title: B55β-associated PP2A complex controls PDK1-directed myc signaling and modulates rapamycin sensitivity in colorectal cancer.
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.
authors.affiliation: Cancer Biology and Pharmacology, Genome Institute of Singapore, Agency for Science, Technology and Research, Biopolis, Singapore.
authors.forename: Jing
authors.initials: J
authors.lastname: Tan
authors.forename: Puay Leng
authors.initials: PL
authors.lastname: Lee
authors.forename: Zhimei
authors.initials: Z
authors.lastname: Li
authors.forename: Xia
authors.initials: X
authors.lastname: Jiang
authors.forename: Yaw Chyn
authors.initials: YC
authors.lastname: Lim
authors.forename: Shing Chuan
authors.initials: SC
authors.lastname: Hooi
authors.forename: Qiang
authors.initials: Q
authors.lastname: Yu
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D016922:Cellular Senescence; D058534:Class I Phosphatidylinositol 3-Kinases; D016000:Cluster Analysis; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D019175:DNA Methylation; D019008:Drug Resistance, Neoplasm; D044127:Epigenesis, Genetic; D006801:Humans; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism* / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism / Q000502:physiology; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000378:metabolism* / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism / Q000502:physiology; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D015398:Signal Transduction; D020123:Sirolimus / Q000627:therapeutic use*; D014183:Transplantation, Heterologous
chemical_list: D000903:Antibiotics, Antineoplastic; D058534:Class I Phosphatidylinositol 3-Kinases; D009419:Nerve Tissue Proteins; D019869:Phosphatidylinositol 3-Kinases; D054648:Protein Phosphatase 2; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D016271:Proto-Oncogene Proteins c-myc; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D020123:Sirolimus; C000631429:PDK1 protein, human; C000631433:Pdk1 protein, mouse; C484760:PIK3CA protein, human; C505936:PPP2R2B protein, human