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Assessing Cellular Target Engagement by SHP2 (PTPN11) Phosphatase Inhibitors
Published on: July 17, 2020
Identification of PP2A complexes and pathways involved in cell transformation
Anna A Sablina1, Melissa Hector, Nathalie Colpaert
1Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. Anna.Sablina@cme.vib-kuleuven.be
Cancer Research
|December 17, 2010
Summary
Simian virus 40 oncoprotein hijacks protein phosphatase 2A (PP2A) to transform cells. Suppressing specific PP2A subunits mimics this effect, revealing key pathways involved in cell transformation.
Area of Science:
- Molecular Biology
- Oncology
- Cell Biology
Background:
- Simian virus 40 small t (SV40ST) oncoprotein interaction with protein phosphatase 2A (PP2A) is critical for human cell transformation.
- Specific PP2A complexes' roles in SV40-mediated cell transformation are not fully understood.
- Several PP2A subunits are implicated as tumor suppressor genes.
Purpose of the Study:
- To identify PP2A regulatory subunits and pathways involved in SV40ST-driven cell transformation.
- To elucidate how specific PP2A complexes influence oncogenic signaling pathways.
Main Methods:
- Utilized a comprehensive loss-of-function approach to suppress PP2A regulatory subunits.
- Investigated the impact of subunit suppression on human cell transformation.
- Analyzed the activation of c-Myc, Wnt, and PI3K/Akt pathways.
Main Results:
- Suppression of PP2A B56α, B56γ, and PR72/PR130 subunits replaced SV40ST's transforming activity.
- Manipulation of these PP2A complexes activated c-Myc, Wnt, and PI3K/Akt pathways.
- PTPA suppression disrupted PP2A complex assembly, activating the same oncogenic pathways.
Conclusions:
- Identified specific PP2A regulatory subunits (B56α, B56γ, PR72/PR130, PTPA) perturbed by SV40ST.
- Delineated the PP2A-controlled pathways (c-Myc, Wnt, PI3K/Akt) critical for human cell transformation.
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