Systems Level Analysis of TORC1 Pathway Signaling in S. cerevisiae

Persistent Link:
http://hdl.handle.net/10150/556430
Title:
Systems Level Analysis of TORC1 Pathway Signaling in S. cerevisiae
Author:
Hughes Hallett, James
Issue Date:
2015
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
The target of rapamycin complex I (TORC1) regulates cell growth and metabolism in all eukaryotes. Previous studies have shown that nitrogen and amino acid signals activate TORC1 via three GTPases; Gtr1, Gtr2, and Rho1, and the SEA-associated Npr2/3 proteins. However, little is known about the way that other nutrient or stress signals are transmitted to TORC1. Here I present two studies identifying how, and at what level, glucose and other environmental stimuli act to tune TORC1 signaling. In the first study I show that the TORC1 pathway populates three additional stress/starvation states. First, in glucose starvation conditions, the AMP-activated protein kinase (AMPK/Snf1) and at least one other factor push the TORC1 pathway into an off state, in which Sch9-branch signaling and PP2A-branch signaling are both inhibited. The TORC1 pathway remains in the glucose starvation state even when cells are simultaneously starved for nitrogen and glucose or treated with rapamycin. Second, in osmotic stress, the MAPK Hog1/p38 drives the TORC1 pathway into a different state, in which Sch9 signaling and PP2A-branch signaling are inhibited, but PP2A-branch signaling can still be activated by nitrogen starvation. Third, in oxidative stress and heat stress, TORC1-Sch9 signaling is blocked while weak PP2A-branch signaling occurs. Together, the data show that the TORC1 pathway acts as an information-processing hub, activating different genes in different conditions to ensure that available energy is allocated to drive growth, amino acid synthesis, or a stress response, depending on the needs of the cell. In the second study I investigate further the observed hierarchy of TORC1 inputs. I show that glucose starvation triggers disassembly of TORC1, and movement of the key TORC1 component Kog1, to a single body near the edge of the vacuole. These events are driven by AMPK/Snf1-dependent phosphorylation of Kog1 at Serine 491/494 and two nearby prion-like motifs. Kog1-bodies then serve to increase the threshold for TORC1 activation in cells that have been starved for a significant period of time. Together, this data shows that Kog1-bodies create hysteresis (memory) in the TORC1 pathway and help ensure that cells remain committed to a quiescent state under suboptimal conditions.
Type:
text; Electronic Dissertation
Keywords:
Molecular & Cellular Biology
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Molecular & Cellular Biology
Degree Grantor:
University of Arizona
Advisor:
Capaldi, Andrew

Full metadata record

DC FieldValue Language
dc.language.isoen_USen
dc.titleSystems Level Analysis of TORC1 Pathway Signaling in S. cerevisiaeen_US
dc.creatorHughes Hallett, Jamesen
dc.contributor.authorHughes Hallett, Jamesen
dc.date.issued2015en
dc.publisherThe University of Arizona.en
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en
dc.description.abstractThe target of rapamycin complex I (TORC1) regulates cell growth and metabolism in all eukaryotes. Previous studies have shown that nitrogen and amino acid signals activate TORC1 via three GTPases; Gtr1, Gtr2, and Rho1, and the SEA-associated Npr2/3 proteins. However, little is known about the way that other nutrient or stress signals are transmitted to TORC1. Here I present two studies identifying how, and at what level, glucose and other environmental stimuli act to tune TORC1 signaling. In the first study I show that the TORC1 pathway populates three additional stress/starvation states. First, in glucose starvation conditions, the AMP-activated protein kinase (AMPK/Snf1) and at least one other factor push the TORC1 pathway into an off state, in which Sch9-branch signaling and PP2A-branch signaling are both inhibited. The TORC1 pathway remains in the glucose starvation state even when cells are simultaneously starved for nitrogen and glucose or treated with rapamycin. Second, in osmotic stress, the MAPK Hog1/p38 drives the TORC1 pathway into a different state, in which Sch9 signaling and PP2A-branch signaling are inhibited, but PP2A-branch signaling can still be activated by nitrogen starvation. Third, in oxidative stress and heat stress, TORC1-Sch9 signaling is blocked while weak PP2A-branch signaling occurs. Together, the data show that the TORC1 pathway acts as an information-processing hub, activating different genes in different conditions to ensure that available energy is allocated to drive growth, amino acid synthesis, or a stress response, depending on the needs of the cell. In the second study I investigate further the observed hierarchy of TORC1 inputs. I show that glucose starvation triggers disassembly of TORC1, and movement of the key TORC1 component Kog1, to a single body near the edge of the vacuole. These events are driven by AMPK/Snf1-dependent phosphorylation of Kog1 at Serine 491/494 and two nearby prion-like motifs. Kog1-bodies then serve to increase the threshold for TORC1 activation in cells that have been starved for a significant period of time. Together, this data shows that Kog1-bodies create hysteresis (memory) in the TORC1 pathway and help ensure that cells remain committed to a quiescent state under suboptimal conditions.en
dc.typetexten
dc.typeElectronic Dissertationen
dc.subjectMolecular & Cellular Biologyen
thesis.degree.namePh.D.en
thesis.degree.leveldoctoralen
thesis.degree.disciplineGraduate Collegeen
thesis.degree.disciplineMolecular & Cellular Biologyen
thesis.degree.grantorUniversity of Arizonaen
dc.contributor.advisorCapaldi, Andrewen
dc.contributor.committeememberCapaldi, Andrewen
dc.contributor.committeememberMontfort, Williamen
dc.contributor.committeememberNagy, Lisaen
dc.contributor.committeememberSerio, Triciaen
dc.contributor.committeememberWeinert, Teden
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