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Select Stabilization of a Tumor-Suppressive PP2A Heterotrimer

Vidhi M Shah1, Isabel A English2, Rosalie C Sears3

  • 1Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA; Brenden Colson Center for Pancreatic Care, Oregon Health and Science University, Portland, OR, USA.

Trends in Pharmacological Sciences
|July 7, 2020
PubMed

Insights

A new activator, DT-061, stabilizes protein phosphatase 2A (PP2A) to counteract cancer signaling. Structural insights into PP2A offer new avenues for developing phosphatase therapeutics.

Area of Science:

  • Oncology
  • Biochemistry
  • Structural Biology

Background:

  • Aberrant signaling in cancer often involves the suppression of protein phosphatases, like protein phosphatase 2A (PP2A).
  • PP2A counteracts kinase activity, and its suppression contributes to uncontrolled cell growth and oncogenesis.

Purpose of the Study:

  • To investigate the potential of small molecules to reactivate suppressed PP2A in cancer.
  • To characterize the structural basis for PP2A activation by a novel compound.

Main Methods:

  • Utilized cryo-electron microscopy (cryo-EM) to determine the structure of a PP2A heterotrimer assembly.
  • Employed a novel small-molecule activator, DT-061, to target and stabilize specific PP2A holoenzymes.

Main Results:

  • DT-061 selectively stabilizes a PP2A holoenzyme crucial for dephosphorylating oncogenic targets, including MYC.
  • A 3.6-Å cryo-EM map revealed the druggable structure of the activated PP2A heterotrimer.

Conclusions:

  • DT-061 demonstrates potential as a therapeutic agent by restoring PP2A function in cancer.
  • The structural information provides a foundation for designing future phosphatase-based cancer therapeutics.
Keywords:
MYCSMAPcancerphosphatase

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