Allosteric Activators of Protein Phosphatase 2A Display Broad Antitumor Activity Mediated by Dephosphorylation of MYBL2

Cell. 2020 Apr 30;181(3):702-715.e20. doi: 10.1016/j.cell.2020.03.051. Epub 2020 Apr 20.

Abstract

Protein phosphatase 2A (PP2A) enzymes can suppress tumors, but they are often inactivated in human cancers overexpressing inhibitory proteins. Here, we identify a class of small-molecule iHAPs (improved heterocyclic activators of PP2A) that kill leukemia cells by allosterically assembling a specific heterotrimeric PP2A holoenzyme consisting of PPP2R1A (scaffold), PPP2R5E (B56ε, regulatory), and PPP2CA (catalytic) subunits. One compound, iHAP1, activates this complex but does not inhibit dopamine receptor D2, a mediator of neurologic toxicity induced by perphenazine and related neuroleptics. The PP2A complex activated by iHAP1 dephosphorylates the MYBL2 transcription factor on Ser241, causing irreversible arrest of leukemia and other cancer cells in prometaphase. In contrast, SMAPs, a separate class of compounds, activate PP2A holoenzymes containing a different regulatory subunit, do not dephosphorylate MYBL2, and arrest tumor cells in G1 phase. Our findings demonstrate that small molecules can serve as allosteric switches to activate distinct PP2A complexes with unique substrates.

Keywords: MYBL2; PP2A; PPZ; cell cycle arrest; dopamine receptor; perphenazine; phenothiazine; prometaphase; protein phosphatase 2A.

Publication types

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

MeSH terms

  • Apoptosis
  • Cell Cycle Proteins / drug effects
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Enzyme Activators / metabolism
  • G1 Phase
  • Humans
  • Multiprotein Complexes / metabolism
  • Multiprotein Complexes / physiology
  • Phenothiazines / pharmacology
  • Phosphorylation
  • Protein Phosphatase 2 / metabolism*
  • Protein Phosphatase 2 / physiology
  • Protein Subunits / metabolism
  • Trans-Activators / drug effects
  • Trans-Activators / metabolism
  • Transcription Factors / metabolism

Substances

  • Cell Cycle Proteins
  • Enzyme Activators
  • MYBL2 protein, human
  • Multiprotein Complexes
  • PPP2R5E protein, human
  • Phenothiazines
  • Protein Subunits
  • Trans-Activators
  • Transcription Factors
  • PPP2CA protein, human
  • Protein Phosphatase 2
  • phenothiazine