During epithelial maturation, a large number of signal transduction molecules are utilized to regulate cell cycle and cell death. When activated by mutation these same factors can provoke uncontrolled growth, a common step in the development of cancer. For example, activating mutations in the Ret receptor tyrosine kinase can provoke oncogenic diseases such as Multiple Endocrine Neoplasia Type 2 (MEN2). By targeting analogous forms of activated Ret to the developing Drosophila retina, an in vivo model was developed to explore the downstream signaling components that are responsible for aspects of the MEN2 disease. This approach identified several pathways that, when mutated, alter the outcome of Ret activation. The importance of these pathways in human tumor tissue is currently being explored. One downstream pathway that modified the Ret (MEN2) phenotype was the Src signaling pathway. Src is a cytoplasmic kinase that has been linked to dozens of cancer types including those of the colon and breast, as well as blood-based cancers. C-terminal Src kinase (Csk) is the major inhibitor of Src signaling. Reducing Drosophila Csk activity led to activation of Src and a concomitant cell-autonomous activation of the cell cycle, which in turn led to uncontrolled growth. The result was an enlarged, abnormally patterned eye. Importantly, reducing activity of the STAT signaling pathway prevented this oncogenic growth: mutations in Drosophila STAT led to death of otherwise proliferative Csk tissue. This suggests a strategy for therapeutic intervention of tumors that contain an activated Src pathway. This Proposal seeks to better understand the nature of STAT's ability to kill Csk-deficient cells by using genetic screens to identify 'killing' pathways. In addition, the role of Src signaling downstream of a number of receptors will be further explored. Finally, the advantages of the Drosophila retina as a sensitive assay of signaling, overgrowth, and cell death will be exploited as an in vivo screen for drugs that can also ameliorate Csk/Src-mediated overgrowth.
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