首页|iRhom2 regulates ERBB signalling to promote KRAS-driven tumour growth of lung cancer cells
iRhom2 regulates ERBB signalling to promote KRAS-driven tumour growth of lung cancer cells
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NSTL
Company Biologists Ltd
Dysregulation of the ERBB/EGFR signalling pathway causes multiple types of cancer. Accordingly, ADAM17, the primary shedding enzyme that releases and activates ERBB ligands, is tightly regulated. It has recently become clear that iRhom proteins, inactive members of the rhomboid-like superfamily, are regulatory cofactors for ADAM17. Here, we show that oncogenic KRAS mutants target the cytoplasmic domain of iRhom2 (also known as RHBDF2) to induce ADAM17- dependent shedding and the release of ERBB ligands. Activation of ERK1/2 by oncogenic KRAS induces the phosphorylation of iRhom2, recruitment of the phospho-binding 14-3-3 proteins, and consequent ADAM17-dependent shedding of ERBB ligands. In addition, cancerassociated mutations in iRhom2 act as sensitisers in this pathway by further increasing KRAS-induced shedding of ERBB ligands. This mechanism is conserved in lung cancer cells, where iRhom activity is required for tumour xenograft growth. In this context, the activity of oncogenic KRAS is modulated by the iRhom2-dependent release of ERBB ligands, thus placing the cytoplasmic domain of iRhom2 as a central component of a positive feedback loop in lung cancer cells. ? 2022. Published by The Company of Biologists Ltd.
A549 cellsADAM17EGFRERBBiRhom2KRAS
Sieber B、Lu F、Stribbling S.M、Grieve A.G、Ryan A.J、Freeman M
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Sir William Dunn School of Pathology, University of Oxford, Oxford, OX1 3RE, United Kingdom
NSTL
Company Biologists Ltd
