iRhoms, non-catalytic rhomboid-like proteins, regulate trafficking of signalling molecules like growth factors and cytokines. Epidermal growth factor receptor (EGFR) signaling in Drosophila is inhibited by iRhom which acts as a negative regulator of EGF proteolysis. In mammals, iRhoms are essential for trafficking and maturation of TACE (ADAM17), a metalloprotease crucial for the activation of growth factors like tumor necrosis factor (TNF). iRhoms are implicated in pathophysiology of inflammatory arthritisand oesophageal cancer which demonstrates their profound biological and medical significance. The central theme of this project is that iRhoms act as regulatory adapters in the endoplasmic reticulum (ER), linking client proteins with trafficking machinery. Most important questions are: what is the range of iRhom clients and how iRhoms are regulated? I will address these applying proteomics, cell biology and model organism methodology in outstanding environment of M. Freeman group.