Genetic Screens for Drosophila p70 S6 Kinase Modifiers

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Stewart 0077618AbstractThe mammalian p70S6 kinase, termed S6K1, is a mitogen-stimulated serine/threonine kinase that lies on a signaling pathway leading to the control of translation and cell growth. The current model for S6K1 function is that upon activation, S6K1 phosphorylated the 40S ribosomal subunit protein S6 and this causes the ribosome to selectively increase the translation of a group of mRNAs that encode ribosomal proteins and translation initiation factors. This series of events would be expected to increase ribosome biogenesis and the translational capacity of the cell and thus allow increased general protein synthesis and cell growth. The activation of S6K1 is complex and is associated with the phosphorylation of eight amino acids in the kinase. The signaling pathways that lead to S6K1 activation are only partially defined and only the identity of one of the kinases that phosphorylates one of the eight phosphorylated amino acids inS6K1 that are associated with the activation of the kinase is known. The Drosophila melanogaster S6 kinase homolog, dS6K, is structurally and functionally conserved with the mammalian S6K1. In cultured cells, dS6K can be activated or inhibited by agents that activate or inhibit S6K1, suggesting that the mechanisms that regulate dS6K and S6K1 activation will be conserved between Drosophila and mammals. Similar to the proposed role for S6K1 in translation and growth, the role for dS6K within the fly appears to be in regulating cell size, cell growth and cell proliferation. The overall goal of this proposal is to use the power of Drosophila genetics to identify novel components of the dS6K pathway. Reaching this goal will entail:1. Testing if mutant alleles of genes that encode suspected components of the dS6K signaling pathway interact genetically with mutant dS6K alleles2. Screening a collection of Drosophila deficiency stocks to identify dose-sensitive modifiers of dS6K mutant phenotypes3. Performing mutagenesis screens designed to identify newly induced mutations in genes that encode components of the dS6K signaling pathways.Identifying components of the dS6K signaling pathways will be important for increasing our knowledge of intracellular signaling and also should impact our understanding of the basic mechanisms that regulate translation and cell growth.