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Met/HGF receptor activation is regulated by juxtamembrane Ser985 phosphorylation in hepatocytes

机译:Met / HGF受体的激活受肝细胞近膜Ser985磷酸化的调节

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摘要

Met/hepatocyte growth factor (HGF) receptor plays a definitive role in hepatocyte proliferation and liver regeneration. Phosphorylation of Ser985 in Met (Met-Ser985) down regulate tyrosine phosphorylation and activation of Met. However, mechanism of Met inactivation by Met-Ser985 phosphorylation and its biological significance on hepatocyte proliferation and liver regeneration are not well known. Here, we investigated biological role of Met-Ser985 phosphorylation in hepatocytes and liver. In primary cultured hepatocytes, HGF-dependent Met activation and mitogenesis were suppressed when Met-Ser985 was phosphorylated. Cell surface Met was decreased upon Met-Ser985 phosphorylation through endocytosis, suggesting a mechanism by which Met activation could be suppressed. In mice, HGF induced proliferation of hepatocyte in injured livers, but not in non-injured livers. Met-Ser985 phosphorylation was decreased after liver injury and associated with Met tyrosine phosphorylation/activation during liver regeneration. These results indicate that Met activation is regulated reciprocally to Met-Ser985 phosphorylation in the primary cultured hepatocytes and the liver following injury. Our study suggests that the phosphorylation of Met-Ser985 in hepatocytes plays a regulatory role in Met activation in response to quiescence, injury, and regeneration.
机译:Met /肝细胞生长因子(HGF)受体在肝细胞增殖和肝脏再生中起决定性作用。 Met中的Ser985磷酸化(Met-Ser985)下调了酪氨酸的磷酸化和Met的活化。然而,由Met-Ser985磷酸化引起的Met失活的机制及其对肝细胞增殖和肝再生的生物学意义尚不清楚。在这里,我们调查了肝细胞和肝脏中Met-Ser985磷酸化的生物学作用。在原代培养的肝细胞中,当Met-Ser985磷酸化时,HGF依赖的Met活化和有丝分裂被抑制。通过内吞作用使Met-Ser985磷酸化后,细胞表面的Met降低,提示Met激活受到抑制的机制。在小鼠中,HGF可以在受伤的肝脏中诱导肝细胞增殖,而在未受伤的肝脏中则不能。肝损伤后Met-Ser985磷酸化降低,并与肝再生过程中Met酪氨酸磷酸化/激活有关。这些结果表明,在损伤后的原代培养的肝细胞和肝脏中,Met的激活与Met-Ser985的磷酸化相互调节。我们的研究表明,肝细胞中Met-Ser985的磷酸化在响应静止,损伤和再生的Met激活中起调节作用。

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