Lucas Bruurs Symmetry breaking signaling mechanisms during cell polarization

141 Pages·2017·11.78 MB·English

Symmetry b
reaking signaling
mechanisms duri
ng cell polarization
Lucas Bruurs
Artwork by:
Василий Васильевич Кандинский
Front: Untitled, 1923
Back: Untitled (drawing for “Diagram 17”), 1925
Insert: Free Curve to the Point - Accompanying Sound of Geometric Curves, 1925
Printed by:
ProefschriftMaken // www.proefschriftmaken.nl // Vianen, The Netherlands
© Lucas Bruurs // 2017 // Utrecht, The Netherlands
Symmetry breaking signaling
mechanisms during cell polarization

Symmetrie-doorbrekende signaleringsmechanismes tijdens cel polarisatie
(met een samenvatting in het Nederlands)
Proefschrift
ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag
van de rector magnificus, prof. dr. G.J. van der Zwaan, ingevolge het besluit
van het college voor promoties in het openbaar te verdedigen op
dinsdag 14 februari 2017 des middags te 12.45 uur
door

Lucas Johan Maria Bruurs
geboren op 21 april 1988 te Veere
Promotor: Prof. dr. J.L. Bos
Dedicated to Willem

Table of Contents
Chapter 1 General introduction: Mechanisms of symmetry 9
breaking during cell polarization
Chapter 2 ATP8B1-mediated spatial organization of Cdc42 37
signaling maintains singularity during enterocyte
polarization
Chapter 3 A two-tiered mechanism enables localized Cdc42 57
signaling during enterocyte polarization
Chapter 4 Apical membrane clustering requires interacting 75
phosphatases PTEN and PTPL1
Chapter 5 Mechanisms and functions of Rap2 signaling 89
Chapter 6 Mechanisms of isoform specific Rap2 signaling during 103
enterocytic brush border formation
Chapter 7 Summarizing discussion 119
Appendices 133
Nederlandse samenvatting 135
Abbreviations 138
Curriculum Vitae 139
Publications 139
Nawoord 140

1
I
General introduction

Mechanisms of symmetry breaking
during cell polarization
Abstract
Tissue morphogenesis requires orchestrated execution of the epithelial cell
1
polarity program. Small GTPases of the Rho family are central players in the
various processes that contribute to cell polarization. Cdc42 in particular has
an evolutionary conserved function in apico-basal polarity establishment by
pioneering the formation of an apical plasma membrane. In order to function
as pioneer factor, Cdc42 must break initial cellular symmetry and establish a
polarity axis. Importantly, polarization at multiple sites can be detrimental to
cellular function and therefore cells must ensure that only one polarity axis is
established.

Here, epithelial cell polarity and signaling by the small GTPase Cdc42 during
cellular polarization will be introduced. An overview is provided on symmetry
breaking by small GTPases and the mechanisms that safeguard singularity in
polarization will be discussed.
10