Regulatory Mechanisms Linking Coenzyme A Synthesis and PI3K Signaling

Abstract

The metabolism of a proliferative cell must meet biosynthetic demand by breaking down multiple nutrients to produce energy and the building blocks of cell growth. Many of the core metabolic reactions of the cell require the cofactor coenzyme A (CoA), a carrier of diverse carbon chains. CoA is synthesized de novo from vitamin B5 (pantothenate), cysteine, and ATP. It is important to understand how CoA synthesis is regulated, because CoA metabolism is important for physiological processes and is dysregulated in various disease states. The most well-established mode of regulating CoA synthesis is through feedback inhibition of the rate-limiting step catalyzed by the pantothenate kinase family members 1-3 (PANK1-3). In this thesis, we define the first mechanism of CoA synthesis regulation by a cellular signaling pathway. Downstream of hormones, growth factors, and oncogenic signaling, the class I phosphoinositide-3-kinase (PI3K) pathway activates CoA synthesis. The PI3K effector kinase AKT phosphorylates PANK4, which we establish as a novel suppressor of CoA synthesis through its metabolite phosphatase activity. PANK4 phosphorylation relieves suppression of CoA synthesis in coordination with PI3K-driven proliferative metabolism. In addition, we expand the known functional role of CoA in cell signaling by characterizing a putative nutrient sensing pathway for CoA metabolism. Cellular CoA depletion inhibits PI3K signaling and causes a stable cell growth arrest. Altogether, these findings encourage investigation of potential therapeutic strategies targeting CoA synthesis in PI3K pathway-mutant cancers and neurodegenerative disorders caused by defective CoA synthesis.