Research ArticleCancer

Deletions in the cytoplasmic domain of iRhom1 and iRhom2 promote shedding of the TNF receptor by the protease ADAM17

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Science Signaling  03 Nov 2015:
Vol. 8, Issue 401, pp. ra109
DOI: 10.1126/scisignal.aac5356

Tumor susceptibility from truncated rhomboids

Tumor necrosis factor (TNF) is an extracellular signal that can trigger cell death through its receptor. The protease ADAM17 has a dual role in regulating TNF signaling: ADAM17 promotes TNF signaling by cleaving and releasing TNF from the cell surface, and ADAM17 dampens TNF signaling by cleaving and releasing TNF receptors from the surface. The rhomboid proteins iRhom1 and iRhom2, which lack catalytic activity, mediate the maturation and delivery of ADAM17 to the cell surface. Maney et al. found that deletions in the cytoplasmic region of iRhom1 or iRhom2, which mimic mutations in the N-terminal cytoplasmic tail of iRhom2 in some patients with susceptibility to esophageal cancer, reduced TNF signaling, despite increasing ADAM17 activity. Expression of N-terminally truncated iRhoms in mouse fibrosarcoma cells increased the abundance of ADAM17 at the surface and the subsequent shedding of the TNF receptors, thereby suppressing TNF-induced intracellular signaling and cell death.

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