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Zhongping Liao Address The Role of Vacuolar Protein Sorting 4 Homolog B in Regulating Epidermal Growth Factor Receptor Signaling in Breast Cancer Item Type dissertation Authors Liao, Zhongping Publication Date 2011 Abstract Breast cancer is the most common cancer among American women. Aberrant signaling by epidermal growth factor receptor (EGFR) is causally involved in the abnormal cell growth, proliferation, invasion and metastasis that occur in breast cancer. Endoso... Keywords liquid chromatography mass spectrometry; vacuolar protein sorting 4 homolog B; Breast--Cancer; Proteomics; Receptor, Epidermal Growth Factor Download date 02/10/2021 22:10:47 Link to Item http://hdl.handle.net/10713/790 Curriculum vitae Name: Zhongping Liao Address: BRB-7-040, 655 W. Baltimore Street, Baltimore, MD, 21201 Phone: 410-328-7824 Email: [email protected] Degree and Date to be Conferred: Ph.D., 2011 Collegiate Institutions Attended: University of Maryland, Baltimore August 2006 – December 2011 Doctor of Philosophy, December 2011 Major: Molecular Medicine Minor: Cancer Biology China Pharmaceutical University September 2000 – June 2003 Master of Science, June 2003 Major: Microbial Pharmaceuticals China Pharmaceutical University September 1996 – June 2000 Bachelor of Science, June 2000 Major: Microbial Pharmaceuticals Professional Publications: 1. Liao Z, Thomas SN, Wan Y, Lin HH, Shapiro P, Ann DK, Yang AJ. Phosphoproteomic analysis reveals activation of EGFR/EPS8/SH3BP1 complex and stabilization of cell adhesion in VPS4B-mediated endosomal EGFR signaling. PLoS ONE. In revision. 2. Liao Z, Wan Y, Thomas SN, Yang AJ. IsoQuant: a software tool for SILAC- based mass spectrometry quantitation. Anal Chem. In revision. 3. Liao Z, Thomas SN, Wan Y, Lin HH, Ann DK, Yang AJ. An internal standard-assisted synthesis and degradation proteomic approach reveals up- regulated fatty acid β-oxidation and down-regulated glycolysis in SKBR3 breast cancer cells with decreased VPS4B expression. In preparation. 4. Thomas SN, Wan Y, Liao Z, Hanson PI, Yang AJ. Stable isotope labeling with amino acids in cell culture based mass spectrometry approach to detect 1 transient protein interactions using substrate trapping. Anal Chem. 2011. Jul 15;83(14):5511-8. 5. Thomas SN, Funk KE, Wan Y, Liao Z, Davies P, Kuret J, Yang AJ. Dual modification of Alzheimer's disease PHF-tau protein by lysine methylation and ubiquitylation: a mass spectrometry approach. Acta Neuropathologica. 2011. In press. 6. Liao Z, Thomas SN, Wan Y, Thompson SM, Yang AJ. Using ex vivo SILAC- labeled brain slice cultures to address the dynamic assembly of synaptic protein complexes. USHUPO 7th Annual Conference, 2011, Raleigh, NC. 7. Liao Z, Wan Y, Thomas, SN, Ann DK, Yang AJ. Quantitative synthesis/degradation proteomic analysis of VPS4B-mediated perturbations in EGFR signaling in breast cancer cells under hypoxic conditions. 58th ASMS Conference, 2010, Salt lake city, UT. 8. Liao Z, Wan Y, Rynarzewski S, Thomas, SN, Yang AJ. Use of iTRAQ and MudPIT to quantify synaptic protein expression changes in post-synaptic density isolated from individual mouse brain. 57th ASMS Conference, 2009, Philadelphia, PA. Professional Positions Held: Graduate Research Assistant University of Maryland, Baltimore Baltimore, MD September 2006 to present Research Scientist in Monoclonal Antibody Shanghai Kehua Bio-Engineering Co., Ltd Shanghai, China July 2004 – June 2006 Genetic Engineering Research Scientist Shanghai Asia United Antibody Medical Co., Ltd Shanghai, China July 2003 – June 2004 Current Committee Memberships: Austin J. Yang, Ph.D. Associate Professor, Department of Anatomy and Neurobiology School of Medicine, University of Maryland, Baltimore Angela Brodie, Ph.D. Professor, Department of Pharmacology and Experimental Therapeutics School of Medicine, University of Maryland, Baltimore 2 David K. Ann, Ph.D. Professor, Department of Molecular Pharmacology Beckman Research Institute, City of Hope Medical Center Dudley K. Strickland, Ph.D. Professor, Center for Vascular and Inflammatory Diseases School of Medicine, University of Maryland, Baltimore Iris Lindberg, Ph.D. Professor, Department of Anatomy and Neurobiology School of Medicine, University of Maryland, Baltimore Yun Qiu, Ph.D. Professor, Department of Pharmacology and Experimental Therapeutics School of Medicine, University of Maryland, Baltimore 3 Abstract Title of Dissertation: The Role of Vacuolar Protein Sorting 4 Homolog B in Regulating Epidermal Growth Factor Receptor Signaling in Breast Cancer Zhongping Liao, Doctor of Philosophy, 2011 Dissertation Directed by: Austin J. Yang, Associate Professor, Department of Anatomy and Neurobiology, School of Medicine, University of Maryland, Baltimore Breast cancer is the most common cancer among American women. Aberrant signaling by epidermal growth factor receptor (EGFR) is causally involved in the abnormal cell growth, proliferation, invasion and metastasis that occur in breast cancer. Endosomal sorting complexes required for transport (ESCRTs) have been suggested to play an important role in regulating EGFR signaling. Dysfunction of vacuolar protein sorting 4 homolog B (VPS4B), an ESCRT-III associated protein, inhibits EGFR degradation and prolongs intracellular EGFR signaling. Although EGFR signaling is one of the most well characterized signaling pathways, it is not known how changes of the endosomal/lysosomal system can affect EGFR signaling in breast cancer. Here, we analyzed the role of VPS4B-mediated ESCRT dysfunction in altering EGFR signaling in breast cancer cells by a proteomics-based systems biology approach. By using a stable isotope labeling with amino acids in cell culture (SILAC)-based quantitative phosphoproteomics approach coupled with an attenuated VPS4B expression 4 breast cancer cell culture model, we found that EGFR activates epidermal growth factor receptor kinase substrate 8 (EPS8)/SH3 domain-binding protein 1 (SH3BP1) signaling and subsequently stabilizes various cell adhesion and junction molecules. In addition, EGFR activates extracellular signal-regulated kinase (ERK) signaling, and attenuates signal transducer and activator of transcription (STAT) signaling. These results suggest that dysfunction of VPS4B differentially activates and attenuates EGFR signaling in breast cancer cells. An internal standard-assisted synthesis and degradation mass spectrometry (iSDMS) method was developed to determine the consequences of altered EGFR signaling as related to protein synthesis, degradation and relative protein abundance. We found that VPS4B down-regulation results in up-regulation of proteins with roles in fatty acid β-oxidation and down-regulation of proteins involved in glycolysis and fatty acid synthesis. The adoption of fatty acid β-oxidation as an alternative energy source could be an unrevealed survival mechanism for breast cancer cells with VPS4B dysfunction. In summary, our study provides the first systems biology evidence demonstrating the potential pathological relevance of altered EGFR signaling caused by endosomal dysfunction. The study casts a new light on the functional mechanisms underlying breast cancer survival, which will aid the development of new breast cancer treatment strategies. 5 The Role of Vacuolar Protein Sorting 4 Homolog B in Regulating Epidermal Growth Factor Receptor Signaling in Breast Cancer by Zhongping Liao Dissertation submitted to the faculty of the Graduate School of the University of Maryland, Baltimore in partial fulfillment of the requirements for the degree of Doctor of Philosophy 2011 6 ©Copyright 2011 by Zhongping Liao All rights Reserved 7 Acknowledgements I would like to thank my mentor Dr. Austin J. Yang for guiding me throughout my dissertation research and helping me mature as a researcher. I would also like to thank Dr. Stefani N. Thomas, Dr. Yunhu Wan, and Noble Nemieboka of the Proteomics Core Facility, for their continued support and assistance. Without Dr. Yang, his lab and the Proteomics Core Facility, I would not have developed my critical thinking skills nor my passion for proteomics and breast cancer research. I would also like to acknowledge my thesis committee members, Dr. Angela Brodie, Dr. Alan E. Tomkinson, Dr. David K. Ann, Dr. Dudley K. Strickland, Dr. Iris Lindberg, and Dr. Yun Qiu for providing valuable insight for my project. I would like to thank the following collaborators who have contributed to my work: Dr. David K. Ann, Dr. Scott M. Thompson, Dr. Frank Yang and Helen H. Lin. Finally I would like to thank my wife Xinli Xu for keeping me grounded and being so patient with me throughout my graduate career. p. iii Table of Contents I. Introduction .................................................................................................................... 1 Breast cancer................................................................................................................ 2 Epidermal growth factor receptor (EGFR) .................................................................. 2 EGFR and breast cancer .............................................................................................. 3 EGFR structure, activation and signaling .................................................................... 4 EGFR endocytosis, sorting and degradation ............................................................... 8 EGFR signaling during endocytosis and endosomal trafficking ............................... 11 Vacuolar protein sorting 4 (VPS4) ...........................................................................
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