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TORC2 downstream signaling in Saccharomyces cerevisiae

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Defense Thèse de doctorat : Univ. Genève, 2015 - Sc. 4836 - 2015/10/02
Abstract During their lives, eukaryotic cells need to adjust their metabolism and growth in response to changes of the surrounding conditions. These cellular responses are tightly coordinated and are required for cell survival and essential for the health of a multicellular organism. A major controller of growth as well as aging related processes is the serine/threonine TOR (Target Of Rapamycin) kinase. This highly conserved protein kinase is linked to many diseases and the model organism Saccharomyces cerevisiae has been a valuable tool in discovering and functionally characterizing this kinase. Unlike most other eukaryotes, S. cerevisiae encodes two TOR genes. TOR1 encodes the Tor1 kinase found in a multiprotein complex called TORC1-A only (Target Of Rapamycin Complex 1A), whereas the TOR2 gene encodes the Tor2 kinase found in TORC1-B and in TORC2. While TORC1-A and TORC1-B are inhibited by the macrocyclic lactone rapamycin, a TORC2 inhibitor has been missing, as well as the reason for its resistance to rapamycin. Consequently, the functions performed by TORC1 (including TORC1-A and TORC1-B) have been well characterized, whereas our understanding of TORC2 signaling remained preliminary. However, research of the past few years has revealed that both TOR complexes regulate their readouts through feedback mechanisms. In this thesis and in our JBC publication (Rispal et al., 2015), we present a tool in which TORC2 can be efficiently inhibited, leading to a model in which this complex regulates its downstream outputs actin cytoskeleton polarization and endocytosis via three pathways, including i) a fast and direct pathway where Ypk1 – a downstream target of TORC2 – could act as direct regulator of proteins involved in these processes; ii) further, an indirect regulator via the flippase kinases Fpk1 and Fpk2 might play a central role in coupling actin polarization and the endocytic machinery to TORC2. Lastly, iii) changes in the composition and especially depletion of complex sphingolipids from the plasma membrane indirectly signals to proteins mediating actin polarization and endocytosis. We also confirm the link of TORC2 to cell cycle progression and calcineurin signalling. Additionally, preliminary data indicates that actin organization and G2/M cell cycle progression could be mediated downstream of calcineurin. Moreover, it seems that TORC2 also influences inositol metabolism, a TORC2 function that hasn’t been described yet. This highlights that TORC2 – like TORC1 – also exerts various functions within a yeast cell. We further wished to determine how TORC1 signals to TORC2 during inhibition with rapamycin. We observed that inhibition of TORC1-A is sufficient to induce TORC2 hyperactivation, as monitored by phosphorylation of Ypk1. However, the factors involved in this signalling event, as well as the physiological significance remain to be determined.
Keywords Target of Rapamycin Complex 2 (TORC2)Cell Wall Integrity (CWI)EndocytosisActin polarizationComplex sphingolipidsPlasma MembraneEnt1
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URN: urn:nbn:ch:unige-775707
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Research group Groupe Loewith
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ELTSCHINGER, Sandra. TORC2 downstream signaling in Saccharomyces cerevisiae. Université de Genève. Thèse, 2015. https://archive-ouverte.unige.ch/unige:77570

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Deposited on : 2015-11-23

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