Kinase-dependent Regulation of Metabolic Enzymes

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 DESCRIPTION (provided by applicant): Growth-promoting signals and changes in metabolism are important mechanisms in the development and progression of cancer and other proliferative disorders, but the mechanisms that mediate interactions between these key regulatory events are poorly understood. Recently, we discovered a surprising and novel mechanism for control of nucleotide synthesis by Ack, a growth-factor regulated tyrosine kinase. Ack controls the activity of the rate-limiting enzyme in CTP synthesis, CTP synthase (CTPS) by regulating the assembly and disassembly of an enzymatically active macromolecular structure composed of CTPS and the rate-limiting enzyme in guanine nucleotide biosynthesis, IMPDH. We call these structures FINS for filaments involved in nucleotide synthesis. Based on this preliminary data, our central hypothesis is that inadequate cellular nucleotide pools trigger Ack-dependent FINS assembly to stimulate balanced purine and pyrimidine biosynthesis. Here, we will test this hypothesis using mechanistic biochemical studies that will be subsequently validated in vivo in Drosophila, where we have shown a critical requirement for this pathway in oogenesis. The work will illuminate how two important fields, signaling and metabolism, intersect through the dynamic assembly of a macromolecular protein assembly. The current use of drugs that inhibit IMPDH and trigger FINS assembly in patients highlights the importance of this work and its potential for discovery of additional therapeutic avenues for immuosuppression as well as anti-neoplastic and anti-parasitic interventions.