Recycling of EGFR and ErbB2 is associated with impaired Hrs tyrosine phosphorylation and decreased deubiquitination by AMSH |
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| Authors: | Inez M J Meijer Walter van Rotterdam Everardus J J van Zoelen Jeroen E M van Leeuwen |
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| Affiliation: | 1. Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, London, UK;2. Tumour Immunology Unit, Department of Medicine, Imperial College London, London, UK;1. Department of Otorhinolaryngology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China;2. Department of Otorhinolaryngology, General Hospital of Jinan Military Region of PLA, Jinan, Shandong 250014, China;3. Department of Immunology, Shandong University School of Medicine, Jinan, Shandong 250012, China;1. Key Laboratory of Functional Small Organic Molecules, Ministry of Education and College of Life Science, Jiangxi Normal University, 99 Ziyang Avenue, Nanchang, Jiangxi, 330022, PR China;2. Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, TX, USA;1. Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7FZ, UK;2. Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK;1. Department of Pathology, Seoul National University College of Medicine, Seoul 110-799, Korea;2. Laboratory of Immune Regulation, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Korea;3. Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul 110-799, Korea;4. Department of Internal Medicine, Seoul National University College of Medicine, Seoul 110-799, Korea;5. Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-799, Korea;6. Graduate School of Cancer Science and Policy, Research Institute, National Cancer Center, Goyang 10408, Korea;7. Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon 440-746, Korea |
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| Abstract: | ErbB receptors play an important role in normal cellular growth, differentiation and development, but overexpression or poor downregulation can result in enhanced signaling and cancerous growth. ErbB signaling is terminated by clathrin-dependent receptor-mediated endocytosis, followed by incorporation in multi-vesicular bodies and subsequent degradation in lysosomes. In contrast to EGFR, ErbB2 displays poor ligand-induced downregulation and enhanced recycling, but the molecular mechanisms underlying this difference are poorly understood. Given our previous observation that both EGFR and an EGFR-ErbB2 chimera undergo Cbl-mediated K63-polyubiquitination, we investigated in the present study whether activation of the EGFR and the EGFR-ErbB2 chimera is associated with tyrosine phosphorylation of the ESCRT-0 complex subunit Hrs and AMSH-mediated deubiquitination. EGF stimulation of the EGFR resulted in efficient Hrs tyrosine phosphorylation and deubiquitination by the K63-polyubiquitin chain-specific deubiquitinating enzyme AMSH. In contrast, EGF activation of EGFR-ErbB2 showed significantly decreased Hrs tyrosine phosphorylation and deubiquitination by AMSH. To test whether this phenotype is the result of endosomal recycling, we induced recycling of the EGFR by stimulation with TGFα. Indeed, even though TGFα-stimulation of EGFR is associated with efficient ligand-stimulated K63-polyubiquitination, we observed that Hrs tyrosine phosphorylation as well as AMSH-mediated deubiquitination is significantly reduced under these conditions. Using various EGFR-ErbB2 chimeras, we demonstrate that enhanced recycling, decreased Hrs tyrosine phosphorylation and decreased AMSH mediated deubiquitination of EGFR-ErbB2 chimeras is primarily due to the presence of ErbB2 sequences or the absence of EGFR sequences C-terminal to the Cbl binding site. We conclude that endosomal recycling of the EGFR and ErbB2 receptors is associated with significantly impaired tyrosine phosphorylation of the ESCRT-0 subunit Hrs as well as decreased deubiquitination by AMSH, which is consistent with the finding that recycling receptors are not efficiently incorporated in the MVB pathway. |
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