title: Glucose activates TORC2-Gad8 protein via positive regulation of the cAMP/cAMP-dependent protein kinase A (PKA) pathway and negative regulation of the Pmk1 protein-mitogen-activated protein kinase pathway.
abstract: The target of rapamycin (TOR) kinase belongs to the highly conserved eukaryotic family of phosphatidylinositol 3-kinase-related kinases. TOR proteins are found at the core of two evolutionary conserved complexes, known as TORC1 and TORC2. In fission yeast, TORC2 is dispensable for proliferation under optimal growth conditions but is required for starvation and stress responses. TORC2 has been implicated in a wide variety of functions; however, the signals that regulate TORC2 activity have so far remained obscure. TORC2 has one known direct substrate, the AGC kinase Gad8, which is related to AKT in human cells. Gad8 is phosphorylated by TORC2 at Ser-546 (equivalent to AKT Ser-473), leading to its activation. Here, we show that glucose is necessary and sufficient to induce Gad8 Ser-546 phosphorylation in vivo and Gad8 kinase activity in vitro. The glucose signal that activates TORC2-Gad8 is mediated via the cAMP/PKA pathway, a major glucose-sensing pathway. By contrast, Pmk1, similar to human extracellular signal-regulated kinases and a major stress-induced mitogen activated protein kinase (MAPK) in fission yeast, inhibits TORC2-dependent Gad8 phosphorylation and activation. Inhibition of TORC2-Gad8 also occurs in response to ionic or osmotic stress, in a manner dependent on the cAMP/PKA and Pmk1-MAPK signaling pathways. Our findings highlight the significance of glucose availability in regulation of TORC2-Gad8 and indicate a novel link between the cAMP/PKA, Pmk1/MAPK, and TORC2-Gad8 signaling.
authors.affiliation: From the Department of Natural and Life Sciences, Open University of Israel, University Road 1, 4353701 Ranana and.
authors.forename: Adiel
authors.initials: A
authors.lastname: Cohen
authors.affiliation: the Department of Molecular Microbiology and Biotechnology, Tel Aviv University, 69978 Tel Aviv, Israel.
authors.forename: Martin
authors.initials: M
authors.lastname: Kupiec
authors.affiliation: From the Department of Natural and Life Sciences, Open University of Israel, University Road 1, 4353701 Ranana and ronitwe@openu.ac.il.
authors.forename: Ronit
authors.initials: R
authors.lastname: Weisman
mesh_terms: D002473:Cell Wall / Q000201:enzymology / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D000076225:Mechanistic Target of Rapamycin Complex 2; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012568:Schizosaccharomyces / Q000201:enzymology / Q000378:metabolism*; D029702:Schizosaccharomyces pombe Proteins / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D046912:Multiprotein Complexes; D029702:Schizosaccharomyces pombe Proteins; D000242:Cyclic AMP; C476401:Gad8 protein, S pombe; D000076225:Mechanistic Target of Rapamycin Complex 2; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; C516338:Pmk1 protein, S pombe; D005947:Glucose
keywords: Cyclic AMP (cAMP); GAD8; Glucose; Mitogen-activated Protein Kinase (MAPK); Protein Kinase A (PKA); S. pombe; Stress Response; TORC2