iRhom2 regulates ERBB signalling to promote KRAS-driven tumour growth of lung cancer cells

Article Article scientifique Article iRhom2 regulates ERBB signalling to promote KRAS-driven tumour growth of lung cancer cells eng 2022-09-08 2022-09-01 author Sieber Boris 0000-0002-8145-3364 Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK. 716436 Département de biologie moléculaire et cellulaire (MOCEL) author Lu Fangfang Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK. author Stribbling Stephen M 0000-0001-6820-4630 Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK. author Grieve Adam G 0000-0001-6420-5724 Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK. author Ryan Anderson J Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK. author Freeman Matthew 0000-0003-0410-5451 Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK. jcs259949 10.1242/jcs.259949 35971826 0021-9533 PMC9482348 https://journals.biologists.com/jcs/article/135/17/jcs259949/276559/iRhom2-regulates-ERBB-signalling-to-promote-KRAS 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, cancer-associated 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. This article has an associated First Person interview with the first authors of the paper. A549 cells ADAM17 EGFR ERBB KRAS IRhom2 Cancer Research UK CRUKDF 0920-MF Medical Research Council 1643127 China Scholarship Council-University of Oxford Scholarship 201806240008 Biotechnology and Biological Sciences Research Council BB/RO16771/1 Wellcome Trust The control of signalling by members of the rhomboid-like superfamily. 101035 European Commission Discovering the signalling pathways and physiology of active rhomboid proteases in the brain 659166 NeuroRhomboid EU H2020 true Journal of cell science 135 17 cd3882ac-4734-4545-945b-86e53f8b7e75 Article (Published version) Public jcs259949.pdf 4219501 application/pdf CC BY-4.0 62706f008e4353f6ec2e7132c2c36cd3c2016d8d056e6e8da6c417631fc394e4 openAccess

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