A
| Autor: | Zachary, Fischer, Rahul, Das, Anna, Shipman, Jin-Yuan, Fan, Laramie, Pence, Samuel, Bouyain, Leonard L, Dobens |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
DNA Mutational Analysis
Fat Body Cell Cycle Proteins Protein Serine-Threonine Kinases Polymorphism Single Nucleotide Mice Animals Drosophila Proteins Humans Insulin Amino Acid Sequence Cell Proliferation Tribbles Akt Dros Enzyme Activation Repressor Proteins Insulin signaling Disease Models Animal Drosophila melanogaster Larva Mutation Drosophila Insulin Resistance Proto-Oncogene Proteins c-akt Protein Binding Signal Transduction Research Article |
| Zdroj: | Disease Models & Mechanisms |
| ISSN: | 1754-8411 |
| Popis: | Members of the Tribbles family of proteins are conserved pseudokinases with diverse roles in cell growth and proliferation. Both Drosophila Tribbles (Trbl) and vertebrate Trib3 proteins bind to the kinase Akt (Akt1) to block its phosphorylation activation and reduce downstream insulin-stimulated anabolism. A single nucleotide polymorphism (SNP) variant in human TRIB3, which results in a glutamine (Q) to arginine (R) missense mutation in a conserved motif at position 84, confers stronger Akt binding, resulting in reduced Akt phosphorylation, and is associated with a predisposition to Type 2 diabetes, cardiovascular disease, diabetic nephropathy, chronic kidney disease and leukemogenesis. Here, we used a Drosophila model to understand the importance of the conserved R residue in several Trbl functions. In the fly fat body, misexpression of a site-directed Q mutation at position R141 resulted in weakened binding to Drosophila Akt (dAkt), leading to increased levels of phospho-dAkt, increased cell and tissue size, and increases in the levels of stored glycogen and triglycerides. Consistent with the functional conservation of this arginine in modulating Akt activity, mouse Trib3 R84 misexpressed in the fly fat body blocked dAkt phosphorylation with a strength similar to wild-type Trbl. Limited mutational analysis shows that the R141 site dictates the strength of Akt binding but does not affect other Trbl-dependent developmental processes, suggesting a specificity that could serve as a drug target for metabolic diseases. Summary: The insulin signaling inhibitor tribbles 3 (TRIB3) variant associated with Type II diabetes has parallel effects in a fly model system on Tribbles-regulated insulin signaling, growth and Akt activation. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|