RRC ID 12546
Author Tatebe H, Morigasaki S, Murayama S, Zeng CT, Shiozaki K.
Title Rab-family GTPase regulates TOR complex 2 signaling in fission yeast.
Journal Curr Biol
Abstract BACKGROUND:From yeast to human, TOR (target of rapamycin) kinase plays pivotal roles in coupling extracellular stimuli to cell growth and metabolism. TOR kinase functions in two distinct protein complexes, TOR complex 1 (TORC1) and 2 (TORC2), which phosphorylate and activate different AGC-family protein kinases. TORC1 is controlled by the small GTPase Rheb, but little is known about TORC2 regulators.
RESULTS:We have identified the Ryh1 GTPase, a human Rab6 ortholog, as an activator of TORC2 signaling in the fission yeast Schizosaccharomyces pombe. Mutational inactivation of Ryh1 or its guanine nucleotide exchange factor compromises the TORC2-dependent phosphorylation of the AGC-family Gad8 kinase. In addition, the effector domain of Ryh1 is important for its physical interaction with TORC2 and for stimulation of TORC2 signaling. Thus, GTP-bound Ryh1 is likely to be the active form stimulatory to TORC2-Gad8 signaling. Consistently, expression of the GTP-locked mutant Ryh1 is sufficient to promote interaction between TORC2 and Gad8 and to induce Gad8 hyperphosphorylation. The loss of functional Ryh1, TORC2, or Gad8 brings about similar vacuolar fragmentation and stress sensitivity, further corroborating their involvement in a common cellular process. Human Rab6 can substitute Ryh1 in S. pombe, and therefore Rab6 may be a potential activator of TORC2 in mammals.
CONCLUSIONS:In its GTP-bound form, Ryh1, an evolutionarily conserved Rab GTPase, activates TORC2 signaling to the AGC kinase Gad8. The Ryh1 GTPase and the TORC2-Gad8 pathway are required for vacuolar integrity and cellular stress resistance in S. pombe.
Volume 20(22)
Pages 1975-82
Published 2010-11-23
DOI 10.1016/j.cub.2010.10.026
PII S0960-9822(10)01290-X
PMID 21035342
PMC PMC3008323
MeSH Humans Monomeric GTP-Binding Proteins / genetics Monomeric GTP-Binding Proteins / metabolism Monomeric GTP-Binding Proteins / physiology* Phosphatidylinositol 3-Kinases / metabolism* Protein Serine-Threonine Kinases / metabolism Schizosaccharomyces / enzymology* Schizosaccharomyces / genetics Schizosaccharomyces / metabolism Schizosaccharomyces pombe Proteins / genetics Schizosaccharomyces pombe Proteins / metabolism Schizosaccharomyces pombe Proteins / physiology* Signal Transduction* rab GTP-Binding Proteins / genetics rab GTP-Binding Proteins / metabolism rab GTP-Binding Proteins / physiology
IF 9.601
Times Cited 50