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

@article{Petrelli2002TheEC,
  title={The endophilin–CIN85–Cbl complex mediates ligand-dependent downregulation of c-Met},
  author={Annalisa Petrelli and Giorgio F. Gilestro and Stefania Lanzardo and Paolo Maria Comoglio and Nicola Migone and Silvia Giordano},
  journal={Nature},
  year={2002},
  volume={416},
  pages={187-190}
}
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… 

Cbl–CIN85–endophilin complex mediates ligand-induced downregulation of EGF receptors

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Endophilin marks and controls a clathrin-independent endocytic pathway

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Cbl-directed monoubiquitination of CIN85 is involved in regulation of ligand-induced degradation of EGF receptors

It is demonstrated that Cbl/Cbl-b can mediate polyubiquitination of cargo as well as monoubiquitinated of CIN85 to control endosomal sorting and degradation of receptor tyrosine kinases.

Rho mediates endocytosis of epidermal growth factor receptor through phosphorylation of endophilin A1 by Rho‐kinase

It is suggested that Rho‐kinase phosphorylates endophilin downstream of Rho and regulates EGF receptor endocytosis through the inhibition of binding between endophileilin and CIN85.

Down-regulation of the met receptor tyrosine kinase by presenilin-dependent regulated intramembrane proteolysis.

It is demonstrated that Met is processed in epithelial cells by presenilin-dependent regulated intramembrane proteolysis (PS-RIP) independently of ligand stimulation, demonstrating the original involvement of a proteolytic process in degradation of the Met receptor implicated in negative regulation of invasive growth.

c-Cbl directs EGF receptors into an endocytic pathway that involves the ubiquitin-interacting motif of Eps15

The capacity of c-Cbl to promote receptor internalization depends on its ubiquitin ligase activity, which functionally connects the EGF receptor to Eps15, a mediator of clathrin-coated pit formation, and is identified as a module that directs the E GF receptor into an endocytic pathway involving Eps15.
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It is demonstrated that Cbl additionally regulates epidermal growth factor (EGF) receptor endocytosis and uses a mechanism that is functionally separable from the ubiquitin ligase activity of Cbl to mediate ligand-dependent downregulation of receptor tyrosine kinases.

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