The role of PRAS40 in insulin action : at the intersection of protein kinase B (PKB/Akt) and mamalian target of
rapamyein (mTOR)
Nascimento, E.B.M.
Citation
Nascimento, E. B. M. (2010, September 9). The role of PRAS40 in insulin action : at the intersection of protein kinase B (PKB/Akt) and mamalian target of rapamyein (mTOR). Retrieved from
https://hdl.handle.net/1887/15934
Version: Corrected Publisher’s Version
License: Licence agreement concerning inclusion of doctoral thesis in the Institutional Repository of the University of Leiden
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The role of PRAS40 in insulin action
At the intersection of protein kinase B (PKB/Akt) and mammalian target of rapamycin (mTOR)
The role of PRAS40 in insulin action
At the intersection of protein kinase B (PKB/Akt) and mammalian target of rapamycin (mTOR)
Proefschrift
ter verkrijging van
de graad Doctor aan de Universiteit Leiden,
op gezag van Rector Magnificus prof. mr. P.F. van der Heijden,
volgens besluit van het College voor Promoties
te verdedigen op donderdag 9 september 2010
klokke 16.15 uur
door
Emmani Bernard Mansangu Nascimento geboren te Rotterdam
in 1981
Promotiecommisie
Promotores: Prof. dr. P. ten Dijke
Prof. dr. J.A. Maassen
Copromotor: Dr. D.M. Ouwens
Overige leden: Prof. dr. M. Diamant
(VUMC, Amsterdam, the Netherlands)
Prof. dr. J. Eckel
(Deutsches diabetes-zentrum, Düsseldorf, Germany)
Prof. dr. A. Krook
(Karolinska institutet, Stockholm, Sweden)
ISBN: 9789461080622
The research described in this thesis was performed at the department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands. This work was supported by a grant from the Dutch Diabetes Research Foundation.
Printing of this thesis was financially supported by the Dutch Diabetes Research Foundation and the J.E. Jurriaanse Stichting.
Cover design by Jenneke Buiter.
The thesis was printed by Gildeprint Drukkerijen, Enschede, the Netherlands.
Table of contents
List of abbreviations 7
Chapter 1 9
General introduction
Chapter 2 23
PRAS40: Target or modulator of mTORC1 signalling and insulin action?
Chapter 3 57
Insulin-mediated phosphorylation of PRAS40 is impaired in insulin target
tissues of high-fat diet-fed rats
Chapter 4 73
Phosphorylation of PRAS40 on Thr246 by PKB/Akt facilitates efficient phosphorylation of Ser183 by mTORC1
Chapter 5 97
PRAS40 contains a nuclear export signal
Chapter 6 113
PRAS40 protects A14 fibroblasts against palmitate-induced insulin resistance
Chapter 7 127
Summary and general discussion
Nederlandse samenvatting 141
List of publications 145
Curriculum Vitae 147
Appendix (Full colour illustrations) 149
7 List of abbreviations
4EBP1 eukaryotic translation initiation factor 4E binding protein 1 AKT1S1 Akt1 substrate 1
AMPK AMP-activated kinase AS160 Akt substrate of 160 kDa BMI body mass index
ERK extracellular-signal regulated kinase GSK glycogen synthase kinase
HFD high fat diet
HIF1D hypoxia-inducible factor 1D IRS insulin receptor substrate LFD low fat diet
mLST8 mammalian ortholog of yeast Lethal with Sec13 protein 8 mTOR mammalian target of rapamycin
mTORC mTOR complex NES nuclear export signal
PI3K phosphatidylinositol 3’-kinase PKB/Akt protein kinase B
PKC protein kinase C
PDGF platelet-derived growth factor PRAS40 proline-rich Akt substrate of 40 kDa PRR5 proline-rich repeat protein 5 PTEN phosphatase and tensin homolog Raptor regulatory associated protein of mTOR Rheb Ras homolog-enriched in brain
Rictor rapamycin-insensitive companion of mTOR S6K p70 S6 kinase
SGK serum- and glucocorticoid-regulated kinase T2DM type 2 diabetes mellitus
TBC1D4 TBC1 domain family member 4 TOS mTOR signalling motif
TSC tuberous sclerosis complex YY1 yin yang 1
List of abbreviations
8
