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Reference: Bond S and Forgac M (2008) The Ras/cAMP/Protein Kinase A Pathway Regulates Glucose-dependent Assembly of the Vacuolar (H+)-ATPase in Yeast. J Biol Chem 283(52):36513-21

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Abstract

V-ATPases are ubiquitous, ATP-driven proton pumps that acidify organelles or the extracellular space. A rapid and effective mechanism for regulating V-ATPase activity involves reversible dissociation of the two functional domains of the pump, V1 and V0. This process is best characterized in yeast, where V-ATPases are reversibly disassembled in response to glucose depletion. To identify regulators that control this process in vivo, a genetic screen was performed in yeast to search for mutants that cannot disassemble their V-ATPases when grown in the absence of glucose. This screen identified IRA1 and IRA2 as essential genes for regulating V-ATPase dissociation in vivo. IRA1 and IRA2 encode GTPase activating proteins (GAPs) that negatively regulate Ras in nutrient-poor conditions. Downregulation of Ras lowers cAMP levels by reducing adenylate cyclase activity. Decreased cAMP levels in turn lead to reduced activity of protein kinase A (PKA). Our results show that targeted deletion of IRA2 results in defective disassembly of the V-ATPase in response to glucose depletion, and re-expression of the gene rescues this phenotype. Glucose-dependent dissociation is also blocked in strains expressing the dominant-active RAS2val19 allele or in strains deficient for the regulatory subunit of PKA, both of which lead to constitutively active PKA. These results reveal a role for PKA in controlling glucose-dependent V-ATPase assembly in yeast.

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Journal Article
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Bond S, Forgac M
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