The ADAM17 sheddase complex regulator iTAP modulates inflammation, epithelial repair, and tumor growth

Abstract

The metalloprotease ADAM17 catalyzes the shedding of key signalling molecules from the cell surface, including the inflammatory cytokine TNF (tumour necrosis factor) and activating ligands of the EGFR (epidermal growth factor receptor). ADAM17 exists within an assemblage called the "sheddase complex" containing a rhomboid pseudoprotease (iRhom1 or iRhom2). iRhoms control multiple aspects of ADAM17 biology, including its vesicular trafficking, maturation from its precursor pro-form, activation on the cell surface and specificity for subsets of proteolytic targets. Previous studies from our laboratory and others identified the FERM domain-containing protein Frmd8/iTAP as an iRhom-binding protein. iTAP is required to maintain the cell surface stability of the sheddase complex, thereby preventing the precocious shunting of ADAM17 and iRhom2 to lysosomes and their consequent degradation. As pathophysiological role(s) of iTAP have not been addressed, here we sought to characterize the impact of loss of iTAP on ADAM17-associated phenotypes in mice. Our data show that iTAP KO mice exhibit defects in ADAM17 activity in inflammatory and intestinal epithelial barrier repair functions, but do not exhibit the collateral effects associated with global loss of ADAM17. Furthermore, we show that iTAP promotes 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 may be beneficial to target ADAM17 activity in specific compartments during chronic inflammatory diseases or cancer, avoiding the deleterious impact on vital functions associated with the widespread inhibition of ADAM17 in normal tissues.