Alix/AIP1 Antagonizes Epidermal Growth Factor Receptor Downregulation by the Cbl-SETA/CIN85 Complex
Autor: | Frank B. Furnari, Ivan Dikic, Jiuhong Yu, Oliver Bogler, Daniela Hoeller, Webster K. Cavenee, Mirko H. H. Schmidt |
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Rok vydání: | 2004 |
Předmět: |
Macromolecular Substances
Recombinant Fusion Proteins Ubiquitin-Protein Ligases media_common.quotation_subject education Down-Regulation Plasma protein binding Biology Cell Line Mice chemistry.chemical_compound Downregulation and upregulation Ubiquitin Cricetinae Proto-Oncogene Proteins Animals Humans Epidermal growth factor receptor RNA Small Interfering Internalization Cell Growth and Development Molecular Biology Adaptor Proteins Signal Transducing media_common Calcium-Binding Proteins Signal transducing adaptor protein Tyrosine phosphorylation Cell Biology Ligand (biochemistry) Molecular biology Endocytosis Cell biology ErbB Receptors chemistry biology.protein Carrier Proteins Acyltransferases Protein Binding |
Zdroj: | Molecular and Cellular Biology. 24:8981-8993 |
ISSN: | 1098-5549 |
Popis: | The assembly of the Cbl-SETA/CIN85-endophilin complex at the C terminus of the epidermal growth factor receptor (EGFR) following ligand activation mediates its internalization and ubiquitination. We found that the SETA/CIN85-interacting protein Alix/AIP1, which also binds endophilins, modulates this complex. Alix was found to associate indirectly with EGFR, regardless of its activation state, and with DeltaEGFR, which signals at low intensity and does not bind Cbls or SETA/CIN85. In agreement with this, Alix interaction did not occur via SETA/CIN85. However, SETA/CIN85 and Alix were capable of mutually promoting their interaction with the EGFR. Increasing the level of Alix weakened the interaction between SETA/CIN85 and Cbl and reduced the tyrosine phosphorylation of c-Cbl and the level of ubiquitination of EGFR, SETA/CIN85, and Cbls. This antagonism of the Cbl-SETA/CIN85 complex by Alix was reflected in its diminution of EGFR internalization. In agreement with this, small interfering RNA-mediated knockdown of Alix promoted EGFR internalization and downregulation. It has been suggested that SETA/CIN85 promotes receptor internalization by recruiting endophilins. However, Alix was also capable of increasing the level of endophilin associated with EGFR, implying that this is not sufficient to promote receptor internalization. We propose that Alix inhibits EGFR internalization by attenuating the interaction between Cbl and SETA/CIN85 and by inhibiting Cbl-mediated ubiquitination of the EGFR. |
Databáze: | OpenAIRE |
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