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Understanding the control of size is of fundamental biological and clinical importance. Insulin/IGF signaling during development controls growth and size, possibly by coordinating the activities of the Ras and PI 3-kinase signaling pathways. We show that in Drosophila mutating the consensus binding site for the Ras pathway adaptor Drk/Grb2 in Chico/IRS does not interfere with growth whereas mutating the binding sites of the PI 3-kinase adaptor p60 completely abrogates Chico function. Furthermore, we present biochemical and genetic evidence that loss of the homolog of the tumor suppressor gene, Pten, results in increased PtdInsP(3) levels and that these increased levels are sufficient to compensate for the complete loss of the Insulin/insulin-like growth factor receptor function. This reduction of Pten activity is also sufficient to vastly increase organism size. These results suggest that PtdInsP(3) is a second messenger for growth and that levels of PtdInsP(3) during development regulate organismal size.

Background: Insulin and insulin-like growth factors (IGFs) signal through a highly conserved pathway and control growth and metabolism in both vertebrates and invertebrates. In mammals, insulin-like growth factor binding proteins (IGFBPs) bind IGFs with high affinity and modulate their mitogenic, anti-apoptotic and metabolic actions, but no functional homologs have been identified in invertebrates so far. Results: Here, we show that the secreted Imaginal morphogenesis protein-Late 2 (Imp-L2) binds Drosophilainsulin-like peptide 2 (Dilp2) and inhibits growth non-autonomously. Whereas overexpressing Imp-L2 strongly reduces size, loss of Imp-L2 function results in an increased body size. Imp-L2 is both necessary and sufficient to compensate Dilp2-induced hyperinsulinemia in vivo. Under starvation conditions, Imp-L2 is essential for proper dampening of insulin signaling and larval survival. Conclusions: Imp-L2, the first functionally characterized insulin-binding protein in invertebrates, serves as a nutritionally controlled suppressor of insulin-mediated growth in Drosophila. Given that Imp-L2 and the human tumor suppressor IGFBP-7 show sequence homology in their carboxy-terminal immunoglobulin-like domains, we suggest that their common precursor was an ancestral insulin-binding protein. [ABSTRACT FROM AUTHOR]