Sarcoglycans are a multimeric, integral membrane protein complex that is part of the dystrophin glycoprotein complex. Previous findings suggest that the dystrophin glycoprotein complex plays roles not only in maintaining the mechanical structure of the cell membrane but also in signal transduction. To evaluate the functions of sarcoglycans, we here took advantage of Drosophila, which is useful for screening genetic interactions. Morphological aberrancy was observed in the adult compound eyes of Drosophila beta-sarcolgycan (dscg beta) knockdown flies. We also detected genetic interactions between dscg beta and Egfr related genes, such as rhomboid-1, rhomboid-3, and mirror. Furthermore two extra cell types with strong expression of Rhomboid were found in the ommatidia of dscg beta knockdown pupal retina. These cells exhibited phosphorylation of ERKA, suggesting that Egfr signaling is activated via Rhomboid. Through these in vivo analyses, we conclude that dseg beta negatively regulates the Egfr signaling pathway. (c) 2006 Elsevier Inc. All rights reserved.