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

Annalisa Petrelli, Giorgio F. Gilestro, Stefania Lanzardo, Paolo M. Comoglio, Nicola Migone and Silvia Giordano ()
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Annalisa Petrelli: Biology and Biochemistry, University of Torino
Giorgio F. Gilestro: Institute for Cancer Research and Treatment (IRCC), University of Torino Medical School
Stefania Lanzardo: Biology and Biochemistry, University of Torino
Paolo M. Comoglio: Institute for Cancer Research and Treatment (IRCC), University of Torino Medical School
Nicola Migone: Biology and Biochemistry, University of Torino
Silvia Giordano: Institute for Cancer Research and Treatment (IRCC), University of Torino Medical School

Nature, 2002, vol. 416, issue 6877, 187-190

Abstract: 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 polyubiquitinated1 and degraded2; 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. Endophilins3 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 endocytosis4. 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-oncogene5. 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.

Date: 2002
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DOI: 10.1038/416187a

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