iRhom2 regulates ERBB signalling to promote KRAS-driven oncogenesis
iRhom2 regulates ERBB signalling to promote KRAS-driven oncogenesis
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DOI：
10.1101/2021.08.06.455383
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发表时间：
2021-08
期刊：
影响因子：
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通讯作者：
Boris Sieber;Fangfang Lu;S. Stribbling;A. Grieve;A. Ryan;M. Freeman
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作者：
Boris Sieber;Fangfang Lu;S. Stribbling;A. Grieve;A. Ryan;M. Freeman
ERBB/EGFR信号通路的失调导致多种类型的癌症（1，2）。因此，释放和激活ERBB配体的主要脱落酶ADAM 17受到严格调控。最近已经清楚的是，iRhoms，菱形样超家族的非活性成员，是ADAM 17的调节辅因子（3，4）。在这里，我们发现致癌KRAS突变体靶向iRhom 2的胞质结构域，以诱导ADAM 17依赖性脱落和ERBB配体的释放。致癌KRAS对ERK 1/2的激活诱导iRhom 2的磷酸化、磷酸结合14-3-3蛋白的募集以及随后ERBB配体的ADAM 17依赖性脱落。此外，iRhom 2中的癌症相关突变通过进一步增加KRAS诱导的ERBB配体脱落而在该途径中充当敏化剂。这种机制在肺癌细胞中是保守的，其中肿瘤异种移植物生长需要iRhom活性。在这种情况下，致癌KRAS的活性通过ERBB配体的iRhom 2依赖性释放来调节，因此将iRhom 2作为肺癌细胞中正反馈环的中心组分。总之，iRhom 2的胞质结构域是KRAS诱导的肺癌细胞肿瘤发生的关键组分。ADAM 17和iRhom 2也与广泛的其他癌症有关（5-10），因此我们揭示的机制也可能具有更广泛的致癌意义。
Dysregulation of the ERBB/EGFR signalling pathway causes multiple types of cancer (1, 2). Accordingly, ADAM17, the primary shedding enzyme that releases and activates ERBB ligands, is tightly regulated. It has recently become clear that iRhoms, inactive members of the rhomboid-like superfamily, are regulatory cofactors for ADAM17 (3, 4). Here we show that oncogenic KRAS mutants target the cytoplasmic domain of iRhom2 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 iRhom2 as a central component of a positive feedback loop in lung cancer cells. Overall, the cytoplasmic domain of iRhom2 is a critical component of KRAS-induced oncogenesis of lung cancer cells. Both ADAM17 and iRhom2 have also been implicated in a wide range of other cancers (5–10), so the mechanism we have revealed may also have wider oncogenic significance.