First Functional Insulin-binding Protein In Invertebrates

Insulin and insulin-like growth factors (IGFs) signal through a highly conserved pathway and control growth and metabolism in both vertebrates and invertebrates. The well-studied mammalian IGF binding proteins (IGFBPs) do not, however, have obvious sequence homologs in the fruit fly Drosophila. The discovery of a functional ortholog transforms Drosophila into a powerful model system in which to explore metabolic regulation and presents a significant advance in our understanding of the mechanisms by which the actions of insulin-like peptides are regulated.

A research team led by Ernst Hafen from the Institute of Molecular Systems Biology at the ETH in Zürich, Switzerland, employed a genetic strategy to search for negative insulin/insulin-like growth factor signaling (IIS) regulators in Drosophila. The team identified a new functional insulin-binding protein that acts as an IIS antagonist. Dubbed imaginal morphogenesis protein-late 2 (Imp-L2), the new antagonist binds the Drosophila insulin-like peptide 2 (Dilp2), inhibiting its growth-promoting function. Imp-L2 not only has a role in growth regulation - it is also essential for the dampening of insulin signaling under adverse conditions.

The authors hope that better understanding of Imp-L2's role in growth control and insulin signaling in Drosophila will ultimately impact on our understanding of the human ortholog IGFBP-7. This has a regulatory role in pathways that impact upon diabetes and cancer. IGFBP-7 acts as a tumor suppressor in a variety of human organs and differs in the C-terminus from the other IGFBPs.

"Since Imp-L2 and the human tumor suppressor IGFBP-7 display sequence homology in their C-terminal immunoglobulin-like domains, we suggest that their common precursor represents an ancestral insulin-binding protein," says Hafen.

Journal reference:  Imp-L2, a homolog of vertebrate IGF-binding protein 7, counteracts insulin signaling in Drosophila and is essential for starvation resistance. Basil Honegger, Milos Galic, Katja Kohler, Franz Wittwer, Walter Brogiolo, Ernst Hafen and Hugo Stocker. Journal of Biology (in press)