Inactivation of PP2A by a recurrent mutation drives resistance to MEK inhibitors

Oncogene. 2020 Jan;39(3):703-717. doi: 10.1038/s41388-019-1012-2. Epub 2019 Sep 20.


The serine/threonine Protein Phosphatase 2A (PP2A) functions as a tumor suppressor by negatively regulating multiple oncogenic signaling pathways. The canonical PP2A holoenzyme comprises a scaffolding subunit (PP2A Aα/β), which serves as the platform for binding of both the catalytic C subunit and one regulatory B subunit. Somatic heterozygous missense mutations in PPP2R1A, the gene encoding the PP2A Aα scaffolding subunit, have been identified across multiple cancer types, but the effects of the most commonly mutated residue, Arg-183, on PP2A function have yet to be fully elucidated. In this study, we used a series of cellular and in vivo models and discovered that the most frequent Aα R183W mutation formed alternative holoenzymes by binding of different PP2A regulatory subunits compared with wild-type Aα, suggesting a rededication of PP2A functions. Unlike wild-type Aα, which suppressed tumorigenesis, the R183W mutant failed to suppress tumor growth in vivo through activation of the MAPK pathway in RAS-mutant transformed cells. Furthermore, cells expressing R183W were less sensitive to MEK inhibitors. Taken together, our results demonstrate that the R183W mutation in PP2A Aα scaffold abrogates the tumor suppressive actions of PP2A, thereby potentiating oncogenic signaling and reducing drug sensitivity of RAS-mutant cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Arginine / genetics
  • Calmodulin-Binding Proteins / metabolism
  • Carcinogenesis / drug effects
  • Carcinogenesis / genetics
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / genetics*
  • Humans
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / genetics
  • Membrane Proteins / metabolism
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Molecular Dynamics Simulation
  • Mutagenesis, Site-Directed
  • Mutation
  • Neoplasms / drug therapy*
  • Neoplasms / genetics
  • Nerve Tissue Proteins / metabolism
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Protein Phosphatase 2 / genetics*
  • Protein Phosphatase 2 / isolation & purification
  • Recombinant Proteins / genetics*
  • Recombinant Proteins / isolation & purification
  • Transfection
  • Tyrosine / genetics
  • Xenograft Model Antitumor Assays


  • Calmodulin-Binding Proteins
  • Membrane Proteins
  • Nerve Tissue Proteins
  • PPP2R1A protein, human
  • Protein Kinase Inhibitors
  • Recombinant Proteins
  • STRN protein, human
  • Tyrosine
  • Arginine
  • Mitogen-Activated Protein Kinase Kinases
  • Protein Phosphatase 2