The ADAM17 sheddase complex regulator iTAP/Frmd8 modulates inflammation and tumor growth

Abstract

The metalloprotease ADAM17 is a sheddase of key molecules, including TNF and epidermal growth factor receptor ligands. ADAM17 exists within an assemblage, the “sheddase complex,” containing a rhomboid pseudoprotease (iRhom1 or iRhom2). iRhoms control multiple aspects of ADAM17 biology. The FERM domain–containing protein iTAP/Frmd8 is an iRhom-binding protein that prevents the precocious shunting of ADAM17 and iRhom2 to lysosomes and their consequent degradation. As pathophysiological role(s) of iTAP/Frmd8 have not been addressed, we characterized the impact of iTAP/Frmd8 loss on ADAM17-associated phenotypes in mice. We show that iTAP/Frmd8 KO mice exhibit defects in inflammatory and intestinal epithelial barrier repair functions, but not the collateral defects associated with global ADAM17 loss. Furthermore, we show that iTAP/Frmd8 regulates cancer cell growth in a cell-autonomous manner and by modulating the tumor microenvironment. Our work suggests that pharmacological intervention at the level of iTAP/Frmd8 may be beneficial to target ADAM17 activity in specific compartments during chronic inflammatory diseases or cancer, while avoiding the collateral impact on the vital functions associated with the widespread inhibition of ADAM17.

The protease ADAM17 at the crossroads of disease: revisiting its significance in inflammation, cancer, and beyond

“…With respect to interacting partners, tissue inhibitor of metalloproteinases-3 (TIMP3) inhibits dimerized ADAM17 activity via association with its ectodomain at the cell membrane [39,40]. Recently, the iRhom tail-associated protein (iTAP) has also been identified as a novel regulator of ADAM17 activity by binding to iRhoms, enhancing the cell surface stability of iRhoms/ADAM17 sheddase complex, and preventing its lysosomal degradation [41,42].…”