Cell biology of signalling: how members of the rhomboid-like superfamily regulate multiple pathways

• Applicant: Dr. Stefan Düsterhöft
• Subject Area: Biochemistry
• Term: from 2015 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 280679981

Summary Communication between cells is an important process in multicellular organisms and a dysregulation of the intercellular communication can have a severe outcome. iRhoms (inactive rhomboids) are inactive pseudoproteases and members of the rhomboid-like superfamily. They are located in the Endoplasmic reticulum (ER) and involved in intercellular signalling. Since iRhom mediates the degradation of ligands of the EGFR (epidermal growth factor receptor) by the ERAD-system (ER-associated degradation) in Drosophila melanogaster, it acts as a negative regulator of the EGFR pathway. On the other hand in mammalians there are two iRhoms (iRhom1 and iRhom2), which act as positive regulators by mediating the trafficking and maturation of the transmembrane protease ADAM17 (A Disintegrin And Metalloproteinase). ADAM17 has a huge substrate variety and therefore is involved in many physiological and pathophysiological processes such as regeneration and development but also chronic inflammation and tumour development. The reason for this is that among other substrates ligands of the EGFR and cytokines are proteolytically released by ADAM17. This demonstrates the importance of an ADAM17 regulation and therefore the significance of iRhoms for intercellular signalling. Neither the underlying mechanism of the iRhom-mediated trafficking of ADAM17 is clear nor is it known, if there are other iRhom functions beyond ADAM17 trafficking. Therefore the aim of the proposed project will be to characterise human iRhom1 and human iRhom2. The project is divided in three parts: 1. Characterising the interaction between ADAM17 and iRhoms 2. Structural and functional characterisation of the conserved luminal iRhom domain 3. Functional characterisation of the cytoplasmic region and identification of interaction partners of this region

• DFG Programme: Research Fellowships
• International Connection: United Kingdom
• Host: Professor Matthew Freeman, Ph.D.