The human iRHOM2 interactome upon KRAS expression

ABSTRACT: ADAM17 is a cell surface protease that controls the release of the ectodomains of signalling proteins including EGFR ligands and the primary inflammatory cytokine TNF. Reflecting this important role in signalling, dysregulated ADAM17 activity is linked to many human diseases including immunodeficiency, inflammatory bowel disease (IBD), rheumatic arthritis, cancer, and Alzheimer’s disease. iRhom2, a pseudoprotease of the rhomboid-like superfamily, has evolved to be a multifunctional regulatory co-factor of ADAM17. Recent structural and functional work has begun to reveal how the iRhom2 transmembrane and extracellular domains act to control ADAM17 activity. The cytoplasmic domain, however, remains less explored. Here, using a combination of proteomic, genetic and biochemical approaches, we report three distinct mechanisms by which the cytoplasmic domain of iRhom2 contributes to ADAM17 regulation. First, upon oncogenic KRAS signalling, the serine/threonine kinase RSK2 is recruited to the iRhom2 cytoplasmic N-terminus, and coordinates with phosphorylated ERK to mediate the activation of ADAM17. Second, we show that iRhom2 may have an inhibitory function on ADAM17 at the cell surface: stabilising iRhom2 at cell surface by overexpressing iRhom2’s cytoplasmic binding partner, FRMD8, inhibits PMA-stimulated ADAM17 activity. Third, we have identified a previously undefined motif (RKR) in the iRhom2 cytoplasmic domain that represses unstimulated ADAM17 activity. Overall, these findings reveal the complex regulatory system by which the iRhom2 cytoplasmic tail transduces cellular signals to regulate ADAM17 activation, potentially paving the way towards understanding and possibly manipulating the iRhom2/ADAM17 complex in health and disease.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Marjorie Fournier  

LAB HEAD: Matthew Freeman

PROVIDER: PXD063983 | Pride | 2025-10-20

REPOSITORIES: Pride