B55β-Associated PP2A Complex Controls PDK1-Directed Myc Signaling and Modulates Rapamycin Sensitivity in Colorectal Cancer
B55β-Associated PP2A Complex Controls PDK1-Directed Myc Signaling and Modulates Rapamycin Sensitivity in Colorectal Cancer
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DOI：
10.1016/j.ccr.2010.10.021
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发表时间：
2010-11-16
期刊：
影响因子：
50.3
通讯作者：
Yu, Qiang
中科院分区：
文献类型：
--
作者：
Tan, Jing;Lee, Puay Leng;Yu, Qiang
PP 2A丝氨酸/苏氨酸蛋白磷酸酶作为细胞生长、增殖和存活的关键细胞调节剂。然而，这一途径如何在人类癌症中改变以赋予生长优势在很大程度上是未知的。在这里，我们表明PPP 2 R2 B，编码PP 2A复合物的B55 β调节亚基，在结直肠癌中被DNA超甲基化表观遗传失活。B55 β相关的PP 2A与PDK 1相互作用并调节其对Myc磷酸化的活性。在PPP 2 R2 B缺失时，mTORC 1抑制剂雷帕霉素以PDK 1依赖性但PI 3 K和AKT不依赖性的方式触发Myc的补偿性磷酸化，导致耐药。PPP 2 R2 B的再表达、PDK 1的基因消除或PDK 1的药理学抑制消除雷帕霉素诱导的Myc磷酸化，导致雷帕霉素敏化。因此，PP 2A-B55 β拮抗PDK 1-Myc信号传导并调节雷帕霉素敏感性。
The PP2A serine/threonine protein phosphatase serves as a critical cellular regulator of cell growth, proliferation, and survival. However, how this pathway is altered in human cancer to confer growth advantage is largely unknown. Here, we show that PPP2R2B, encoding the B55 beta regulatory subunit of the PP2A complex, is epigenetically inactivated by DNA hypermethylation in colorectal cancer. B55 beta-associated PP2A interacts with PDK1 and modulates its activity toward Myc phosphorylation. On loss of PPP2R2B, mTORC1 inhibitor rapamycin triggers a compensatory Myc phosphorylation in PDK1-dependent, but PI3K and AKT-independent manner, resulting in resistance. Reexpression of PPP2R2B, genetic ablation of PDK1 or pharmacologic inhibition of PDK1 abrogates the rapamycin-induced Myc phosphorylation, leading to rapamycin sensitization. Thus, PP2A-B55 beta antagonizes PDK1-Myc signaling and modulates rapamycin sensitivity.