Activated Cdc42 kinase is an anti-apoptotic signal in Drosophila melanogaster
Activated Cdc42 kinase (Ack) is a non-receptor tyrosine kinase that is regulated by Cdc42 and implicated in various developmental processes. Mammalian Ack has been shown to be essential for the growth of Ras transformed cells. Activated Ras has been identified in over a third of human cancers, thus we investigated Ack's influence on survival to determine if Ack can serve as a therapeutic target to treat cancers with deregulated Ras. We have identified a novel role for Ack in the regulation of programmed cell death in Drosophila melanogaster. Genetic interaction studies using the fly eye demonstrate that Ack influences the death-inducing activity of Head Involution Defective (hid). Using the hid induced small eye phenotype as a baseline, we determined that Ack influences cell survival through an uncharacterized pathway. This pathway is dependent on Ack kinase activity, functions with the adaptor proteins Drk as well as the transcriptional co-activator Yorkie and is independent of epidermal growth factor receptor signaling. We have also identified a genetic interaction between Ack and Ras in flies. Overexpressing Ras causes lethality within an Ack null background and Ack is activated by RasGTP or by downstream MAP kinase pathway components. Overall, our data suggest that Ack promotes cell survival through a novel pathway that has potential therapeutic value for the treatment of cancers containing deregulated Ras.
James C. Clemens, Purdue University.
Biology, Molecular|Biology, Genetics|Chemistry, Biochemistry