Activin signaling in Drosophila. L. Parker , K. Arora. Developmental and Cell Biology, Univ. of California at Irvine, Irvine, CA.

   The transforming growth factor-b (TGF-b) superfamily is a large group of secreted ligands that are involved in key cell-cell signaling events. Three major subgroups exist, BMPs, activins and archetypal TGF-bs. The ligands signal via a complex of type I and type II receptors to activate intracellular transducing molecules known as R-smads. In Drosophila, 7 ligands have been identified. Three are BMP homologs; Decapentaplegic, Glass Bottom Boat-60A and Screw. There is also an activin homolog, dActivin, and a Myostatin homolog, Myoglianin. Finally there are two orphan ligands, Maverick (Mav) and Activin-Like Protein (Alp), which possess the characteristic nine cysteine residues of TGF-b and activin ligands. Only 2 type II receptors; Wishful Thinking and Punt, 3 type I receptors; Thickveins (Tkv), Saxophone (Sax), and Baboon (Babo), and 2 R-smads; Mothers Against Dpp (Mad) and dSmad2, exist in Drosophila. Therefore seven different extracellular inputs must be integrated to result in activation of a limited number of smads. Our aim is to understand how the cell can interpret signaling from 7 different ligands when these signals result in the activation of only two R-smads. We are examining the activin signaling pathway, which theoretically comprises 4 potential ligands, dActivin, Myoglianin, Mav and Alp, the activin type I receptor Babo, and dSmad2. We are using cell culture assays to determine which ligands, receptors and smads constitute the activin pathway. Using constitutively active versions of each receptor we have determined which R-smad they activate. Ongoing experiments are using dominant negative versions of the receptors and RNAi to suppress endogenous receptor activity. This will allow us to define the signaling pathway for each of the ligands and elucidate the mechanism by which the cell distinguishes between different signals.