Genetic analysis of the catalytic activity of integrin-linked kinase (ILK) in vivo [Elektronische Ressource] / Anika Lange

Lange Anika

Informations

• Publié par: ludwig-maximilians-universitat_munchen
• Publié le: 01 janvier 2010
• Nombre de lectures: 19
• Langue: Deutsch
• Poids de l'ouvrage: 1 Mo

Extrait

Dissertation zur Erlangung des Doktorgrades
der Fakultät für Chemie und Pharmazie
der Ludwig-Maximilians-Universität München





Genetic analysis of the catalytic activity of
Integrin-linked kinase (ILK) in vivo






Anika Lange
aus
Osterburg/Altmark
2010


Erklärung

Diese Dissertation wurde im Sinne von § 13 Abs. 3 der Promotionsordnung vom
29. Januar 1998 von Herrn Prof. Dr. Reinhard Fässler betreut.




Ehrenwörtliche Versicherung

Diese Dissertation wurde selbstständig, ohne unerlaubte Hilfe erarbeitet.

München, am



----------------------------
Anika Lange





Dissertation eingereicht am: 22.01.2010


1. Gutachter Prof. Dr. Reinhard Fässler

2. Gutachter Prof. Dr. Christian Wahl-Schott


Mündliche Prüfung am: 04.03.2010




Für meine lieben Eltern

Table of Contents
Table of Contents

Table of Contents ............................................................................................................... I
List of Publications ......................................................................................................... III
Abbreviations .................................................................................................................. IV
Summary.......................................................................................................................... VI
Introduction....................................................................................................................... 1
1. The integrin receptor family.................................................................................... 1
1.1 Structure of integrins.......................................................................................... 1
1.2 Integrins and their ligands ................................................................................. 4
1.3 Bidirectional regulation of integrin signaling................................................... 8
1.3.1 Inside-out signaling...................................................................................... 8
1.3.2 Outside-in signalling .................................................................................. 12
1.4 Assembly of integrin-dependent adhesion structures.................................... 16
1.4.1 The integrin-actin connection ................................................................... 18
1.5 The ILK/PINCH/parvin (IPP) complex.......................................................... 20
1.5.1 The molecular composition of the IPP complex...................................... 21
1.5.2 The biological functions of the IPP complex ........................................... 22
1.5.3 The putative kinase activity of ILK 24
2. Kidney physiology................................................................................................... 26
2.1 Kidney development in mice............................................................................ 30
2.1.1 Kidney morphogenesis – pronephros, mesonephros and metanephros 30
2.1.2 Mesenchymal signals initiate kidney development ................................. 33
2.1.3 Ureteric bud outgrowth and branching................................................... 36
2.1.4 Tubulogenesis – MET................................................................................ 42
2.1.5 Role of stroma in kidney development..................................................... 44
2.2 Renal abnormalities in humans ....................................................................... 46
2.2.1 The glomerulus and proteinuria............................................................... 49
2.2.2 Cystic kidney diseases 54
2.3 Integrins and kidney......................................................................................... 56
2.3.1 ECM and its receptors in mammalian nephrogenesis............................ 56
I Table of Contents
2.3.2 Role of integrins and their binding partners in the development of the
collecting system.................................................................................................. 59
2.3.3 Role of integrins and their binding partners in the development and
function of the glomerulus.................................................................................. 60
Aim of the Thesis............................................................................................................. 63
Short Summaries of Publications 64
Publication I: Local call: from integrins to actin assembly .................................... 64 II: How ILK and kindlins cooperate to orchestrate integrin signaling
....................................................................................................................................... 65
Publication III: Integrin-linked kinase is an adaptor with essential functions
during mouse development ........................................................................................ 66
Publication IV: The ILK/PINCH/parvin complex: the kinase is dead, long live the
pseudokinase! .............................................................................................................. 67
Publication V: Integrin-mediated signals control microtubule dynamics required
for plasma membrane targeting of caveolae ............................................................ 68
Publication VI: Bacteria hijack integrin-linked kinase to stabilize focal adhesions
and block cell detachment.......................................................................................... 68
References........................................................................................................................ 69
Acknowledgements ......................................................................................................... 83
Curriculum Vitae............................................................................................................ 84
Supplements..................................................................................................................... 85

II List of Publications
List of Publications


This thesis is based on the following publications, which are referred to in the text by
their Roman numerals (I-VI):

I. Wiesner S, Lange A and Fässler R. Local call: from integrins to actin
assembly. Trends in Cell Biology 2006, 16

II. Böttcher RT, Lange A and Fässler R. How ILK and kindlins cooperate to
orchestrate integrin signaling. Current Opinion in Cell Biology 2009, 21(5):
670-5

III. Lange A, Wickström SA, Jakobson M, Zent R, Sainio K and Fässler R. Integrin-
linked kinase is an adaptor with essential functions during mouse
development. Nature 2009, 461: 1002-1006 .

IV. Wickström SA, Lange A, Montanez E and Reinhard Fässler. The
ILK/PINCH/parvin complex: the kinase is dead, long live the pseudokinase!
EMBO J 2010, 29(2): 281-91.

The following publications were not the focus of my project but I contributed to them:

V. Wickström SA, Lange A, Hess MW, Krüger M, Pfaller K, Mann M, Bloch W,
Huber LA and Fässler R. Integrin-mediated signals control microtubule
dynamics required for plasma membrane targeting of caveolae. Submitted
manuscript

VI. Kim M, Ogawa M, Fujita Y, Yoshkawa Y, Nagai T, Koyama T, Nagai S, Lange
A, Fässler R and Sasakawa C. Bacteria hijack integrin-linked kinase to
stabilize focal adhesions and block cell detachment. Nature 2009, 459: 578-
583.
III Abbreviations
Abbreviations
ADAM a disintegrin and metalloproteinase
ADP adenosine diphosphate
Akt RAC-alpha serine/threonine protein kinase
APC adenomatous polyposis coli
Arp2/3 actin-related protein 2/3 complex
ATP adenosine triphosphate
BMP bone morphogenetic protein
Cdc42 cell division cycle 42
CH calponin homology
Cre cyclization recombinase
DAG diacylglycerol
E embryonic day
ECM extracellular matrix
EGF epidermal growth factor
ERK extracellular signal-regulated kinase
FA focal adhesion
F-actin filamentous actin
FAK focal adhesion kinase
FERM 4.1, ezrin, radixin, moesin
FGF fibroblast growth factor
FGFR fibroblast growth factor receptor
FP foot process
GAP GTPase activating protein
GBM glomerular basement membrane
GDI GDP dissociation inhibitor
GDNF glial-cell-derived neurotrophic factor
GDP guanosine diphosphate
GEF guanine nucleotide exchange factor
GFR growth factor receptor
GPCR G protein coupled receptor
Gsk-3β glycogen synthase kinase-3 β
HGF hepatocyte growth factor
ICAM intercellular adhesion molecule
ILK integrin-linked kinase
IP3 inositol triphosphate
IPP ILK/PINCH/parvin
JNK c-jun N-terminal kinase
MAPK mitogen-activated protein kinase
MET me