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Role of the LPA2 Receptor in Protecting Against Apoptosis Shuyu E University of Tennessee Health Science Center

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Role of the LPA2 Receptor in Protecting Against Apoptosis Shuyu E University of Tennessee Health Science Center University of Tennessee Health Science Center UTHSC Digital Commons Theses and Dissertations (ETD) College of Graduate Health Sciences 12-2008 Role of the LPA2 Receptor in Protecting Against Apoptosis Shuyu E University of Tennessee Health Science Center Follow this and additional works at: https://dc.uthsc.edu/dissertations Part of the Medical Physiology Commons Recommended Citation E, Shuyu , "Role of the LPA2 Receptor in Protecting Against Apoptosis" (2008). Theses and Dissertations (ETD). Paper 336. http://dx.doi.org/10.21007/etd.cghs.2008.0079. This Dissertation is brought to you for free and open access by the College of Graduate Health Sciences at UTHSC Digital Commons. It has been accepted for inclusion in Theses and Dissertations (ETD) by an authorized administrator of UTHSC Digital Commons. For more information, please contact [email protected]. Role of the LPA2 Receptor in Protecting Against Apoptosis Document Type Dissertation Degree Name Doctor of Philosophy (PhD) Program Physiology Research Advisor Gabor Tigyi, M.D., Ph.D. Committee Polly Hofmann, Ph.D. Anjaparavanda P. Naren, Ph.D. Abby L. Parrill, Ph.D. Christopher Waters, Ph.D. DOI 10.21007/etd.cghs.2008.0079 This dissertation is available at UTHSC Digital Commons: https://dc.uthsc.edu/dissertations/336 ROLE OF THE LPA2 RECEPTOR IN PROTECTING AGAINST APOPTOSIS A Dissertation Presented for The Graduate Studies Council The University of Tennessee Health Science Center In Partial Fulfillment Of the Requirements for the Degree Doctor of Philosophy From The University of Tennessee By Shuyu E December, 2008 Chapter 2 © 2007 by the American Gastroenterological Association Institute. All other material © 2008 by Shuyu E. ii DEDICATION This dissertation is dedicated to my husband Xu Liu for his endless love and support. and to my children Eilene Liu Nolan Liu iii ACKNOWLEDGEMENTS I am greatly indebted to my supervisor, Dr. Gabor Tigyi, who accepted me into his lab while I was relocating two years ago. The training in his lab greatly benefited me in both science and my personal life. Being exposed to his multi-dimensional lab and broad research capability, I was trained to have an open mind. During this time I regained my confidence, which is critical for my success. In retrospect, I cherished the two years spent in his lab. I am also grateful to all the members in his lab: Billy Walentine, Yuko Fujiwara, Tamotsu Tsukahara, Ryoko Tsukahara, Alyssa Bolen, Daniel Osborne, Huazhang Guo and Dianna Liu. In such a united family, I received support anytime I needed it. This environment made it enjoyable to work everyday. Also, I want to thank Dr. Wenlin Deng for invaluable help in apoptosis studies and Dr. Junming Yue for lentiviral transduction and making stable MEFs. In particular, I want to thank Dr. Fannie Lin who was the collaborator of my project. It was an exciting and inspiring experience to work with her. She is the most energetic, enthusiastic, persevering and intelligent scientist I have ever known. I would like to acknowledge that Fig.3.3, Fig.3.4, Fig.3.5, Fig.3.6, Fig3.8, Fig3.9, Fig3.12, Fig3.16, Fig.3.19, and Fig.3.21 were done in collaboration with her. Also thanks go to Yun-Ju Lai, and Chen-Shan Chen from her lab for providing us the constructs and help in some of the CoIP experiments. I acknowledge Dr. Akio Kihara for his work on the palmitoylation study. I would also like to sincerely thank the other committee members: Dr. Hofmann, Dr. Waters, Dr. Naren, and Dr. Parrill for always being understanding and providing valuable and critical suggestions. I would also like to thank Dr. Schneider, Dr. Watsky, Dr. Hofmann, and Dr. Leffler, whose support encouraged me to continue my Ph.D. in spite of my setback that forced me to change mentors after four years and resulted in a lack of confidence. Also, I could not forget the help from Dr. Johnson’s lab members: Dr. Shi Jin and Dr. Ramsey Ray. I also want to express my gratitude to my parents, mother-in-law, and sister-in- law for their support and helping me care for my daughter, which allowed me time to concentrate on my work. I greatly appreciate the support from Gerwin Scholarship. I appreciate the permission of reuse of the illustrations from Radiation Research Society and Nature Publishing Group. iv ABSTRACT Lysophosphatidic acid (LPA) is a naturally occurring lipid mediator. It exists abundantly in biological fluids such as serum, saliva, follicular fluid, seminal fluid and malignant effusions and induces a vast array of biological responses affecting cell growth, survival, differentiation, migration and morphology. We recently identified lysophosphatidic acid (LPA) as a potent antiapoptotic agent for the intestinal epithelium. Based on computational modeling octadecenyl thiophosphate (OTP) was synthesized: a novel rationally designed, metabolically stabilized LPA mimic. OTP was more efficacious than LPA in reducing !-irradiation-, camptothecin-, or TNF- "//cycloheximide-induced apoptosis and caspase 3, 8 and 9 activity in the IEC-6 cell line. The OTP- and LPA-elicited antiapoptotic effects were completely blocked by the MEK inhibitor PD98059 and the PI3K inhibitor LY294002. Pertussis toxin partially abolished OTP-induced ERK1/2 and apoptotic protection. In RH7777 cells lacking LPA receptors, OTP selectively protected LPA2 but not LPA1 and LPA3 transfectants. In C57BL/6 and LPA1 knockout mice exposed to 15 Gy !-irradiation, orally applied OTP reduced the number of apoptotic bodies and activated caspase 3 positive cells but was ineffective in LPA2 knockouts. OTP, with higher efficacy than LPA, enhanced intestinal crypt survival in C57BL/6 mice but had no effect in LPA2 knockouts. Intraperitonealy administered OTP reduced death caused by LD100/30 radiation by 50%. Our data indicate that OTP is a highly effective antiapoptotic agent that engages similar prosurvival pathways to LPA through the LPA2 receptor subtype. Unique sequence motifs in the LPA2 carboxyl-terminal (CT) enable it to form macromolecular complexes with PDZ and LIM domain proteins, which link it to G protein-independent signaling networks. Using deletion and site-specific mutagenesis, we mapped out C311xxC314 motif of LPA2-CT that is required for interaction with LIM domain proteins thyroid hormone receptor interactive protein 6 (TRIP6) and the proapoptotic molecule Siva-1 in vitro and in vivo. Palmitoylation that occurs on these cysteine residues, however, did not affect the association with TRIP6 or Siva-1. The L351A mutation in the PDZ motif weakened but did not abolish interaction with LIM proteins. Alanine mutation of the LIM binding motif or PDZ domain binding motif attenuated LPA-induced activation of the prosurvival ERK1/2 and Akt pathways in mouse embryonic fibroblasts (MEF) derived from LPA1 and LPA2 double knockout mice and reconstituted with mutants of LPA2. Neither of these mutations alone nor in combination had a detectable effect on G-protein-linked activation of Ca2+ mobilization. Triple alanine mutations modifying residues Cys311, Cys314, and Leu351 abolished the antiapoptotic effect of LPA. Together, these findings suggest the macromolecular complex formed between LPA2, TRIP6/Siva-1, and PDZ domain proteins plays an important role in mediating the anti-apoptotic effects of LPA2. v TABLE OF CONTENTS CHAPTER 1. GENERAL INTRODUCTION................................................................1 1.1 LPA RECEPTOR AND SIGNALING .................................................................1 1.1.1 LPA Receptors and Signaling.................................................................1 1.1.2 OTP: A Rationally Designed LPA Mimic...............................................2 1.2 APOPTOSIS IN SMALL INTESTINE EPITHELIUM.......................................3 1.2.1 Intrinsic (Mitochondria-mediated) Apoptotic Pathway .........................3 1.2.2 Extrinsic (Death Receptor-mediated) Apoptotic Pathway .....................6 1.2.3 Physiology of Small Intestinal Stem Cells..............................................6 1.2.4 Radiobiology in Mouse Small Intestinal Stem Cells..............................8 1.3 LIM AND PDZ DOMAIN PROTEINS INTERACTING WITH LPA2 C- TERMINUS..........................................................................................................9 1.3.1 PDZ Domain Proteins ...........................................................................11 1.3.2 LIM Domain Proteins ...........................................................................11 CHAPTER 2. THE LYSOPHOSPHATIDIC ACID TYPE 2 RECEPTOR IS REQUIRED FOR PROTECTING AGAINST RADIATION-INDUCED INTESTINAL INJURY ..................................................................................................15 2.1 INTRODUCTION ..............................................................................................15 2.2 MATERIALS AND METHODS........................................................................17 2.2.1 Reagents.................................................................................................17 2.2.2 Computational Modeling.......................................................................18 2.2.3 Radiolabeling of OTP............................................................................18 2.2.4 Determining OTP Absorption from the Gut.........................................18 2.2.5 Assaying OTP Metabolism by Pancreatic Lipase and Lipid Phosphate Phosphatase 1 (LPP1).........................................................20 2.2.6 Cell Culture and Induction of Apoptosis In Vitro................................20
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