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

Abstract

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 vesicles) to form a complex with activated EGF receptors, thus controlling receptor internalization. CIN85 was constitutively associated with endophilins, whereas CIN85 binding to the distal carboxy terminus of Cbl was increased on EGF stimulation. Inhibition of these interactions was sufficient to block EGF receptor internalization, delay receptor degradation and enhance EGF-induced gene transcription, without perturbing Cbl-directed receptor ubiquitination. Thus, the evolutionary divergent C terminus of Cbl uses a mechanism that is functionally separable from the ubiquitin ligase activity of Cbl to mediate ligand-dependent downregulation of receptor tyrosine kinases.

hSef potentiates EGF-mediated MAPK signaling through affecting EGFR trafficking and degradation

“…Furthermore, Cbl has also been found to be required for EGFR exit from the early endosomes but not for the internalization of FGFR [38]. In contrast, studies in mammalian cultured cells have suggested that in addition to mediating lysosomal/proteasomal degradation, Cbl-containing complexes promote the assembly of active intracellular EGFR signaling modules, either by traffic to particular endosomal structures or through receptor recycling [39]. It is of interest to study whether Sef interacts with such a kind of adaptor to stabilize EGFR in the endosomes.…”

The epidermal growth factor receptor family: Biology driving targeted therapeutics

“…Cbl appears to be recruited to EGFR by Grb2, and this complex alone may be sufficient for endocytosis of the receptor [88]. Further complex formation with CIN85 and endophilin promotes receptor endocytosis into early endosomes [89]. EPS15 also associates with the clathrin adaptor protein AP-2 on receptor activation and may bind ubiquitinated EGFR through ubiquitin-interacting motifs (UIMs) to promote receptor endocytosis [90].…”

“…Further complex formation with CIN85 and endophilin promotes receptor endocytosis into early endosomes [89]. EPS15 also associates with the clathrin adaptor protein AP-2 on receptor activation and may bind ubiquitinated EGFR through ubiquitin-interacting motifs (UIMs) to promote receptor endocytosis [90]. Parkin, an E3 ubiquitin ligase, promotes signaling through the PI(3)K/Akt pathway by activated EGFR by binding the UIM of EPS15 and limiting receptor endocytosis [91].…”

A Multiscale Computational Approach to Dissect Early Events in the Erb Family Receptor Mediated Activation, Differential Signaling, and Relevance to Oncogenic Transformations

“…Models for the transient release of calcium have been developed on the basis of several published experimental studies. 39,59 We work under the hypothesis that the signal transduction in the endocytosis pathway is coupled to membrane deformation via two functional interactions: (1) the direct induction of curvature via the interaction of the membrane lipids with epsin; 24,50,56,62 and (2) through the assembly of the clathrin coat, 56,73 which is triggered by an increase in the local concentration of Ca 2+ ions released in the PLCc pathway. 4 In the latter case, above a threshold value of Ca 2+ concentration the clathrin monomers spontaneously self-assemble to form a lattice.…”