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SELECTIVE REGULATION of BMP4 SIGNALING by the RECEPTOR TYROSINE KINASE Musk

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SELECTIVE REGULATION of BMP4 SIGNALING by the RECEPTOR TYROSINE KINASE Musk SELECTIVE REGULATION OF BMP4 SIGNALING BY THE RECEPTOR TYROSINE KINASE MuSK ATILGAN YILMAZ B.S. MOLECULAR BIOLOGY AND GENETICS, BOĞAZİÇİ UNIVERSITY, 2005 A DISSERTATION SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY IN THE DIVISION OF BIOLOGY AND MEDICINE AT BROWN UNIVERSITY PROVIDENCE, RHODE ISLAND May 2013 i Copyright© 2012 by AtılgAn Yılmaz ii This dissertAtion by AtılgAn Yılmaz is accepted in its present form by the Division of Biology And Medicine, DepArtment of MoleculAr Biology, Cell Biology And Biochemistry As sAtisfying the dissertAtion requirement for the degree of Doctor of Philosophy. Date_____________ __________________________________ Dr. Justin R. Fallon, Advisor Recommended to the GrAduAte Council Date_____________ __________________________________ Dr. Kristi Wharton, Reader (ChAirman) Date_____________ __________________________________ Dr. GilAd BArnea, Reader Date_____________ __________________________________ Dr. Mark Zervas, Reader Date_____________ __________________________________ Dr. Steven Burden, Outside Reader Approved by the GrAduAte Council Date_____________ __________________________________ Dr. Peter Weber, Dean of the GraduAte School iii ATILGAN YILMAZ DOB: November 21, 1982 Mailing Address: DepArtment of Neuroscience, Brown University, Box G-LN 185 Meeting Street, Providence, RI 02912 Phone: 401 919 7262 E-mail: [email protected] EDUCATION Ph.D. in MoleculAr Biology, CellulAr Biology And Biochemistry (expected) Summer 2012 Brown University, Providence, RI Thesis: “Selective regulAtion of BMP4 signAling by the receptor tyrosine kinAse MuSK” B.S. in MoleculAr Biology And Genetics June 2005 Bogazici University, IstAnbul, Turkey, with Honors RESEARCH EXPERIENCE 04/06 – Graduate Student, Brown University, Providence, USA Selective regulation of BMP4 signaling by the receptor tyrosine kinase MuSK Advisor: Prof. Justin Fallon, DepArtment of Neuroscience 06/04 – 09/04 Undergraduate Summer Research Trainee. UCLA, Los Angeles, USA MechAnism of cofilin-mediAted Actin depolymerizAtion. Advisor: Prof. Emil Reisler, DepArtment of Chemistry & Biochemistry 07/03 – 10/03 Undergraduate Summer Research Trainee, Georg August University, Göttingen, Germany MoleculAr mechAnisms of endocytosis And synAptic vesicle formation in neurons. (Supported by the Science And Culture Ministry of NiedersAchsen) Advisor: Prof. Volker Haucke, Biochemistry Institute (relocAted to Freie Universität Berlin) 11/01 – 06/05 Undergraduate Research Assistant. Bogazici University, Istanbul, Turkey Role of FGF fAmily in development And physiopAthology in vertebrAte retinA. Advisor: Prof. Kuyas Bugra, DepArtment of MoleculAr Biology And Genetics iv PUBLICATIONS AmentA AR, YilmAz A, BogdAnovich S, McKechnie BA, Abedi M, KhurAnA TS, FAllon JR. (2011) BiglycAn recruits utrophin to the sArcolemmA And counters dystrophic pAthology in mdx mice. PNAS 108(2), 762-767 Bobkov AA, MuhlrAd A, PAvlov DA, KokAbi K, YilmAz A, Reisler E. (2006) CooperAtive effects of cofilin (ADF) on actin structure suggest allosteric mechanism of cofilin function. J Mol Biol. 356(2), 325-334 Manuscripts in Progress: YilmAz A, FAllon JR. (in prepArAtion) The receptor tyrosine kinAse MuSK regulAtes BMP4 signAling. YilmAz A, FAllon JR. (in prepArAtion) BMP4 induces acetylcholine receptor clustering in a MuSK-dependent mAnner. PATENT APPLICATIONS “BiglycAn mutAnts and relAted therApeutics And methods of use” Inventors: AmentA AR, McKechnie BA, Dechene M, YilmAz A, FAllon JR. U.S. PAtent ApplicAtion No.: 13/109,558 “TherApeutic and diAgnostic methods involving biglycAn and utrophin” Inventors: Amenta AR, YilmAz A, McKechnie BA, Fallon JR. Provisional ApplicAtion No.: 61/427,468 ABSTRACTS and INVITED LECTURES YilmAz A, AmentA A, McKechnie B, FAllon J. BiglycAn recruits utrophin to the muscle membrAne And is A potentiAl therApeutic for Duchenne MusculAr Dystrophy. Poster. EMBO Conference Series: MoleculAr And cellulAr bAsis of regenerAtion And tissue repAir, SesimbrA, PortugAl. September 26-30, 2010. A, YilmAz. MechAnisms of action of biglycAn, a potentiAl therApeutic for Duchenne MusculAr Dystrophy. Invited Lecturer. DepArtment of MoleculAr Biology And Genetics, Boğaziçi University, IstAnbul, Turkey. July, 2008 TEACHING EXPERIENCE Spring 2009 – FAll 2011 Rotation student trainer, 6 rotAtion students and 1 MD-PhD student JanuAry 2011 Graduate student assistant, SunA KırAç Workshop on NeurodegenerAtive DiseAse: From Genetic Models to Therapies, Boğaziçi University, IstAnbul, Turkey Spring 2011 Guest Lecturer, AnAlysis of Development, Axolotl Embryo LAb, Brown University v Spring 2010 Guest Lecturer, AnAlysis of Development, Axolotl Embryo LAb, Brown University Spring 2007 Teaching Assistant, AnAlysis of Development, Brown University AWARDS and HONORS 2011 GrAduAte International Colloquium GrAnt, Approved by Brown University Office of InternAtionAl AffAirs LANGUAGES Turkish, English, German, French, Greek vi To my mother, fAther And sister... vii Acknowledgements I would like to first thAnk my Advisor, Dr. Justin FAllon. Without his support and ideas this work would not hAve been possible. I Am especiAlly grAteful to Dr. FAllon for trusting my ideAs And for All our fruitful discussions which helped my trAining to become An independent scientist tremendously. I also want to thank my thesis committee members, Dr. Kristi WhArton, Dr. GilAd Barnea and Dr. Mark Zervas for their vAluAble ideAs thAt helped me bring together the work presented in this thesis. They were always available to discuss ideas and give me feedbAck. I would like to specificAlly thAnk Dr. WhArton with whom I hAd A phone interview before I cAme to Brown University. ThAnk you for giving me the chance to be here, Dr. Wharton! I Am Also thAnkful to the pAst And present members of our lAborAtory: Beatrice Lechner for trAining me when I joined Dr. FAllon’s lAborAtory, Anne Booker whom I will mention below, Michelle Dechene for her protein purifications thAt helped move my project greAtly And Also for AdvAncing my bAking skills, Julia Najera, Emily Stackpole and Hanna Berk Rauch for their discussions and friendship, Carolyn Schmiedel And EAmon Quick for helping me with cell cultures, Beth McKechnie and Sarah Mentzer for making sure thAt the lAborAtory is running efficiently, Michael Akins And Alison Amenta for their ideas, and all rotation students I worked with for their help in the experiments And for their interest in my thesis project. I would also like to mention A few people who hAve greAt impActs on my life. Very special thanks go to two dear friends of mine: İlker Öztop, with whom I shared both lAughter And teArs very many times. I cAnnot imagine A life without such A greAt friend And I feel very lucky for knowing. İyi ki varsın! And Anne Booker, who not only wAs A greAt lAb mate but is also a life-long friend. Without her, so many good memories would be missing from my life. I want to thank Konstantinos Kotakis for his constAnt support and life advices, GökhAn DemirkAn And Ahmet Eken for their compAny throughout the grAduAte school And their friendship. I will always be grateful to all of you. I would like to thank Theocharis Vadivoulis for reviving me At one of the most hopeless times of my life And for reminding me thAt life is “plAstic”. I now hope for iluke-full of years. Ευχαριστώ πολύ! All other friends whose nAmes I could not mention here deserve many thAnks. FinAlly, I would like to thank three most special people to whom I dedicAte my thesis: My mother And fAther , FAdime And Hüseyin Yılmaz, As well As my sister NAgihAn Yılmaz. No matter how fAr we Are, you have always been by my side. Sizi çok seviyorum.... viii Preface CommunicAtion between the extrAcellulAr matrix And the intrAcellulAr environments of the cells is cruciAl for multiple processes such As survivAl, proliferation or maintenAnce of cellulAr stAtes. FAilure or mistAkes in this communicAtion leAds to inAbility to form subcellulAr orgAnizAtions or to give AppropriAte responses to the chAnges in the cellulAr environment or severAl diseAse stAtes such As cancer. Therefore it is importAnt to understAnd how cells employ different mechAnisms to relAy information from the extrAcellulAr matrix to their cytoplAsm. One common wAy of such communicAtion is estAblished by the use of signAling molecules thAt Are recognized by their receptors At the cell surface And the signaling cascades initiated by this receptor-ligAnd interAction. This mechAnism is key to both the intercellulAr communicAtion And the Autocrine regulAtory events. In this thesis I discuss two exAmples of interActions between signaling pathways, as well As mechAnisms in which extrAcellulAr molecules regulAte cytosolic proteins. The first project detAils the studies bAsed on An incidentAl observation showing that the receptor tyrosine kinAse MuSK And the signAling molecule BMP4 bind to eAch other. I Also demonstrAte how the muscle-specific receptor tyrosine kinase MuSK regulAtes BMP4 signAling in muscle cells (ChApter 2). The results of these studies show that MuSK binds to BMP4 And is required for the transcription of A subset of genes in response to BMP4. In ChApter 3, I demonstrAte A role for BMP4 in the induction of AChR clusters in cultured muscle cells. My results suggest thAt this BMP4 effect requires MuSK and Wnt11 activities. In the last data chapter, I present ix the work detAiling biglycAn’s regulAtion of sArcolemmal utrophin expression, the therapeutic effect of this regulation for Duchenne Muscular Dystrophy (DMD)
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