Defects in insulin signaling have impacts on both metabolic disease, notably Type 2 diabetes (T2D) whose prevalence is increasing rapidly in populations worldwide. Genome-wide association studies have identified susceptibility loci linked to T2D risk, however the mechanisms by which genes contribute to obesity-linked insulin insensitivity are complex. At the other extreme, insulin hypersensitivity is the hallmark of many tumors, conferring an ability of these cells to outcompete normal tissues for nutrients. Thus, there is an urgent need to understand how metabolic pathways are modulated during both normal development and in the disease state.
Dissecting these signaling pathways is facilitated in model genetic organisms, which offer a powerful genetic tools to uncover conserved mechanisms that connect the insulin signaling to cell growth and tissue homeostasis. We explore the structure and function of the Drosophila Tribbles gene, a member of the Trib family of pseudokinases, which have been connected to metabolic disease and cancer in humans. Work from our lab shows that Trbl antagonizes insulin signaling by binding and inhibiting the activation of Akt kinase, a key mediator of the insulin response.
Because the fly model recapitulates many aspects of the human metabolic disease, including the effect of mutations and the impact diet-induced T2D, our identification of fly Trbl as a antagonist of insulin signaling puts us in the advantageous position to use the genetic tools available in this simple model organism to identify interacting genes, pathways and drug candidates that influence the pathophysiology of the disorder. The fly system also enables discrete control of diet as well as the opportunity to carry out rapid dissection of the genetic mechanisms, neither of which is feasible in higher model organisms.
Current work in the lab seeks to identify the role of conserved sequence motifs in Trbl protein required for the diverse functions of the protein and to use the genetic tools in Drosophila to flesh out the signaling pathways that mediate Trbl regulation of cell growth and proliferation.
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- Das, R., Sebo, Z., Pence, P. and Dobens, L.L. Drosophila Tribbles antagonizes insulin signaling-mediated growth and metabolism via interactions with Akt kinase. PLoS ONE 9(10): e109530, 2014. http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0109530
- Dobens, L.L. and Das, R. REVIEW: Conservation of gene and tissue networks regulating insulin signaling in flies and vertebrates. Biochemical Society Transactions 43(5) 1057-1062, 2015. http://www.biochemsoctrans.org/content/43/5/1057
- Fischer, Z., Das, R., Shipman, A., Price, J.-Y., Pence, L., Bouyain, S. and Dobens, L.L. A Drosophila model of insulin resistance associated with the human Trib3 Q/R polymorphism. Disease Mechanisms and Models, 10(12):1453-1464, 2017. http://dmm.biologists.org/content/10/12/1453.long
- Shipman, A., Nauman, C., Haymans, B., Silverstein, R. and Dobens, L.L. A screen for targets of the Drosophila pseudokinase Tribbles identifies Neuralized and Mindbomb, ubiquitin ligases that mediate Notch signaling. bioRxiv doi:10.1101/406249. 2018.
- Cui, B., Eyers, P.A., Dobens, L. et al.. MEETING REPORT: Highlights for the 2nd International Symposium on Tribbles and Diseases: Tribbles in therapeutics for immunity, metabolism, fundamental cell biology and cancer. Acta Pharmaceutica Sinica B, in press, 2019. https://www.sciencedirect.com/science/article/pii/S2211383518305628