CNRS UMR 8161, Institut de Biologie de Lille, Institut Pasteur de Lille, B.P.447, 59021 Lille, France.
FASEB J. 2012 Apr;26(4):1387-99. doi: 10.1096/fj.11-197723. Epub 2012 Jan 5.
The receptor tyrosine kinase Met and its high-affinity ligand, the hepatocyte growth factor/scatter factor (HGF/SF), are essential to embryonic development. Deregulation of their signaling is associated with tumorigenesis and metastasis, notably through receptor overexpression. It is thus important to understand the mechanisms controlling Met expression. The ligand-dependent internalization of Met and its subsequent degradation in the lysosomal compartment are well described. This process is known to attenuate downstream Met signaling pathways. Yet internalized Met takes part directly in intracellular signaling by chaperoning signaling factors in the course of its trafficking. Furthermore, recent studies describe various new degradation mechanisms of membrane-anchored Met, involving proteolytic cleavages or association with novel partners. Although all these degradations are ligand-independent, they share, to different extents, some common features with canonical HGF/SF-dependent degradation. Interestingly, activated Met variants display resistance to degradation, suggesting defective degradation is involved in tumorigenesis. Conversely, forced degradation of Met through reinduction of one or more degradation pathways is a promising therapeutic strategy.
受体酪氨酸激酶 Met 及其高亲和力配体，肝细胞生长因子/分散因子（HGF/SF），对胚胎发育至关重要。它们信号的失调与肿瘤发生和转移有关，特别是通过受体过表达。因此，了解控制 Met 表达的机制非常重要。Met 的配体依赖性内化及其随后在溶酶体隔室中的降解过程已有很好的描述。这一过程已知可减弱下游 Met 信号通路。然而，内化的 Met 通过在其运输过程中充当信号因子的伴侣，直接参与细胞内信号转导。此外，最近的研究描述了各种新的膜锚定 Met 降解机制，涉及蛋白水解切割或与新的伴侣结合。虽然所有这些降解都是配体非依赖性的，但它们在不同程度上与经典的 HGF/SF 依赖性降解具有一些共同特征。有趣的是，激活的 Met 变体显示出对降解的抗性，表明缺陷降解参与了肿瘤发生。相反，通过重新诱导一种或多种降解途径来强制降解 Met 是一种很有前途的治疗策略。
