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

  title={Cbl–CIN85–endophilin complex mediates ligand-induced downregulation of EGF receptors},
  author={Philippe Soubeyran and Katarzyna Kowanetz and Iwona Szymkiewicz and Wallace Y. Langdon and Ivan Dikic},
Cbl is a multi-adaptor protein involved in ligand-induced downregulation of receptor tyrosine kinases. It is thought that Cbl-mediated ubiquitination of active receptors is essential for receptor degradation and cessation of receptor-induced signal transduction. Here we demonstrate that Cbl additionally regulates epidermal growth factor (EGF) receptor endocytosis. Cbl rapidly recruits CIN85 (Cbl-interacting protein of 85K; ref. 6) and endophilins (regulatory components of clathrin-coated… 

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

Inhibition of complex formation is sufficient to block HGF receptor internalization and to enhance HGF-induced signal transduction and biological responses, and disclose a novel functional role for Cbl in HGF receptors signalling.

CIN85 Participates in Cbl-b-mediated Down-regulation of Receptor Tyrosine Kinases*

A common pathway utilized by Cbl and Cbl-b that may have an important and redundant function in negative regulation of ligand-activated as well as oncogenically activated RTKs in vivo is revealed.

Epidermal growth factor receptor signaling intensity determines intracellular protein interactions, ubiquitination, and internalization

It is shown that ΔEGFR did not interact with Cbls, SETA, or endophilin A1, providing a mechanistic explanation for its lack of internalization.

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.

CIN85 associates with multiple effectors controlling intracellular trafficking of epidermal growth factor receptors.

It is proposed that CIN85 functions as a scaffold molecule that binds to numerous endocytic accessory proteins, thus controlling distinct steps in trafficking of EGF receptors along theendocytic and recycling pathways.

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 Epidermal Growth Factor Receptor Cortactin Overexpression Inhibits Ligand-Induced

It is shown that overexpression of cortactin in HeLa cells markedly inhibits ligand-induced down-regulation of the E3 ubiquitin ligase c-Cbl, and enhanced EGFR signaling due to Cortactin overeexpression may provide an alternative explanation for EMS1 gene amplification in human cancers.

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.

Cbl promotes clustering of endocytic adaptor proteins

These results provide molecular explanations for a novel mechanism by which Cbl controls receptor downregulation and ternary complexes of CIN85 and Cbl are formed in vivo and are important for the ability of Cbl to promote epidermal growth factor receptor (EGFR) downregulation.

Intersectin Regulates Epidermal Growth Factor Receptor Endocytosis, Ubiquitylation, and Signaling

It is demonstrated that ITSN is a scaffold for the E3 ubiquitin ligase Cbl, a complex with Cbl in vivo mediated by the Src homology (SH) 3 domains binding to the Pro-rich COOH terminus of Cbl.



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

Inhibition of complex formation is sufficient to block HGF receptor internalization and to enhance HGF-induced signal transduction and biological responses, and disclose a novel functional role for Cbl in HGF receptors signalling.

c-Cbl/Sli-1 regulates endocytic sorting and ubiquitination of the epidermal growth factor receptor.

An endosomal sorting machinery capable of controlling the fate, and, hence, signaling potency, of growth factor receptors is revealed.

c-Cbl ubiquitinates the EGF receptor at the plasma membrane and remains receptor associated throughout the endocytic route.

Using low temperature and a dynamin mutant, it is found that c-Cbl associates with and ubiquitinates the activated epidermal growth factor (EGF) receptor at the plasma membrane in the absence of endocytosis.

Epidermal Growth Factor Receptor Interaction with Clathrin Adaptors Is Mediated by the Tyr974-containing Internalization Motif*

It is suggested that whereas one mechanism of EGF receptor recruitment into coated pits involves high-affinity binding of AP-2 to Tyr974-containing motif, another pathway may be mediated by weak receptor/AP-2 interactions or by proteins other than AP- 2.

Cloning and characterization of a novel adaptor protein, CIN85, that interacts with c-Cbl.

The results suggest that CIN85 may play a specific role in the EGF receptor-mediated signaling cascade via its interaction with c-Cbl.

The tyrosine kinase negative regulator c-Cbl as a RING-type, E2-dependent ubiquitin-protein ligase.

The c-Cbl protein acted as an E3 that can recognize tyrosine-phosphorylated substrates, such as the activated platelet-derived growth factor receptor, through its SH2 domain and that recruits and allosterically activates an E2 ubiquitin-conjugating enzyme through its RING domain.

Molecular mechanisms underlying endocytosis and sorting of ErbB receptor tyrosine kinases

Characterization of the CIN85 adaptor protein and identification of components involved in CIN85 complexes.

The data suggest that CIN85 may serve for regulation of various signaling events through formation of its diverse complexes throughformation of its SH3 domains.

Pyk2 and FAK regulate neurite outgrowth induced by growth factors and integrins

It is shown that co-stimulation of growth-factor receptors and integrins activates the focal-adhesion kinase (FAK) family to promote outgrowth of neurites in PC12 and SH-SY5Y cells.