Phosphorylation of iRhom2 Is Essential for Stimulated Proteolytic Shedding by the Metalloprotease ADAM17/TACE
43 Pages Posted: 10 Apr 2018 Publication Status: Published
More...Abstract
Cell surface metalloproteases coordinate signaling during development, tissue homeostasis and disease. TACE (TNFa Converting Enzyme), is the metalloprotease responsible for proteolytic release, ('shedding'), of membrane-tethered signaling molecules including the cytokine TNF, and activating ligands of the EGFR. A key step in TACE biogenesis involves its interaction with iRhom2, controlling TACE trafficking from the ER to the trans-Golgi network. Another important, but mechanistically unclear, feature of TACE biology is its ability to be rapidly stimulated on the cell surface, by numerous agents. Here we report a novel role for cell surface iRhom2 in TACE stimulation. Stimuli that provoke TACE shedding trigger iRhom2 phosphorylation within its cytoplasmic tail, dependent on MAP kinases. Blocking iRhom2 phosphorylation does not affect TACE trafficking, but impairs the shedding of TACE substrates, through defective proteolytic activity. Our data suggest that shedding stimuli utilize an 'inside out' signaling mechanism, transducing cytoplasmic signals through iRhom2, engaging TACE sheddase activity.
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