1. UBE4B Protein Couples Ubiquitination and Sorting Machineries to Enable Epidermal Growth Factor Receptor (EGFR) Degradation*
- Author
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Sirisaengtaksin, Natalie, Gireud, Monica, Yan, Qing, Kubota, Yoshihisa, Meza, Denisse, Waymire, Jack C, Zage, Peter E, and Bean, Andrew J
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Underpinning research ,1.1 Normal biological development and functioning ,Generic health relevance ,Cell Membrane ,Endopeptidases ,Endosomal Sorting Complexes Required for Transport ,Endosomes ,ErbB Receptors ,HeLa Cells ,Humans ,Membrane Proteins ,Phosphoproteins ,Protein Interaction Domains and Motifs ,Protein Structure ,Tertiary ,Protein Transport ,Proteolysis ,Signal Transduction ,Tumor Suppressor Proteins ,Ubiquitin Thiolesterase ,Ubiquitin-Protein Ligase Complexes ,Ubiquitin-Protein Ligases ,Ubiquitination ,Deubiquitination ,E3 Ubiquitin Ligase ,Endocytosis ,Protein Sorting ,ESCRT ,USP8 ,Hela Cells ,Chemical Sciences ,Medical and Health Sciences ,Biochemistry & Molecular Biology ,Biological sciences ,Biomedical and clinical sciences ,Chemical sciences - Abstract
The signaling of plasma membrane proteins is tuned by internalization and sorting in the endocytic pathway prior to recycling or degradation in lysosomes. Ubiquitin modification allows recognition and association of cargo with endosomally associated protein complexes, enabling sorting of proteins to be degraded from those to be recycled. The mechanism that provides coordination between the cellular machineries that mediate ubiquitination and endosomal sorting is unknown. We report that the ubiquitin ligase UBE4B is recruited to endosomes in response to epidermal growth factor receptor (EGFR) activation by binding to Hrs, a key component of endosomal sorting complex required for transport (ESCRT) 0. We identify the EGFR as a substrate for UBE4B, establish UBE4B as a regulator of EGFR degradation, and describe a mechanism by which UBE4B regulates endosomal sorting, affecting cellular levels of the EGFR and its downstream signaling. We propose a model in which the coordinated action of UBE4B, ESCRT-0, and the deubiquitinating enzyme USP8 enable the endosomal sorting and lysosomal degradation of the EGFR. more...
- Published
- 2014