Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK.
Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
J Cell Sci. 2022 Sep 1;135(17). doi: 10.1242/jcs.259949. Epub 2022 Sep 8.
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.
ERBB/EGFR 信号通路的失调会导致多种类型的癌症。因此，ADAM17 作为主要的脱落酶，能够释放和激活 ERBB 配体，其活性受到严格调控。最近人们清楚地认识到，iRhom 蛋白（一种无活性的类 rhomboid 超家族成员）是 ADAM17 的调节性辅助因子。在这里，我们发现致癌性 KRAS 突变体靶向 iRhom2（也称为 RHBDF2）的细胞质结构域，以诱导 ADAM17 依赖性脱落和 ERBB 配体的释放。致癌性 KRAS 通过激活 ERK1/2 诱导 iRhom2 的磷酸化，招募磷酸结合蛋白 14-3-3，从而导致 ADAM17 依赖性 ERBB 配体脱落。此外，iRhom2 中的癌症相关突变通过进一步增加 KRAS 诱导的 ERBB 配体脱落，作为该途径中的敏化剂发挥作用。该机制在肺癌细胞中是保守的，其中 iRhom 活性是肿瘤异种移植物生长所必需的。在这种情况下，致癌性 KRAS 的活性受 iRhom2 依赖性 ERBB 配体释放的调节，从而将 iRhom2 的细胞质结构域置于肺癌细胞中正反馈回路的核心组成部分。本文附有对该论文第一作者的第一人称采访。
