ERBB/EGFR signalling pathway defects are associated with cancers, and it is known that depletion or inhibition of ADAM17, a sheddase that releases ERBB ligands from the plasma membrane, can suppress KRAS-induced lung tumour growth. Matthew Freeman’s group studies iRhoms, rhomboid-like proteins that regulate ADAM17. Here (Sieber, Lu et al., 2022), they demonstrate that iRhom2 is required for the increased shedding of ERBB ligands observed in HEK293T cells expressing oncogenic KRAS. Delving into the underlying mechanism, they find that oncogenic KRAS induces phosphorylation of cytoplasmic domain of iRhom2 via the Raf/MEK/ERK pathway. This phosphorylation step is essential for amplified ERBB shedding, given that it allows iRhom2 to recruit 14-3-3ε, a process known to be sufficient for ADAM17 activation. This mechanism is conserved in A549 cells, a model for human lung adenocarcinoma. Knocking out iRhom1 and iRhom2 using CRISPR/Cas9 in A549 cells decreased proliferation and, when these cells were injected into immunodeficient mice, there was no detectable tumour growth. Importantly, cancer-associated iRhom2 mutations promote an increase in both ERBB shedding and the growth in vitro of tumour-like ‘spheroids’ when compared with wild-type iRhom2 A549 cells, and this amplified ERBB signalling sustains KRAS activity. This work therefore identifies iRhom2 as a key player in a positive feedback loop that contributes to lung tumorigenesis.
