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SPEECH Conference
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Jason S. Wasserman

Jason Wasserman poster session
FAM122A is a Substrate-Competitive Inhibitor of the B55⍺/PP2A Phosphatase Required for Timely Progression Through the Cell Cycle Interphase

Name Jason S. Wasserman
Institution Temple University
Research Field Basic Research
Role at Institution Graduate Student
Presenter(s) Jason S. Wasserman

Abstract

FAM122A is a Substrate-Competitive Inhibitor of the B55⍺/PP2A Phosphatase Required for Timely Progression Through the Cell Cycle Interphase

Jason S. Wasserman1, Kishan R. Patel1, Alison N. Kurimchak2, Holly Fowle1, Ziran Zhao1, Rebecca Page3, Arminja N. Kettenbach4, Roland L. Dunbrack Jr2, Wolfgang Peti3, James S. Duncan2 and Xavier Graña1

1Fels Cancer Institute for Personalized Medicine. Temple University Lewis Katz School of Medicine, Philadelphia, United States.
2Fox Chase Cancer Center, Philadelphia, United States.
3Department Cell Biology, UConn Health, Farmington, United States.
4Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Medical Center Drive, Lebanon, United States

The heterotrimeric Ser/Thr protein phosphatase 2A (PP2A) is responsible for the dephosphorylation of many regulated phosphoproteins. B regulatory subunits mediate substrate recognition where substrates contain Short Linear Motifs (SLiMs) that mediate docking to holoenzyme subunits. Substrates of B55a/PP2A, the most abundant PP2A holoenzyme, are diverse, and the first consensus SLiM, [RK]-V-x-x-[VI]-R, has only recently been identified (Fowle et al. eLife 2021;10:e63181). Here we report the identification of this SLiM in FAM122A, an inhibitor of B55a/PP2A. This SLiM is necessary for FAM122A binding to B55a in vitro and in cells and the inhibition of the holoenzyme. Computational modeling predicts an interaction consistent with mutational and biophysical data supporting a mechanism whereby FAM122A uses the SLiM to dock to B55a and spatially constrains substrate access by occluding the catalytic subunit. Consistently, FAM122A functions as a competitive inhibitor as it prevents binding of substrates in in-vitro competition assays and the dephosphorylation of CDK substrates by B55a/PP2A in cell lysates. Time-lapse and immunofluorescent microscopy show that FAM122A is nuclear in interphase suggesting a role in controlling B55a/PP2A nuclear function. Consistently, knockout of FAM122A in HEK293 and T98G cells results in cell cycle interphase defects. FAM122A-KO cells proliferate slowly, exhibiting an elongated S-phase characterized by severely reduced DNA synthesis. Quiescent FAM122A-KO cells also show delayed pRB phosphorylation kinetics and cyclin expression upon cell cycle re-entry. Overall, these data strongly suggest that FAM122A is a SLiM-dependent, substrate-competitive inhibitor of B55a/PP2A that suppresses its activity to ensure timely progression through the cell cycle interphase.

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