Function of Rhomboids in mouse and Drosophila development

Rhomboids are a unique class of proteases that activate Epidermal Growth Factor receptor (EGFR) signalling in Drosophila, by cleaving EGFR ligands within their transmembrane domain, in the lipid bilayer of the Golgi apparatus. Although conserved throughout evolution, nothing is known about the function of mammalian Rhomboids and the seven Drosophila family members have yet to be fully characterised. Since the mammalian EGFR is strongly implicated in human cancers the characterization of Rhomboids holds great potential as a target for novel cancer therapies. EGFR is a member of the receptor tyrosine kinase family, which allows cells to sense their environment correctly and achieve precise proliferative and developmental responses. Drosophila EGFR signalling is used repeatedly in different stages of development mainly determining cell fate. For one receptor to have such diverse roles, its activation requires precise temporal and spatial control. A major strategy for EGFR activation is the production of active ligands, mediated in Drosophila by Rhomboids. It has been shown that in mammals EGFR ligands are proteolytically cleaved at the plasma membrane rather than in the Golgi apparatus. However the process of mammalian EGFR activation is not fully understood, and given the conserved nature of Rhomboids, it will be exciting to determine whether Rhomboids are involved in mammalian EGFR signalling or play a novel but yet uncharacterised role in development. We will analyse the effects on mouse and fly development caused by the deletion of the respective Rhomboid gene. Given the conserved nature of Rhomboids, we will attempt to develop a computer based search algorithm, which allows substrate identification based on the known substrate specificity of Drosophila Rhomboid-1. Subsequently we will test candidates including all known EGFR ligands using a cell-based assay. We hope to provide insights into the function of Rhomboids in mammals as well as invertebrates. From an evolutionary point of view it will be interesting to find out in which signalling pathway(s) this conserved family of proteins participates. The analysis of mammalian Rhomboids promises to be of particular interest since there is potentially a link to EGFR signalling, which is implicated in a variety of human cancers.