Receptor tyrosine kinases (RTK) are key molecules controlling cell growth and differentiation, and mutation in major RTKs have been implicated in certain forms of cancer. The goal of this project is the analysis of the signal transduction pathway involving torpedo, the Drosophila EGF receptor homolog (top/DER). Similar to its vertebrate counterpart, top/DER is involved in several specific cell signaling events during Drosophila development. During Drosophila oogenesis, activation of top/DER in the somatic follicle cells establishes the anterior-posterior and dorso-ventral pattern of both the egg and the embryo. We propose to analyze the molecular mechanisms by which torpedo (=top/DER) is activated during oogenesis and the response mechanisms operating in the follicle cells. We will construct an activated form of top/DER that will mimic the oncogenic forms of the receptor found in certain vertebrate tumors, and express this form in follicle cells. We will determine what phenotypes are produced by such an activated construct, and we will use the construct to search for suppressor genes that might identify downstream targets of top/DER in follicle cells. Our previous work has shown that top/DER is activated by a growth factor- like molecule, gurken (grk), that is secreted by the germline. During normal development the production of such growth factors must be tightly controlled to prevent unregulated receptor activation. To understand the control mechanisms operating in the germline we are analyzing three genes, cornichon, okra and spindle-B, that act in the germ line. We have cloned the gene cornichon (cni). It is required for activation of the top/DER receptor and encodes a novel protein. We propose to analyze the function of cni in detail, using Drosophila as well as other species, including yeast. We will also determine the molecular function of the genes okra and spindle-B. We will also focus on-the three cellular responses that we have shown to depend on top/DER activity: the establishment of posterior and dorsal follicle cell fates, and the negative regulation of a new, ventralizing signal which is produced in the follicle cells and is transmitted back to the embryo. We will test genes that may act as targets of top/DER in follicle cell mosaics. We have identified a gene (windbeutel) that acts in the second response pathway and participates in the production of a new signal that establishes ventral embryonic cell fates. We will clone this gene and characterize its interaction with top/DER. The proposed research will allow us to describe how activation of a major RTK is controlled in the egg chamber of Drosophila. Our analysis will complement the biochemical description of the role of such receptors that has been obtained in vertebrate tissue culture systems, and will allow an understanding of the regulation and cellular responses to such signaling processes during development.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Ferguson, Scott B; Blundon, Malachi A; Klovstad, Martha S et al. (2012) Modulation of gurken translation by insulin and TOR signaling in Drosophila. J Cell Sci 125:1407-19
Capra, John A; Laskowski, Roman A; Thornton, Janet M et al. (2009) Predicting protein ligand binding sites by combining evolutionary sequence conservation and 3D structure. PLoS Comput Biol 5:e1000585
Klovstad, Martha; Abdu, Uri; Schupbach, Trudi (2008) Drosophila brca2 is required for mitotic and meiotic DNA repair and efficient activation of the meiotic recombination checkpoint. PLoS Genet 4:e31
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