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

doi:10.1016/j.ccr.2010.10.021

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.

Keywords

Protein phosphatase 2mTORC1PhosphorylationBiologyCancer researchPI3K/AKT/mTOR pathwayProtein kinase BCell biologyRPTORSignal transductionCell growthPhosphataseBiochemistry

MeSH Terms

AnimalsAntibioticsAntineoplasticCell ProliferationCell TransformationNeoplasticCellular SenescenceClass I Phosphatidylinositol 3-KinasesCluster AnalysisColorectal NeoplasmsDNA MethylationDrug ResistanceNeoplasmEpigenesisGeneticHumansMiceNerve Tissue ProteinsPhosphatidylinositol 3-KinasesPhosphorylationProtein Phosphatase 2Protein Serine-Threonine KinasesProto-Oncogene Proteins c-aktProto-Oncogene Proteins c-mycPyruvate Dehydrogenase Acetyl-Transferring KinaseSignal TransductionSirolimusTransplantationHeterologous

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Publication Info

Year: 2010
Type: article
Volume: 18
Issue: 5
Pages: 459-471
Citations: 120
Access: Closed

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APA Style

                            
                                
                                    Jing Tan, 
                                
                                    Puay Leng Lee, 
                                
                                    Zhimei Li
                                
                                et al.
                            
                            (2010). 
                            B55β-Associated PP2A Complex Controls PDK1-Directed Myc Signaling and Modulates Rapamycin Sensitivity in Colorectal Cancer. 
                            Cancer Cell
                            , 18
                            (5)
                            , 459-471.
                            https://doi.org/10.1016/j.ccr.2010.10.021
                        

Identifiers

DOI: 10.1016/j.ccr.2010.10.021
PMID: 21075311

Data Quality

Data completeness: 86%