B55β-associated PP2A complex controls PDK1-directed myc signaling and modulates rapamycin sensitivity in colorectal cancer

Cancer Cell. 2010 Nov 16;18(5):459-71. doi: 10.1016/j.ccr.2010.10.021.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / therapeutic use*
  • Cell Proliferation
  • Cell Transformation, Neoplastic / genetics
  • Cellular Senescence
  • Class I Phosphatidylinositol 3-Kinases
  • Cluster Analysis
  • Colorectal Neoplasms / drug therapy
  • Colorectal Neoplasms / enzymology*
  • Colorectal Neoplasms / genetics
  • DNA Methylation
  • Drug Resistance, Neoplasm
  • Epigenesis, Genetic
  • Humans
  • Mice
  • Nerve Tissue Proteins / metabolism*
  • Nerve Tissue Proteins / physiology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphatidylinositol 3-Kinases / physiology
  • Phosphorylation
  • Protein Phosphatase 2 / metabolism*
  • Protein Phosphatase 2 / physiology
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins c-akt / physiology
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Signal Transduction
  • Sirolimus / therapeutic use*
  • Transplantation, Heterologous


  • Antibiotics, Antineoplastic
  • Nerve Tissue Proteins
  • PDK1 protein, human
  • Pdk1 protein, mouse
  • Proto-Oncogene Proteins c-myc
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • PPP2R2B protein, human
  • Protein Phosphatase 2
  • Sirolimus