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.

Role of iRhom2 in Olfaction: Implications for Odorant Receptor Regulation and Activity-Dependent Adaptation

“…Inactive Rhomboid 2 (iRhom2) and the related iRhom1 are seven membrane-spanning proteins that regulate the function of the cell surface metalloprotease a disintegrin and metalloprotease 17 (ADAM17) [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ]. Both iRhoms are widely expressed, with two notable exceptions: iRhom1 expression is low or absent in myeloid cells, and iRhom2 expression is low or absent in the brain in mice, except for microglia [ 5 , 12 ].…”

Semaphorin 4B is an ADAM17-cleaved inhibitor of adipocyte thermogenesis

“…Work from our group and others established that iRhom2 plays a crucial role in multiple aspects of ADAM17 biology including the control of its vesicular trafficking in the secretory pathway (which is coupled to the removal of its inhibitory prodomain) [46,47], its substrate specificity [48], and the activation of its activity on the cell surface by various stimuli [49,50]. In addition, an interactor called iTAP/FRMD8 is necessary to stabilize and maintain the function of the complex formed by iRhom2 and ADAM17 [51–53]. Notably, iRhom2-null mice also exhibit elevated energy expenditure and show increased thermogenesis (characterized by elevated BAT temperature)[45].…”