RRC ID 60864
Author Morita K, He S, Nowak RP, Wang J, Zimmerman MW, Fu C, Durbin AD, Martel MW, Prutsch N, Gray NS, Fischer ES, Look AT.
Title Allosteric Activators of Protein Phosphatase 2A Display Broad Antitumor Activity Mediated by Dephosphorylation of MYBL2.
Journal Cell
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.
Volume 181(3)
Pages 702-715.e20
Published 2020-4-30
DOI 10.1016/j.cell.2020.03.051
PII S0092-8674(20)30344-5
PMID 32315619
PMC PMC7397863
IF 36.216
Times Cited 2
Resource
DNA material CSII-EF-MCS-IRES2-Venus (RDB04384) CSII-EF-MCS-IRES2-hKO1 (RDB07915) pENTR4-H1tetOx1 (RDB07916) CS-RfA-ETBsd (RDB07917)