CIN85 phosphorylation is essential for EGFR ubiquitination and sorting into multivesicular bodies |
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Authors: | Barbara Schroeder Subhashini Srivatsan Andrey Shaw Daniel Billadeau Mark A McNiven |
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Affiliation: | Department of Biochemistry and Molecular Biology, Rochester, MN 55905 Center for Basic Research in Digestive Diseases, Rochester, MN 55905 Department of Immunology, Mayo Clinic, Rochester, MN 55905 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110. |
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Abstract: | Ubiquitination of the epidermal growth factor receptor (EGFR) by cbl and its cognate adaptor cbl-interacting protein of 85 kDa (CIN85) is known to play an essential role in directing this receptor to the lysosome for degradation. The mechanisms by which this ubiquitin modification is regulated are not fully defined, nor is it clear where this process occurs. In this study we show that EGFR activation leads to a pronounced src-mediated tyrosine phosphorylation of CIN85 that subsequently influences EGFR ubiquitination. Of importance, phospho-CIN85 interacts with the Rab5-positive endosome, where it mediates the sequestration of the ubiquitinated receptor into multivesicular bodies (MVBs) for subsequent degradation. These findings provide novel insights into how src- kinase-based regulation of a cbl adaptor regulates the fate of the EGFR. |
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