Trends in Endocrinology & Metabolism
ReviewGenetic analysis of insulin signaling in Drosophila
Section snippets
The Drosophila insulin receptor
Determination of the complete structure of Inr (see Glossary) 7., 8., confirmed the results of biochemical studies suggesting that the Drosophila receptor, like its mammalian counterparts, comprised two α and two β subunits, with a cytoplasmic tyrosine kinase in its β subunit that was activated upon insulin binding [9]. The degree of sequence conservation between the fly and human receptors in some domains, especially the kinase domain, is remarkable, given the evolutionary distance between
Insulin-like peptides in Drosophila
The ability of INR to bind mammalian insulin suggests that insulin-like ligands should be present in Drosophila. Accordingly, a new family of genes was recently identified that encodes seven Drosophila insulin-like peptides [16] (dilp1–5). The deduced amino acid sequences predict a signal peptide, a B chain, a C peptide and an A chain. The presence of consensus proteolytic processing sites suggests that the mature peptides are composed of A and B chains and lack the C peptide, as in mammalian
Insulin signaling and growth control
The most obvious role of insulin signaling uncovered by genetic analysis in Drosophila is in the regulation of growth and body size. The ability to generate visible aberrant phenotypes by perturbation of cellular growth has allowed studies of growth regulation to progress rapidly. However, strong InR mutations are recessive embryonic lethal 8., 22., indicating an essential function for InR during normal development beyond growth control. This is consistent with the position of InR as the first
Insulin signaling and metabolism, reproduction and lifespan
Recent data also implicate INR signaling in metabolic regulation in flies. The first genetic evidence that insulin signaling impacted on metabolism in lower organisms came from daf-2 mutations in C. elegans. Worms with decreased DAF-2 function have greater lipid stores than their wild-type counterparts [46]. Similarly, dwarf flies with mutations in chico [15] and InR 4., 16. exhibit up to a fivefold increase in stored triglyceride. Because insulin receptor activation stimulates lipogenesis in
Conclusions
Molecular and genetic analysis of the insulin signaling pathway in Drosophila has revealed striking conservation at both the structural and functional levels. Recent studies emphasize the central role of insulin in the coordinated regulation of growth, metabolism, reproduction and lifespan. These data suggest that the level of activity of the insulin pathway reflects environmental conditions, in particular, nutrient availability, and serves to adapt many aspects of physiology for optimum
Glossary
- Age-1
- Caenorhabditis elegans homolog of PI3K
- CHICO
- Drosophila homolog of IRS
- daf-2
- gene encoding Caenorhabditis elegans insulin receptor homolog
- Dakt
- gene encoding Drosophila homolog of PKB/Akt
- dilp1–7
- Drosophila insulin-like peptide genes 1–7
- Dp110
- gene encoding Drosophila homolog of the catalytic subunit of PI3K
- Dstpk61
- Drosophila homolog of PDK-1
- FKHR
- Forkhead-related transcription factor
- GAP
- GTPase-activating protein.
- GSK-3
- Glycogen synthase kinase-3
- IGF
- Insulin-like growth factor
- InR
- Insulin receptor gene in
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