Abstract 2455 Fig4 disease-related variants confer a Ste20-dependent growth advantage on rapamycin independent of Vac14

Fig4, a phosphoinositide (PI) lipid phosphatase, dephosphorylates the 5-position of the inositol ring of PI3,5P2, a low abundance and highly regulated signaling lipid. Mutations in Fig4 have been implicated in childhood-onset and developmental neurological disorders including Charcot-Marie-Tooth disease type 4J and leukoencephalopathy involving hypomyelination. Work in eukaryotic systems from yeast to humans has revealed that Fig4 modulates both the production and turnover of PI3,5P2 through participation in a complex including its opposing PI3P 5-kinase, Fab1, the sole producer of PI3,5P2 in the cell. Assembly of the complex with Fab1 is mediated by contacts between Fig4 and the scaffold protein Vac14. Disease-related variants of Fig4 display impaired association with Fab1 and Vac14 and corresponding defects in the dynamic elevation and turnover of PI3,5P2. We recently found that in Saccharomyces cerevisiae Fig4 disease-related variants confer a growth advantage on rapamycin independent of Fig4 catalytic activity. We have further shown that this growth advantage is dependent on the activity of the p21-activated kinase Ste20. Here we demonstrate that the Ste20-dependent growth advantage conferred by Fig4 mutants persists in the absence of Vac14. Our findings suggest that Fig4 confers a rapamycin-associated growth advantage independent of its influence on the production and turnover of PI3,5P2. This work is supported by a Max and Minnie Tomerlin Voelcker Fund Young Investigator Award and NIGMS R00 GM 120511-03.