CNRS UMR 8161, Institut de Biologie de Lille, Institut Pasteur de Lille, Université de Lille 1, Université de Lille 2, Lille cedex, France.
Traffic. 2012 Sep;13(9):1261-72. doi: 10.1111/j.1600-0854.2012.01384.x. Epub 2012 Jun 20.
The receptor tyrosine kinase Met and its ligand, the hepatocyte growth factor/scatter factor, are essential for embryonic development, whereas deregulation of Met signaling pathways is associated with tumorigenesis and metastasis. The presenilin-regulated intramembrane proteolysis (PS-RIP) is involved in ligand-independent downregulation of Met. This proteolytic process involves shedding of the Met extracellular domain followed by γ-secretase cleavage, generating labile intracellular fragments degraded by the proteasome. We demonstrate here that upon shedding both generated Met N- and C-terminal fragments are degraded directly in the lysosome, with C-terminal fragments escaping γ-secretase cleavage. PS-RIP and lysosomal degradation are complementary, because their simultaneous inhibition induces synergistic accumulation of fragments. Met N-terminal fragments associate with the high-affinity domain of HGF/SF, confirming its decoy activity which could be reduced through their routing to the lysosome at the expense of extracellular release. Finally, the DN30 monoclonal antibody inducing Met shedding promotes receptor degradation through induction of both PS-RIP and the lysosomal pathway. Thus, we demonstrate that Met shedding initiates a novel lysosomal degradation which participates to ligand-independent downregulation of the receptor.
受体酪氨酸激酶 Met 及其配体肝细胞生长因子/分散因子对于胚胎发育至关重要，而 Met 信号通路的失调与肿瘤发生和转移有关。早老素调节的跨膜蛋白水解（PS-RIP）参与配体非依赖性的 Met 下调。这个蛋白水解过程涉及到 Met 细胞外结构域的脱落，随后是 γ-分泌酶的切割，产生不稳定的细胞内片段，被蛋白酶体降解。我们在这里证明，在脱落之后，产生的 Met N-和 C-末端片段都直接在溶酶体中降解，C-末端片段逃避 γ-分泌酶的切割。PS-RIP 和溶酶体降解是互补的，因为它们的同时抑制会导致片段的协同积累。Met N-末端片段与 HGF/SF 的高亲和力结构域结合，证实了其诱饵活性，这种活性可以通过将其路由到溶酶体而减少，代价是细胞外释放。最后，诱导 Met 脱落的 DN30 单克隆抗体通过诱导 PS-RIP 和溶酶体途径促进受体降解。因此，我们证明 Met 脱落启动了一种新的溶酶体降解，参与了受体的配体非依赖性下调。
