Understanding PKB Function via Drosophila Genetics

Our laboratory is interested in signal transduction pathways which regulate Protein Kinase B (PKB) and Glycogen Synthase Kinase-3 (GSK-3). These serine/threonine kinases are involved in multiple signaling pathways and have been shown to be linked to a variety of human diseases. For example, the hyperactivation of PKB has been shown to be involved in all stages of tumorigenesis. We use a combination of genetic, biochemical, cell biological and pharmacological approaches to the study of the cellular processes which require the function of these kinases. In order to gain insight into the mechanism of action of these enzymes, we use Drosophila melanogaster as a genetic model system. Our laboratory initiated these studies via identification of “loss of function” alleles of Drosophila PKB . We have used this allele as a tool for second site genetic modifier screens to identify many novel components of PKB function as well as identifying novel roles for PKB during development. Recently, we have used Drosophila as a drug discovery model in the identification and design of novel small molecule therapeutics using genetic tools in Drosophila.

Our goal is to combine the powerful genetics of Drosophila with pharmacology to fast track the process of drug discovery. Using our approach, we have also linked GSK-3 to the regulation of the circadian clock in Drosophila and in mammalian cells. This work has provided provocative links between GSK-3 function and bipolar therapeutics including lithium. We will be using our genetic and pharmacogenetic tools in Drosophila to further explore the “mechanism of action” of these therapeutics in the design and identification of novel therapeutics.

Graduate Student(s):

• Sevag Kaladchibachi

Selected References:

• Staveley BE, Ruel L, Jin J, Stambolic V, Mastronardi FG, Heitzler P, Woodgett JR, Manoukian AS (1998) Genetic analysis of PKB in Drosophila. Current Biology 8, 599-602.

• Jin J, Anthopoulos N, Wetsch B, Binari RC, Isaac DD, Andrew DJ, Woodgett JR, Manoukian AS (2001) Regulation of Drosophila tracheal system development by PKB. Developmental Cell 1, 817-827.

• Martinek S, Inonog S, Manoukian AS, Young MW (2001) A role for the segment polarity gene shaggy/GSK-3 in the Drosophila circadian clock. Cell 105, 769-779.

• Kaladchibachi SA, Doble B, Anthopoulos N, Woodgett JR, Manoukian AS (2007) GSK-3, circadian rhythms, and bipolar disorder: a molecular link in the therapeutic action of lithium. Journal of Circadian Rhythms 5, 3.