Petrelli Annalisa, Gilestro Giorgio F, Lanzardo Stefania, Comoglio Paolo M, Migone Nicola, Giordano Silvia
CNR-CIOS and Department of Genetics, Biology and Biochemistry, University of Torino, 10126 Torino, Italy.
Nature. 2002 Mar 14;416(6877):187-90. doi: 10.1038/416187a.
Ligand-dependent downregulation of tyrosine kinase receptors is a critical step for modulating their activity. Upon ligand binding, hepatocyte growth factor (HGF) receptor (Met) is polyubiquitinated and degraded; however, the mechanisms underlying HGF receptor endocytosis are not yet known. Here we demonstrate that a complex involving endophilins, CIN85 and Cbl controls this process. Endophilins are regulatory components of clathrin-coated vesicle formation. Through their acyl-transferase activity they are thought to modify the membrane phospholipids and induce negative curvature and invagination of the plasma membrane during the early steps of endocytosis. Furthermore, by means of their Src-homology 3 domains, endophilins are able to bind CIN85, a recently identified protein that interacts with the Cbl proto-oncogene. Cbl, in turn, binds and ubiquitinates activated HGF receptor, and by recruiting the endophilin-CIN85 complex, it regulates receptor internalization. Inhibition of complex formation is sufficient to block HGF receptor internalization and to enhance HGF-induced signal transduction and biological responses. These data provide further evidence of a relationship between receptor-mediated signalling and endocytosis, and disclose a novel functional role for Cbl in HGF receptor signalling.
酪氨酸激酶受体的配体依赖性下调是调节其活性的关键步骤。在配体结合后，肝细胞生长因子（HGF）受体（Met）会发生多聚泛素化并降解；然而，HGF受体内吞作用的潜在机制尚不清楚。在此，我们证明一种包含内吞蛋白、CIN85和Cbl的复合物控制这一过程。内吞蛋白是网格蛋白包被小泡形成的调节成分。通过其酰基转移酶活性，它们被认为在早期内吞步骤中修饰膜磷脂并诱导质膜的负曲率和内陷。此外，通过其Src同源3结构域，内吞蛋白能够结合CIN85，CIN85是一种最近鉴定出的与Cbl原癌基因相互作用的蛋白质。反过来，Cbl结合并泛素化活化的HGF受体，并通过募集内吞蛋白-CIN85复合物来调节受体内化。抑制复合物形成足以阻断HGF受体内化并增强HGF诱导的信号转导和生物学反应。这些数据进一步证明了受体介导的信号传导与内吞作用之间的关系，并揭示了Cbl在HGF受体信号传导中的新功能作用。
