Our Research

The iRhom/ADAM17 signaling axis: a key regulator of TNFa, IL-6R and EGFR signaling

Major Focus: Uncovering the role of iRhoms and ADAM17 in development and disease, with an emphasis in autoimmune diseases such as Rheumatoid Arthritis (RA), Systemic Lupus Erythematosis Glomerulonephritis (SLE GN) and neuroinflammation.

Research in my lab is focused on elucidating the functions of cell surface metalloproteinases termed ADAMs (a disintegrin and metalloproteinase) in development and disease. ADAMs have emerged as critical modulators of cell-cell interactions because they regulate the bioavailability of membrane proteins such as the pro-inflammatory cytokine TNFa and ligands of the EGF-receptor (EGFR).  Studies in my lab employ a synergistic combination of approaches, including biochemistry, cell biology, mouse models for development and disease and analysis of patient samples.  Work in my lab has helped establish that ADAM17 is a key regulator of the EGFR signaling pathway, which is essential for maintaining the skin and intestinal barrier but can cause a variety of human pathologies when it is dysregulated.  Moreover, my lab has pioneered studies on the newly discovered iRhom1 and 2 as crucial upstream regulators of ADAM17-dependent EGFR and TNFa-signaling.  By elucidating how exactly iRhoms and ADAM17 interact, we have provided exciting new insights into the basic biology of these fascinating proteins and have identified new and attractive potential targets for treatment of autoimmune diseases and cancer.

What are the main iRhom/ADAM17-dependent signaling pathways?

The cell surface metalloprotease ADAM17 (a disintegrin and metalloprotease 17) has a crucial role in regulating several major medically relevant signaling pathways, including TNFa and IL-6R signaling, both established targets for treatment of autoimmune diseases, and EGF-receptor signaling, which is important for normal development and adult homeostasis, but can also promote cancer and autoimmune disease.  ADAM17 is controlled by its essential partners, the seven membrane-spanning inactive Rhomboid proteins iRhom1 and 2.  Together with the iRhoms, ADAM17 acts as a set of signaling scissors that cleave and release membrane proteins from cells. This process, referred to as “protein ectodomain shedding”, can activate or inactivate the substrate protein, or substantially change its functional properties. Dysregulation of iRhom/ADAM17 signaling can cause Rheumatoid Arthritis, Systemic Lupus Erythematosis-Glomerulonephritis and other diseases such as neuroinflammation and defects in heart valve development.  ADAM17 can be rapidly and post-translationally activated by a variety of signaling pathways, and the iRhoms have emerged as essential regulators of ADAM17 and of its substrate targeting.  Work in our lab set the stage for the foundation of the biotech startup SciRhom, which has developed novel function blocking antibodies against iRhom2 in order to improve the treatment of patients suffering from autoimmune diseases. Our current knowledge of the iRhom/ADAM17 complex is just the tip of the iceberg, and many exciting questions remain regarding the regulation and function of these fascinating molecules, such as how they target and process their substrates, how these functions are controlled, and what role the iRhom/ADAM17 signaling hub has in development, autoimmune diseases, neuroinflammation and cancer