Global ETD Search

1	A Global Kinase and Phosphatase Interaction Network in the Budding Yeast Reveals Novel Effectors of the Target of Rapamycin (TOR) Pathway Sharom, Jeffrey Roslan 31 August 2011 (has links) In the budding yeast Saccharomyces cerevisiae, the evolutionarily conserved Target of Rapamycin (TOR) signaling network regulates cell growth in accordance with nutrient and stress conditions. In this work, I present evidence that the TOR complex 1 (TORC1)-interacting proteins Nnk1, Fmp48, Mks1, and Sch9 link TOR to various facets of nitrogen metabolism and mitochondrial function. The Nnk1 kinase controlled nitrogen catabolite repression-sensitive gene expression via Ure2 and Gln3, and physically interacted with the NAD+-linked glutamate dehydrogenase Gdh2 that catalyzes deamination of glutamate to alpha-ketoglutarate and ammonia. In turn, Gdh2 modulated rapamycin sensitivity, was phosphorylated in Nnk1 immune complexes in vitro, and was relocalized to a discrete cytoplasmic focus in response to NNK1 overexpression or respiratory growth. The Fmp48 kinase regulated respiratory function and mitochondrial morphology, while Mks1 linked TORC1 to the mitochondria-to-nucleus retrograde signaling pathway. The Sch9 kinase appeared to act as both an upstream regulator and downstream sensor of mitochondrial function. Loss of Sch9 conferred a respiratory growth defect, a defect in mitochondrial DNA transmission, lower mitochondrial membrane potential, and decreased levels of reactive oxygen species. Conversely, loss of mitochondrial DNA caused loss of Sch9 enrichment at the vacuolar membrane, loss of Sch9 phospho-isoforms, and small cell size suggestive of reduced Sch9 activity. Sch9 also exhibited dynamic relocalization in response to stress, including enrichment at mitochondria under conditions that have previously been shown to induce apoptosis in yeast. Taken together, this work reveals intimate connections between TORC1, nitrogen metabolism, and mitochondrial function, and has implications for the role of TOR in regulating aging, cancer, and other human diseases. Target of Rapamycin budding yeast Saccharomyces cerevisiae yeast kinase phosphatase protein-protein interactions TOR nutrients growth rapamycin signaling network metabolism nitrogen catabolite repression retrograde response glutamate dehydrogenase glutamine glutamate alpha-ketoglutarate cell size aging lifespan mitochondria uncoupled respiration petite reactive oxygen species free radical theory of aging apoptosis cancer glutaminolysis TORC1 Nnk1 Fmp48 Mks1 Sch9 Gdh2 Ure2 ribosomal protein S6 kinase S6K cell biology molecular biology 0307 0379 0369 0410 0306
2	A Global Kinase and Phosphatase Interaction Network in the Budding Yeast Reveals Novel Effectors of the Target of Rapamycin (TOR) Pathway Sharom, Jeffrey Roslan 31 August 2011 (has links) In the budding yeast Saccharomyces cerevisiae, the evolutionarily conserved Target of Rapamycin (TOR) signaling network regulates cell growth in accordance with nutrient and stress conditions. In this work, I present evidence that the TOR complex 1 (TORC1)-interacting proteins Nnk1, Fmp48, Mks1, and Sch9 link TOR to various facets of nitrogen metabolism and mitochondrial function. The Nnk1 kinase controlled nitrogen catabolite repression-sensitive gene expression via Ure2 and Gln3, and physically interacted with the NAD+-linked glutamate dehydrogenase Gdh2 that catalyzes deamination of glutamate to alpha-ketoglutarate and ammonia. In turn, Gdh2 modulated rapamycin sensitivity, was phosphorylated in Nnk1 immune complexes in vitro, and was relocalized to a discrete cytoplasmic focus in response to NNK1 overexpression or respiratory growth. The Fmp48 kinase regulated respiratory function and mitochondrial morphology, while Mks1 linked TORC1 to the mitochondria-to-nucleus retrograde signaling pathway. The Sch9 kinase appeared to act as both an upstream regulator and downstream sensor of mitochondrial function. Loss of Sch9 conferred a respiratory growth defect, a defect in mitochondrial DNA transmission, lower mitochondrial membrane potential, and decreased levels of reactive oxygen species. Conversely, loss of mitochondrial DNA caused loss of Sch9 enrichment at the vacuolar membrane, loss of Sch9 phospho-isoforms, and small cell size suggestive of reduced Sch9 activity. Sch9 also exhibited dynamic relocalization in response to stress, including enrichment at mitochondria under conditions that have previously been shown to induce apoptosis in yeast. Taken together, this work reveals intimate connections between TORC1, nitrogen metabolism, and mitochondrial function, and has implications for the role of TOR in regulating aging, cancer, and other human diseases. Target of Rapamycin budding yeast Saccharomyces cerevisiae yeast kinase phosphatase protein-protein interactions TOR nutrients growth rapamycin signaling network metabolism nitrogen catabolite repression retrograde response glutamate dehydrogenase glutamine glutamate alpha-ketoglutarate cell size aging lifespan mitochondria uncoupled respiration petite reactive oxygen species free radical theory of aging apoptosis cancer glutaminolysis TORC1 Nnk1 Fmp48 Mks1 Sch9 Gdh2 Ure2 ribosomal protein S6 kinase S6K cell biology molecular biology 0307 0379 0369 0410 0306

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A Global Kinase and Phosphatase Interaction Network in the Budding Yeast Reveals Novel Effectors of the Target of Rapamycin (TOR) Pathway

A Global Kinase and Phosphatase Interaction Network in the Budding Yeast Reveals Novel Effectors of the Target of Rapamycin (TOR) Pathway