The endophilin-CIN85-Cbl complex mediates ligand-dependent downregulation of c-Met

Annalisa Petrelli, Giorgio F. Gilestro, Stefania Lanzardo, Paolo M. Comoglio, Nicola Migone, Silvia Giordano

Research output: Contribution to journalArticle

Abstract

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 acyltransferase 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.

Original languageEnglish
Pages (from-to)187-190
Number of pages4
JournalNature
Volume416
Issue number6877
DOIs
Publication statusPublished - Mar 14 2002

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