Modulation der Insulinsignalübertragung durch Phosphorylierung von Serin-357 im Insulin-Rezeptor-Substrat-1 [Elektronische Ressource] = Modulation of insulin signal transduction by serine-357 phosphorylation of insulin receptor substrate-1 / vorgelegt von Rizwana Sanaullah Waraich

Besitzer

Sujets

• Biologie

Informations

• Publié par: eberhard_karls_universitat_tubingen
• Publié le: 01 janvier 2008
• Nombre de lectures: 37
• Langue: English
• Poids de l'ouvrage: 2 Mo

Extrait

Modulation der Insulinsignalübertragung
durch Phosphorylierung von Serin-357 im
Insulin-Rezeptor-Substrat-1

Modulation of Insulin Signal Transduction by
Serine-357 Phosphorylation of Insulin Receptor
Substrate-1

Dissertation

der Fakultät für Chemie und Pharmazie
der Eberhard–Karls–Universität Tübingen

zur Erlangung des Grades eines Doktors
der Naturwissenschaften



2008

vorgelegt von


Rizwana Sanaullah Waraich





I





































Tag der mündlichen Prüfung: 29.04.2008

Dekan : Prof. Dr. Lars Wesemann
1. Berichterstatter: Prof. Dr. St. Stevanovic
2. Berichterstatter: Prof. Dr. Dr. h.c. W. Voelter




II ACKNOWLEDGMENTS
The studies included in this thesis were carried out at the Department of Internal Medicine,
Division of Clinical Chemistry and Pathobiochemistry, University of Tuebingen. My sincere
gratitude goes to my supervisor, Prof. Dr. Dr. h. c. mult. Wolfgang Voelter and my immediate
supervisors Priv. Doz. Dr. Rainer Lehmann and Priv. Doz. Dr. Cora Weigert for their
supportive interest and unstinting encouragement throughout the thesis process. I especially
want to thank them for keeping a watchful eye on the progress of my study, patiently
emboldened me at critical periods and for making me take pride in my work. Their
commitment and invaluable help in my research work, editing text and insightful comments in
posters, abstracts, manuscripts and thesis is highly acknowledged.
I warmly acknowledge Prof. Dr. Hans-Ulrich Häring and Prof. Dr. Erwin
Schleicher, for the provision of work place in the laboratory of the medical clinic, travel
grants and for their support and interest in my work.
Financial support received from the Higher Education Commission of Pakistan and DAAD is
greatly acknowledged.
My gratitude is recorded for the examiners of this thesis, Prof. Dr. St. Stevanovic, Prof. Dr.
W. Voelter, Prof. Dr. Thilo Stehle, Prof. Dr. Erwin Schleicher, and Prof. Dr. H. J. Machulla,
University of Tuebingen, for their insights and valuable constructive criticism of this thesis.
I owe my sincerest thanks to all co-authors and collaborator especially to Dr. Hubert
Kalbacher for peptide synthesis and antibody production.
Many thanks to all of my co-workers: Louise Fritsche, Meriam Hoene, Xinjie Zhao, Katrin
Brodbeck, Myriam Schäuble, Roman Werner, Andreas Dittmar, Ann Kathrin Pohl and Heike
Runge. I want to thank all of my other colleagues at the University, all assistant staff
including the cleaners who smilingly clean my chaos in the lab.
To my lovely friends Zaigham Mahmood, Nousheen Zaidi and Omima Nasir who have kept
me focused and happy along this journey, I owe more than I can say.
A special big thank goes to my beloved sister Rukh-e-shahla and my brothers, Aamir, Amjad
and Fahad who have supported me all the way.
Last but, by no means least, all this would not have been possible without the kind support of
my parents Razia and Sanaullah. No formal thanks are ever sufficient, no words are ever
enough to express the gratitude to them.


III



















To Ammin and Abboo,
Who provided the environment which facilitates me to
choose right path of life!
To my most sincere friend, Zaigham
Who always stood beside me during the ups and downs of my
PhD
IV
PUBLICATIONS DERIVED FROM THE WORK FOR
DOCTORAL THESIS

Original Publications:

1. Rizwana Sanaullah Waraich, Cora Weigert, Hubert Kalbacher, Hans-Ulrich Häring,
Erwin Schleicher, Wolfgang Voelter, Rainer Lehmann. Phosphorylation of Ser357of rat
insulin receptor substrate -1 mediates adverse effects of protein kinase C-delta on insulin
action in skeletal muscle cells. J Biol Chem. 2008 Feb 19; [Epub ahead of print]

2. Rizwana Sanaullah Waraich, Nousheen Zaidi, K. Moeschel, A. Beck, Wolfgang Voelter,
Hubert Kalbacher1, and R.Lehmann. Development and precise characterization of phospho-
site-specific antibody for novel Ser-357 of IRS-1: elimination of cross reactivity with adjacent
Ser-358 (Manuscript Submitted)


Abstracts/ Poster presentation:

During the period of this dissertation the work was presented in the following conferences:


rd1. 43 Annual meeting of European Association for the study of diabetes (EASD)
Amsterdam 2007.
Protein kinase C- δ -induced phosphorylation of Ser-357 in insulin
Receptor Substrate-1(IRS-1) attenuates insulin action
R. Sanaullah Waraich, C. Weigert, E. D. Schleicher, H. U. Häring, R. Lehmann;
Department of Internal Medicine IV, Eberhard-Karls University, Tuebingen,
Germany. Diabetologia (2007) 50: [Suppl1] S1–S538

2. Xth International Symposium on Insulin Receptors and Insulin Action Stockholm
Sweden May 2-6, 2007.
Role of the new protein kinase C-dependent Serine 357 phosphorylation of insulin
receptor substrate-1 on insulin action in skeletal muscle cells
R. Sanaullah Waraich, C. Weigert, E. D. Schleicher, H. U. Häring, R. Lehmann;
Department of Internal Medicine IV, Eberhard-Karls University, Tuebingen,
Germany.

nd3. 42 EASD Annual Meeting of the European Association for the Study of Diabetes
Copenhagen, Denmark, 14 – 17 September 2006
Function of the novel, protein kinase C-dependent Serine 357 phosphorylation of
insulin receptor substrate-1 on insulin action in skeletal muscle cells
R. Sanaullah Waraich, C. Weigert, A. Beck, W. Voelter,E. D. Schleicher, H. U.
Häring, R. Lehmann;
Department of Internal Medicine IV, Eberhard-Karls University,
Tuebingen, Germany. Diabetologia (2006) 49: [Suppl1]1–755

V
CONTENTS
1 ABBREVIATIONS…………………………………………………………………....................

SUMMARY………………………………………………………………………………............. 3

1. INRODUCTION ……………………………………………………………………………... 4

1.1 Diabetes…………………………………………………………………………………….. 4

1.2 Insulin resistance………………………………………………………………………….. 4

1.3 Insulin signaling - the basics…………………………………………………………….. 5

1.3.1 Insulin receptor………………………………………………………….. 5
1.3.2 Binding partners of insulin receptor…………………………………….. 6
1.3.3 Insulin receptor substrates (IRS)………………………………………… 6
1.3.4 Structural organization of IRS proteins ………………………………… 6
1.3.5 IRS isoforms…………………………………………………………….. 7

1.3.5.1 Insulin receptor substrate 1 (IRS- 1)…………………………... 7
1.3.5.2 Insulin receptor substrate 2 (IRS-2)…………………………… 8
1.3.5.3 Insulin receptor substrate 3 (IRS- 3)…………………………... 8
1.3.5.4 Insulin receptor substrate 4 (IRS- 4)…………………………... 9
1.3.5.5 Insulin receptor substrate 5 and 6 (IRS- 5, - 6)………………... 9

1.3.6 Binding partners of IRS-1……………………………………………….. 9
1.3.7 The PI3-Kinase cascade…………………………………………………. 9
1.3.8 Insulin-activated AKT/PKB ……………………………………………. 11
1.3.9 Insulin-activated GSK-3………………………………………………… 11

1.4 Regulatory aspects of insulin signaling: cause of type 2 diabetes ………………... 12

1.4.1 Genetic aspects………………………………………………….. 12
1.4.2 Tyrosine phosphorylation of IRS-proteins……………………… 12
1.4.3 Serine phosphorylation of IRS-1: Modulator of insulin
signaling…………………………………………………………… 13
1.4.3.1 Serine phosphorylation as a feedback regulatory mechanism of
insulin signaling……………………………………………………………………….
13
1.4.3.2 Serine phosphorylation of IRS proteins as a negative modulator of
insulin signaling……………………………………………………………….. 14
1.4.3.3 Mechanisms employed by Ser phosphorylation of IRS-1 to inhibit its
function…........................................................................................................... 15
1.4.3.4 Serine phosphorylation as a positive modulator of insulin
signaling……………………………………………….………………………. 16
1.4.3.5 Important serine phosphorylation sites of IRS-1……………………… 16

1.5 Protein kinase C as modulators of insulin signal transduction……………………. 17



VI
1.5.1 PKCs mediated upregulation of insulin signaling……………………… 18

1.5.2 PKCs mediated downregulation of insulin signaling …………………... 18
1.5.2.1 Regulation of serine phosphorylation of IRS-1 by PKC
isoforms……………………………………………………………………….. 19
1.5.2.2 PKC-δ-mediated downregulation of insulin signaling via serine
phosphorylation of IRS-1……………………………………………………………... 19

1.6 Aims of the study…………………………………………………………………. 20