ADrosophilamodel of insulin resistance associated with the human Trib3 Q/R polymorphism
| Autor: | Rahul Das, Samuel Bouyain, Jin-Yuan Fan, Leonard L. Dobens, Laramie Pence, Zachary Fischer, Anna Shipman |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Neuroscience (miscellaneous) lcsh:Medicine Medicine (miscellaneous) AKT1 General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Immunology and Microbiology (miscellaneous) lcsh:Pathology Protein kinase B Genetics Tribbles biology Akt lcsh:R biology.organism_classification Cell biology Insulin signaling Insulin receptor 030104 developmental biology TRIB3 biology.protein Phosphorylation Drosophila Signal transduction Drosophila melanogaster Drosophila Protein lcsh:RB1-214 |
| Zdroj: | Disease Models & Mechanisms, Vol 10, Iss 12, Pp 1453-1464 (2017) |
| ISSN: | 1754-8411 1754-8403 |
| 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. |
| Databáze: | OpenAIRE |
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