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CHAPTER 1: Introduction Experimental and Computational Analysis of Epidermal Growth Factor Receptor Pathway Phosphorylation Dynamics By Laura B. Kleiman B.A. Biomathematics B.A. Mathematics Rutgers University, 2004 Submitted to the Computational and Systems Biology Program in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Computational and Systems Biology at the Massachusetts Institute of Technology June 2010 © 2010 Massachusetts Institute of Technology. All rights reserved. Signature of Author:_______________________________________________________ Computational and Systems Biology Program May 21, 2010 Certified by:_____________________________________________________________ Peter K. Sorger Professor of Systems Biology (Harvard Medical School) Professor of Biological Engineering (Massachusetts Institute of Technology) Thesis Supervisor Certified by:_____________________________________________________________ Douglas A. Lauffenburger Ford Professor of Biological Engineering, Chemical Engineering, and Biology Thesis Supervisor Accepted by:_____________________________________________________________ Christopher Burge Associate Professor of Biology Director, Computational and Systems Biology Graduate Program - 2 - Experimental and Computational Analysis of Epidermal Growth Factor Receptor Pathway Phosphorylation Dynamics By Laura B. Kleiman Submitted to the Computational and Systems Biology Program on May 21, 2010, in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Computational and Systems Biology Abstract The epidermal growth factor receptor (EGFR, also known as ErbB1) is a prototypical receptor tyrosine kinase (RTK) that activates multi-kinase phosphorylation cascades to regulate diverse cellular processes, including proliferation, migration and differentiation. ErbB1 hetero- oligomerizes with three close homologues: ErbB2, ErbB3 and ErbB4. ErbB1-3 receptors are frequently mutated, overexpressed or activated by autocrine or paracrine ligand production in solid tumors and have been the target of extensive drug discovery efforts. Multiple small molecule kinase inhibitors and therapeutic antibodies against ErbB receptors are in clinical use or development. Despite their importance as RTKs, oncogenes and drug targets, regulation of ErbB receptors by the interplay of conformational change, phosphorylation, phosphatases and receptor trafficking remains poorly understood, and the impact of these dynamics on physiological activity and cellular responses to anti-ErbB drugs is largely unknown. This thesis investigates the dynamic opposition of kinases and phosphatases within the ErbB pathway. By standard biochemical analysis, ErbB receptors and downstream proteins appear to become phosphorylated and then dephosphorylated in approximately 30 minutes. However, pulse- chase experiments where cells are exposed to ligand and then to small molecule kinase inhibitors reveal that individual proteins must in fact cycle rapidly between being phosphorylated and dephosphorylated in seconds. We construct a succession of differential equation-based models of varying biochemical resolution, each model appropriate for analyzing a different aspect of ErbB regulation, to help interpret the data and gain quantitative insight into receptor and drug biology. Rapid phosphorylation and dephosphorylation of receptors has important implications for the assembly dynamics of signalosomes. We find that signals are rapidly propagated through some downstream pathways but slowly through others, resulting in prolonged activation in the absence of upstream signal. We show that fast phosphorylation/dephosphorylation may provide cells with the flexibility necessary to rapidly detect and respond to changes in their extracellular environment. These fast dynamics also play a crucial role in determining the response to ErbB1-targeting cancer therapies, which we find to vary significantly between drugs with different mechanisms of action. We show that treatment with one class of these drugs results in sustained signaling, instead of inhibition, and thus may actually promote tumor proliferation or invasion. Our work may help explain why certain drugs have been more effective in patients than others and suggests new approaches for evaluating biochemical signaling networks and targeted therapeutics. Thesis Supervisor: Peter K. Sorger, Ph.D. Title: Professor of Systems Biology, Harvard Medical School and Professor of Biological Engineering, Massachusetts Institute of Technology - 3 - Thesis Supervisor: Douglas A. Lauffenburger, Ph.D. Title: Ford Professor of Biological Engineering, Chemical Engineering, and Biology, Massachusetts Institute of Technology - 4 - Thesis Committee Forest M. White Associate Professor of Biological Engineering (Massachusetts Institute of Technology) Thesis Committee Chair Peter K. Sorger Professor of Biological Engineering (Massachusetts Institute of Technology) Professor of Systems Biology (Harvard Medical School) Thesis Supervisor Douglas A. Lauffenburger Ford Professor of Biological Engineering, Chemical Engineering, and Biology (Massachusetts Institute of Technology) Thesis Supervisor Tyler Jacks David H. Koch Professor of Biology (Massachusetts Institute of Technology) Thesis Committee Member Dennis Vitkup Assistant Professor of Biomedical Informatics (Columbia University) Thesis Committee Member - 5 - Table of Contents Abstract ..................................................................................................................... 3 Figures and Tables ................................................................................................... 9 Acknowledgements ................................................................................................ 11 CHAPTER 1: Introduction ...................................................................................... 13 Protein phosphorylation regulates signal transduction and physiological processes .... 14 Net phosphorylation levels are determined by kinases and phosphatases ............................14 Receptor tyrosine kinases (RTKs) sense the extracellular environment and initiate phosphorylation cascades .....................................................................................................15 General goals of this work .....................................................................................................15 The ErbB receptor family ............................................................................................... 17 Mechanisms regulating activation of the ErbB receptors and downstream signaling pathways ..............................................................................................................................................17 Mechanisms leading to downregulation of ErbB signaling .....................................................18 Protein tyrosine phosphatases (PTPs) .......................................................................... 20 Identification and characterization of PTPs and their substrates ............................................22 Evidence for ErbB1 PTPs......................................................................................................22 Hyperactivation of the ErbB pathway in cancer ............................................................. 28 Drugs targeting the ErbB receptors .......................................................................................28 Inhibitors elucidate the dynamic opposition of phosphorylation and dephosphorylation 33 Specific goals of this thesis and key findings ................................................................ 36 CHAPTER 2: Results .............................................................................................. 37 ErbB1 receptors rapidly dephosphorylated were actively signaling ............................... 42 Estimating rates of phospho-ErbB1 turnover using a kinetic model .............................. 45 ErbB1 dephosphorylation dynamics in response to different drugs ............................... 52 - 6 - Development of a more detailed computational scheme to understand different inhibitor effects ............................................................................................................................ 54 Investigating the role of ErbB1 phosphatases ............................................................... 58 Low dosing with gefitinib results in sustained ErbB1 phosphorylation ........................... 61 Physiological consequences of fast phosphorylation cycling ........................................ 65 Stochastic simulation illustrates switching times between phosphorylation states ........ 67 Supplementary Data...................................................................................................... 70 Effects of gefitinib on levels of cell surface ErbB1 .................................................................70 Dose-response behavior of the irreversible ErbB1 inhibitor canertinib ...................................71 ErbB3 is dephosphorylated slowly after heregulin stimulation ...............................................73 Development of a more complete mathematical model that describes ErbB receptor trafficking ..............................................................................................................................74 The role of degradation and phosphatases in regulating the lower steady state ErbB1 pY levels after EGF pulses of different durations followed
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