A Drosophila model of insulin resistance associated with the human TRIB3 Q/R polymorphism

Dis Model Mech. 2017 Dec 19;10(12):1453-1464. doi: 10.1242/dmm.030619.

Abstract

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.

Keywords: Akt; Drosophila; Insulin signaling; Tribbles.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cell Cycle Proteins / chemistry
  • Cell Cycle Proteins / genetics*
  • Cell Proliferation
  • DNA Mutational Analysis
  • Disease Models, Animal
  • Drosophila Proteins / chemistry
  • Drosophila Proteins / genetics
  • Drosophila melanogaster / cytology
  • Drosophila melanogaster / metabolism*
  • Enzyme Activation
  • Fat Body / metabolism
  • Humans
  • Insulin / metabolism
  • Insulin Resistance*
  • Larva / growth & development
  • Mice
  • Mutation / genetics
  • Polymorphism, Single Nucleotide / genetics*
  • Protein Binding
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / chemistry
  • Protein Serine-Threonine Kinases / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Repressor Proteins / chemistry
  • Repressor Proteins / genetics*
  • Signal Transduction

Substances

  • Cell Cycle Proteins
  • Drosophila Proteins
  • Insulin
  • Repressor Proteins
  • TRIB3 protein, human
  • trbl protein, Drosophila
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt