表达ΔJxt形式的c-Met的敲入小鼠。纯合子突变小鼠在新生期死亡。病理分析正在进行中。

(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.