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Published on: November 8, 2006
Fission yeast Ryh1 GTPase activates TOR Complex 2 in response to glucose
Tomoyuki Hatano1, Susumu Morigasaki, Hisashi Tatebe
1a Graduate School of Biological Sciences , Nara Institute of Science and Technology , Ikoma , Nara , Japan.
Abstract:
The Target Of Rapamycin (TOR) is an evolutionarily conserved protein kinase that forms 2 distinct protein complexes referred to as TOR complex 1 (TORC1) and 2 (TORC2). Recent extensive studies have demonstrated that TORC1 is under the control of the small GTPases Rheb and Rag that funnel multiple input signals including those derived from nutritional sources; however, information is scarce as to the regulation of TORC2. A previous study using the model system provided by the fission yeast Schizosaccharomyces pombe identified Ryh1, a Rab-family GTPase, as an activator of TORC2. Here, we show that the nucleotide-binding state of Ryh1 is regulated in response to glucose, mediating this major nutrient signal to TORC2. In glucose-rich growth media, the GTP-bound form of Ryh1 induces TORC2-dependent phosphorylation of Gad8, a downstream target of TORC2 in fission yeast. Upon glucose deprivation, Ryh1 becomes inactive, which turns off the TORC2-Gad8 pathway. During glucose starvation, however, Gad8 phosphorylation by TORC2 gradually recovers independently of Ryh1, implying an additional TORC2 activator that is regulated negatively by glucose. The paired positive and negative regulatory mechanisms may allow fine-tuning of the TORC2-Gad8 pathway, which is essential for growth under glucose-limited environment.
Insights
Glucose availability controls the Target Of Rapamycin Complex 2 (TORC2) pathway in fission yeast. The GTPase Ryh1 activates TORC2 in response to glucose, but another activator emerges during starvation.
Area of Science:
- Molecular Biology
- Cellular Signaling
- Yeast Genetics
Background:
- The Target Of Rapamycin (TOR) kinase is crucial for cell growth, existing as TOR Complex 1 (TORC1) and TOR Complex 2 (TORC2).
- TORC1 regulation by GTPases Rheb and Rag is well-studied, but TORC2 regulation remains less understood.
- In fission yeast, Ryh1 (a Rab-family GTPase) was previously identified as a TORC2 activator.
Purpose of the Study:
- To investigate the regulation of TORC2 by Ryh1 in response to glucose availability.
- To elucidate the molecular mechanisms linking glucose signaling to TORC2 activity in Schizosaccharomyces pombe.
- To identify potential alternative pathways for TORC2 activation during nutrient stress.
Main Methods:
- Utilized the fission yeast Schizosaccharomyces pombe as a model system.
- Investigated the nucleotide-binding state of Ryh1 GTPase.
- Monitored TORC2-dependent phosphorylation of its downstream target, Gad8.
- Analyzed pathway activity under varying glucose concentrations (rich media, deprivation, starvation).
Main Results:
- Ryh1's nucleotide-binding state is directly regulated by glucose levels.
- Glucose-rich conditions lead to GTP-bound Ryh1, activating TORC2 and Gad8 phosphorylation.
- Glucose deprivation inactivates Ryh1, shutting down the TORC2-Gad8 pathway.
- During prolonged starvation, Gad8 phosphorylation by TORC2 recovers independently of Ryh1, suggesting an alternative activator.
Conclusions:
- Ryh1 acts as a glucose sensor, mediating nutrient signals to TORC2.
- Dual regulatory mechanisms (Ryh1-dependent and independent) fine-tune TORC2-Gad8 signaling.
- These mechanisms are essential for optimizing cell growth in fluctuating glucose environments.
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