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Wnt Signaling Pathways CROSSTALK BETWEEN INSULIN AND WNT SIGNALING PATHWAYS by JANE SUN A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Graduate Department of Laboratory Medicine and Pathobiology University of Toronto ©Copyright by Jane Sun 2009 CROSSTALK BETWEEN INSULIN AND WNT SIGNALING PATHWAYS Jane Sun Doctor of Philosophy, 2009 Department of Laboratory Medicine and Pathobiology Faculty of Medicine University of Toronto Abstract Type II diabetes and hyperinsulinemia are associated with increased risks of developing colorectal cancer (CRC). Detailed mechanisms underlying this correlation, however, are yet to be explored. The present study demonstrates that insulin increases the expression of proto-oncogenes c-Myc and cyclin D1 via both translational and transcriptional mechanisms. We show here that insulin stimulates c-Myc gene translation via an Akt/PKB-dependent mechanism involving the mTOR signaling pathway. More importantly, we show for the first time that transcriptional stimulation of c-Myc and cyclin D1 expression by insulin involves a novel Akt/PKB- independent signal crosstalk between insulin and canonical Wnt signaling pathways. We then identified p21-activated protein kianse 1 (PAK-1) as a novel mediator for insulin and Wnt/beta-catenin (-cat) molecular crosstalk, involving MEK/ERK signaling. Furthermore, we found that insulin treatment leads to increased -cat phosphorylation at Ser675, and this is associated with increased -cat nuclear content and increased -cat interaction with Tcf/Lef-binding elements (TBEs) of the human c-Myc gene promoter. Lastly, we demonstrated that insulin signaling directly ii alters the expression levels of components of the Wnt signaling pathway, including fizzled homology 4 (Fdz-4) and TCF7L2 (=TCF-4). This study not only demonstrated the existence of signaling crosstalk between insulin and canonical Wnt signaling pathways at multiple levels, it reveals molecular mechanisms for observed correlation between CRC and hyperinsulinemia. The growing evidence implicating PAK-1 in various human tumorigenesis has emerged PAK-1 as a potential therapeutic target. Our discovery of PAK-1 functioning as a novel central mediator for insulin and Wnt signaling crosstalk in intestinal cells suggests that PAK- 1 may potentially be a good target candidate for treating patients with CRC, especially those who have Type II diabetes or experience hyperinsulinemia. iii Acknowledgements I would like to thank my supervisor Dr. Tianru Jin for his continuous support and guidance throughout this project. I would also like to extend my gratitude toward members of my Supervisory Committee, Dr. Donald Branch, Dr. Theodore Brown and Dr. I. George Fantus, whose enthusiasm and constant encouragement made the completion of this research project an enjoyable experience. Thanks to all the past and present members of the Jin lab who helped me overcome the technical challenges during my study. To all the wonderful friends I have made on the 10th floor of TMDT Building and 4th floor of CBS Building, I want to thank you all for making my research experience memorable. I want to give special thanks to my parents, who supported me unconditionally, kept me out of trouble and taught me how to treasure and appreciate life. Last but not least, I want to thank my husband- to-be, whose patience and understanding surpassed any expectation imaginable. I thank him for being my best friend, and for always being the voice of reason when I needed it. Successful completion of this project would not be made possible without his love and support. iv Table of Contents ABSTRACT ....................................................................................................................................................... II ACKNOWLEDGEMENTS .................................................................................................................................. IV TABLE OF CONTENTS ....................................................................................................................................... V LIST OF FIGURES ........................................................................................................................................... VIII LIST OF ABBREVIATIONS ............................................................................................................................... XII LIST OF PUBLICATIONS ................................................................................................................................. XVI CHAPTER 1: INTRODUCTION ........................................................................................................................... 1 1.1 INSULIN SIGNALING...................................................................................................................... 2 1.1.1 Overview of Insulin - Discovery, Synthesis, Secretion and Physiological Roles ....................... 2 1.1.1.1 Insulin Synthesis in Pancreatic beta-cells (-cell) .................................................................................. 3 1.1.1.2 Insulin Secretion .................................................................................................................................... 6 1.1.1.3 Physiological Roles of Insulin ................................................................................................................. 8 1.1.2 Initiation of Insulin Signaling .................................................................................................. 9 1.1.2.1 Insulin Receptor (IR) Activation and Regulation .................................................................................... 9 1.1.2.2 Insulin Receptor Substrate (IRS) – Platform of Insulin Signaling Pathways ......................................... 10 1.1.3 Insulin Action via phosphatidylinosital 3-kinase (PI3K)-Akt/protein kinase B (PKB) ............. 13 1.1.3.1 Activation of PI3K ................................................................................................................................ 17 1.1.3.2 Activation of Akt/PKB .......................................................................................................................... 17 1.1.3.3 Akt/PKB mediated Insulin Effects ........................................................................................................ 19 1.1.3.4 p-21 Activated Protein Kinase 1 (PAK-1) ............................................................................................. 21 1.1.4 Insulin Action via Ras-mitogen-activated protein kinase (MAPK) ........................................ 27 1.1.4.1 Activation of Ras GTPases ................................................................................................................... 27 1.1.4.2 Activation of Raf Family Serine/Threonine Kinases ............................................................................. 29 1.1.4.3 Activation of MEK/Erk ......................................................................................................................... 30 1.1.4.4 Regulation of MAPK Pathway .............................................................................................................. 31 1.1.5 Implication of Insulin Signaling in Cancer ............................................................................. 32 1.1.5.1 Ras/MAPK Signaling-Mediated Cell Transformation ........................................................................... 33 1.1.5.2 PI3K/Akt Signaling-Mediated Cell Transformation .............................................................................. 34 1.1.5.3 Implication of Hyperinsulinemia in Colorectal Cancer – Evidence from Epidemiological and Animal Studies ................................................................................................................................................. 36 1.2 WNT SIGNALING ....................................................................................................................... 40 1.2.1 Initiation of Wnt Signaling.................................................................................................... 40 1.2.1.1 Wnt Ligand Processing and Secretion ................................................................................................. 40 1.2.1.2 Extracellular Transport of Wnt Proteins .............................................................................................. 42 1.2.1.3 Serpentine Receptor Frizzled (Fzd) ...................................................................................................... 43 1.2.2 Non-canonical Wnt Signaling Pathways............................................................................... 44 1.2.2.1 Planar Cell Polarity (PCP) – Convergent Extension Pathway ............................................................... 44 1.2.2.2 Wnt/Ca2+ Pathway ............................................................................................................................... 46 1.2.3 Canonical Wnt Signaling Pathway ....................................................................................... 46 1.2.3.1 Transducing Wnt Signals from Receptor to cat ............................................................................... 48 1.2.3.2 Regulation of Cytoplasmic cat ......................................................................................................... 49 1.2.3.3 cat – Nuclear Entry and Function ...................................................................................................
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