B55β-Associated PP2A Complex Controls PDK1-Directed Myc Signaling and Modulates Rapamycin Sensitivity in Colorectal Cancer

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B55β-Associated PP2A Complex Controls PDK1-Directed Myc Signaling and Modulates Rapamycin Sensitivity in Colorectal Cancer
Title:
B55β-Associated PP2A Complex Controls PDK1-Directed Myc Signaling and Modulates Rapamycin Sensitivity in Colorectal Cancer
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Cancer Cell
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Publication Date:
16 November 2010
Citation:
B55β-Associated PP2A Complex Controls PDK1-Directed Myc Signaling and Modulates Rapamycin Sensitivity in Colorectal Cancer Jing Tan, Puay Leng Lee, Zhimei Li, Xia Jiang, Yaw Chyn Lim, Shing Chuan Hooi, Qiang Yu Cancer Cell - 16 November 2010 (Vol. 18, Issue 5, pp. 459-471)
Abstract:
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 B55β regulatory subunit of the PP2A complex, is epigenetically inactivated by DNA hypermethylation in colorectal cancer. B55β-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-B55β antagonizes PDK1-Myc signaling and modulates rapamycin sensitivity.
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ISSN:
1535-6108
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