"Binding of Grb2 and c-Cbl by EGFR is essential for infection."
"Residual ubiquitination was further consistent with the reported findings that Cbl can also interact indirectly with the EGFR through Grb2 ."
"However, it has no effect on the indirect binding of c-Cbl to EGFR via Grb2."
"On the other hand, the binding of Cbl to EGFR via Grb2 is important for receptor internalization [ xref ]."
"In cell culture studies, the indirect binding of EGFR to Cbl through Grb2 is necessary for receptor internalization, whereas endosomal sorting requires direct binding to Cbl xref , xref ."
"Like c-Cbl, Grb2 bound EGFR more efficiently following EGF or BTC stimulation for 15 min compared with the other EGFR ligands ( xref )."
"Indeed, EGF-induced Src activation and EGFR interaction with Grb2 and Cbl, early events that are required for EGFR internalization, do not occur in confluent Nf2-expressing cells ( xref ; xref ; xref )."
"Both direct binding of Cbl to the EGFR and indirect binding of Cbl to the EGFR through Grb2 has been reported to result in ubiquitination of the EGFR ."
"However, δ-catenin did not affect the binding between c-Cbl and the EGFR Y1045F mutant, suggesting that indirect binding of c-Cbl to EGFR via Grb2 is not affected by δ-catenin."
"EGFRvIII binds the ubiquitin ligase c-Cbl via Grb2, whereas binding via phosphorylated tyrosine residue 1045 seems to be limited."
"In contrast, Cbl binding to EGFR via Grb2 is necessary for receptor internalization (Huang and Sorkin xref )."
"Although CBL can bind directly to the EGFR at Y1045, GRB2 mediated CBL recruitment to the EGFR is extremely important to properly respond to varying doses of EGF to mediate the proper endocytic response [XREF_BIBR]."
"In agreement with the autophosphorylation data, c-Cbl and Grb2 interact strongly with EGFR homodimers, and poorly with EGFR:HER2 heterodimers ( xref )."
"This fits well with the reports that c-Cbl primarily binds EGFR via Grb2 ( xref )."
"As NS5A did not appear to disrupt the interaction between c-Cbl, Grb2 and EGFR, we next assessed whether the effect on EGFR ubiquitination could be explained by the effects of NS5A on the interactions between the adaptor CMS and either EGFR or c-Cbl."
"Further studies showed that PD153035, which does not reverse ligand-induced EGFR down-regulation, blocks EGF-induced EGFR activation as well as EGFR's binding to c-cbl and Grb2."
"23 It has been shown that direct or GRB2-mediated binding of CBL to EGFR is required for multiple mono-ubiquitylation of the activated receptor."
"Here we use a simple modelling approach together with experiments to show that the establishment of the threshold requires both the multiplicity of binding sites and cooperative binding of Cbl and Grb2 to the EGFR."
"Further, only indirect binding of Cbl to the EGFR through Grb2 is considered important for recruitment of the EGFR to clathrin-coated pits and thus essential for ligand-induced endocytosis of the EGF[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
"In addition, Cbl can bind indirectly to the EGFR via Grb2 [ xref ]."
"Additionally, Cbl can also indirectly bind EGFR through the Grb2 adaptor protein at the Y1068 and Y1086 sites of the receptor xref ."
"Both CME and several NCE pathways are involved in EGFR internalization. [ xref ] The ubiquitination of EGFR is necessary for all internalization pathways, and the ubiquitin ligase responsible for EGFR ubiquitination is Cbl, a ring‐finger domain E3 ubiquitin ligase. [ xref ] Cbl can directly bind to EGFR, or indirectly bind to EGFR via the adaptor protein Grb2. [ xref , xref ] The EGFR‐Grb2‐Cbl complex is necessary for NCE, with previous studies showing that EGFR mutants lacking Grb2 binding sites are completely defective for NCE. [ xref , xref ] Our results indicated that SGCE knockdown caused induction of EGFR internalization, and increased the interaction between EGFR and c‐Cbl but not that between EGFR and Grb2."
"Here the authors show that the establishment of an EGFR signaling threshold requires both a multiplicity of binding sites and cooperative binding of Cbl and Grb2 to the EGFR."
"It has further been demonstrated that the EGFR can be ubiquitinated both by direct interaction of Cbl with the EGFR through pTyr1045 as well as by indirect interaction of Cbl with the EGFR through bin[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
"A plausible explanation for cooperativity is that when Cbl and Grb2 are simultaneously bound to EGFR (via pY1045 and pY1068/pY1086, respectively), they are in a state of enforced proximity, which increases the likelihood of the three species (EGFR, Cbl and Grb2) of binding to each other xref ."
"[48, 74] The EGFR, Grb2, and Cbl complex is necessary for NCE, with previous studies showing that EGFR mutants lacking Grb2 binding sites are completely defective for NCE."
"Together, these results again support the cooperativity model of interaction of the Cbl:Grb2 complex with the EGFR (see also xref for additional information), and argue that this modality of interaction is indeed responsible for the EGFR ubiquitination threshold."
"The EGFR Y1045F mutation profoundly reduces but does not completely eliminate Cbl recruitment and ligand-induced receptor ubiquitination, as Cbl may still bind EGFR indirectly through Grb2 [16,22–24][MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
"In view of the demonstration that EGFR ubiquitination is not essential for internalization, future research should focus on the search of a different type of protein that can mediate internalization of the EGFR, Grb2, and Cbl complex."
"These data suggest that the binding of Cbl to epidermal growth factor receptor through Grb2 is necessary and sufficient for Cbl function during clathrin-mediated endocytosis."
"We propose that while indirect binding of Cbl to the EGFR via Grb2 is required for a ubiquitination pattern allowing endocytosis through clathrin-coated pits, direct binding of Cbl to the EGFR is requ[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
"Here, we use a simple modeling approach together with experiments to show that the establishment of the threshold requires both the multiplicity of binding sites and cooperative binding of Cbl and Grb2 to the EGFR."
"EGFR is ubiquitinated by the E3 ubiquitin ligase Cbl, which binds to activated EGFR directly and indirectly through the Grb2 adaptor protein ( xref ; xref )."