KRAS 抑制诱导的 MYC 降解被 MEK5-ERK5 补偿机制拮抗。
KRAS Suppression-Induced Degradation of MYC Is Antagonized by a MEK5-ERK5 Compensatory Mechanism.
机构信息
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; The Greehey Children's Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
出版信息
Cancer Cell. 2018 Nov 12;34(5):807-822.e7. doi: 10.1016/j.ccell.2018.10.001.
Our recent ERK1/2 inhibitor analyses in pancreatic ductal adenocarcinoma (PDAC) indicated ERK1/2-independent mechanisms maintaining MYC protein stability. To identify these mechanisms, we determined the signaling networks by which mutant KRAS regulates MYC. Acute KRAS suppression caused rapid proteasome-dependent loss of MYC protein, through both ERK1/2-dependent and -independent mechanisms. Surprisingly, MYC degradation was independent of PI3K-AKT-GSK3β signaling and the E3 ligase FBWX7. We then established and applied a high-throughput screen for MYC protein degradation and performed a kinome-wide proteomics screen. We identified an ERK1/2-inhibition-induced feedforward mechanism dependent on EGFR and SRC, leading to ERK5 activation and phosphorylation of MYC at S62, preventing degradation. Concurrent inhibition of ERK1/2 and ERK5 disrupted this mechanism, synergistically causing loss of MYC and suppressing PDAC growth.
我们最近在胰腺导管腺癌 (PDAC) 中进行的 ERK1/2 抑制剂分析表明，ERK1/2 独立的机制维持 MYC 蛋白稳定性。为了确定这些机制，我们确定了突变型 KRAS 调节 MYC 的信号网络。急性 KRAS 抑制通过 ERK1/2 依赖和非依赖机制导致 MYC 蛋白的快速蛋白酶体依赖性丧失。令人惊讶的是，MYC 的降解不依赖于 PI3K-AKT-GSK3β 信号和 E3 连接酶 FBWX7。然后，我们建立并应用了一种用于 MYC 蛋白降解的高通量筛选，并进行了全激酶组蛋白质组学筛选。我们确定了一种 ERK1/2 抑制诱导的反馈机制，该机制依赖于 EGFR 和 SRC，导致 ERK5 激活和 MYC 在 S62 上的磷酸化，从而阻止降解。同时抑制 ERK1/2 和 ERK5 破坏了这种机制，协同导致 MYC 丧失并抑制 PDAC 生长。
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