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ATM-mediated phosphorylation activates the tumor-suppressive function of B56γ-PP2A
G P Shouse1, Y Nobumori, M J Panowicz
1Department of Biochemistry, University of California, Riverside, USA.
Oncogene
|April 5, 2011
Summary
DNA damage activates tumor suppressor functions of B56-PP2A phosphatases. ATM kinase phosphorylates B56 subunits, enhancing PP2A activity toward p53 and inhibiting cell proliferation.
Area of Science:
- Cellular Biology
- Molecular Oncology
- Signal Transduction
Background:
- Protein phosphatase 2A (PP2A) is crucial for diverse cellular functions.
- Specific PP2A holoenzymes containing B56 subunits act as tumor suppressors.
- Regulatory mechanisms for B56-PP2A tumor suppressor activity remain unclear.
Purpose of the Study:
- To elucidate the regulatory mechanisms governing B56-PP2A tumor-suppressive function.
- To investigate the role of ATM in regulating B56-PP2A activity after DNA damage.
- To identify specific B56 subunits and phosphorylation sites involved in this process.
Main Methods:
- Investigated ATM-mediated phosphorylation of B56 subunits (B56γ3, B56γ2, B56δ) post-DNA damage.
- Assessed the impact of B56γ3 phosphorylation at Ser510 on PP2A complex formation and p53 substrate targeting.
- Examined the interplay between ATM, MDM2, and B56γ3 ubiquitination and stability.
- Evaluated the effect of Ser510 phosphorylation on B56γ3's ability to inhibit cell proliferation and anchorage-independent growth.
Main Results:
- ATM directly phosphorylates B56γ3, B56γ2, and B56δ following DNA damage.
- Phosphorylation of B56γ3 at Ser510 increases B56γ3-PP2A complexes, directing activity towards p53 and activating its tumor-suppressive functions.
- ATM-mediated phosphorylation of B56γ3 blocks MDM2-dependent ubiquitination, leading to B56γ3 upregulation.
- Ser510 phosphorylation significantly enhances B56γ3's inhibition of cell proliferation and anchorage-independent growth.
Conclusions:
- ATM-dependent phosphorylation is a key regulator of B56-PP2A tumor-suppressive function.
- This pathway provides mechanistic insight into how DNA damage activates PP2A's role in tumor suppression.
- A model for parallel regulation of p53 and B56γ3 is proposed, highlighting their coordinated role in tumor suppression.
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