Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109, USA; Institute of Hepatobiliary Surgery, Southwest Hospital, The Third Military Medical University (Army Medical University), Chongqing, China.
Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109, USA.
Cell Rep. 2019 Mar 12;26(11):3037-3050.e4. doi: 10.1016/j.celrep.2019.02.052.
FBXW7 is a tumor suppressive E3 ligase, whereas RAS-ERK and mechanistic target of rapamycin kinase (mTORC1) are two major oncogenic pathways. Whether and how FBXW7 regulates these two oncogenic pathways are unknown. Here, we showed that SHOC2, a RAS activator, is a FBXW7 substrate. Growth stimuli trigger SHOC2 phosphorylation on Thr by the mitogen-activated protein kinase (MAPK) signal, which facilitates FBXW7 binding for ubiquitylation and degradation. FBXW7-mediated SHOC2 degradation terminates the RAS-MAPK signals and inhibits proliferation. Furthermore, SHOC2 selectively binds to Raptor to competitively inhibit the Raptor-mTOR binding to inactivate mTORC1 and induce autophagy, whereas Raptor binding of SHOC2 inhibits the SHOC2-RAS binding to block the MAPK pathway and proliferation. Finally, SHOC2 is overexpressed in pancreatic cancer, which correlated with poor patient survival. SHOC2 mutations were found in lung cancer tissues with gain-of-function activity. Collectively, the SHOC2-Raptor interaction triggers negative cross-talk between RAS-ERK and mTORC1 pathways, whereas FBXW7 regulates both pathways by targeting SHOC2 for ubiquitylation and degradation.
FBXW7 是一种肿瘤抑制 E3 连接酶，而 RAS-ERK 和雷帕霉素靶蛋白激酶（mTORC1）是两种主要的致癌途径。FBXW7 是否以及如何调节这两种致癌途径尚不清楚。在这里，我们表明，SHOC2，一种 RAS 激活剂，是 FBXW7 的底物。生长刺激物通过丝裂原活化蛋白激酶（MAPK）信号触发 SHOC2 在 Thr 上的磷酸化，这有利于 FBXW7 结合进行泛素化和降解。FBXW7 介导的 SHOC2 降解终止 RAS-MAPK 信号并抑制增殖。此外，SHOC2 选择性地与 Raptor 结合，以竞争性抑制 Raptor-mTOR 结合，从而使 mTORC1 失活并诱导自噬，而 SHOC2 与 Raptor 的结合抑制 MAPK 途径和增殖。最后，SHOC2 在胰腺癌中过度表达，与患者预后不良相关。在具有功能获得活性的肺癌组织中发现了 SHOC2 突变。总之，SHOC2-Raptor 相互作用触发了 RAS-ERK 和 mTORC1 途径之间的负交叉对话，而 FBXW7 通过靶向 SHOC2 进行泛素化和降解来调节这两条途径。
