The Roles of the Drosophila Protein Tribbles in Oogenesis and Insulin Signaling Pathway
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In this dissertation, I examined the molecular mechanism of function of the Drosophila melanogaster protein Tribbles (Trbl) during oogenesis and larval development. Trbl is the founding member of an evolutionarily conserved family of kinase proteins that play diverse roles in cell signaling and energy homeostasis. In addition to the central Serine/Threonine kinase domain, members of the Tribbles gene family (Trib) shares C terminal mitogen activated protein kinase kinase MEK1 and E3 ubiquitin ligase COP1 binding motifs, the latter required for the degradation of target proteins via proteasome. During oogenesis, Trbl controls border cell (BC) cluster migration by mediating degradation of C/EBP transcription factor Slbo. I first investigated Trbl’s role during oogenesis using a Trbl specific antisera. Trbl localizes to the nucleus of main body follicle cells (MBFC) up to stage 10 of oogenesis. In the case of BC, Trbl expresses in a complementary pattern to Slbo expression. The Trbl level decreases gradually as the BC cluster delaminates from the epithelium and starts migrating when Slbo protein level increases. Moreover, Slbo was found to be essential but not sufficient to decrease the Trbl level required for BC migration. In a wing misexpression screen for Trbl interacting proteins, I identified the Serine/Threonine protein kinase Akt, a major mediator of insulin signaling. In recent years, mammalian Trib3 and Trib2 proteins have been implicated in the regulation of Insulin signaling by inhibiting the activating phosphorylation of Akt, Given the central role of Akt in insulin signaling, I tested whether the function of Trib family in insulin signaling is evolutionarily conserved. Using Drosophila larval development as a model system, I found that Trbl has a conserved role in binding and inhibiting Akt phosphorylation-activation, implicating Trib proteins as novel sites of signaling pathway integration that link nutrient availability with cell growth and proliferation. Finally, I have identified a previously unknown motif (R141) in Trib proteins essential for their function to regulate insulin signaling mediated growth and metabolism.
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Background and significance -- The kinase domain of drosophila tribbles is required for turnover of fly c/ebp during cell migration -- Drosophila tribbles antagonized insulin signaling mediated growth and metabolism via interactions with akt kinase -- Evolutionarily conserved arginine 141 of drosophila tribbles plays crucial roles in the regulation of the insulin-signaling pathway -- Appendix -- Future direcitons
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Ph.D.