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Activation of protein phosphatase 2A (PP2A) is a promising anti-cancer therapeutic strategy, as this tumor suppressor has the ability to coordinately downregulate multiple pathways involved in the regulation of cellular growth and proliferation. In order to understand the systems-level perturbations mediated by PP2A activation, we carried out mass spectrometry-based phosphoproteomic analysis of two KRAS mutated non-small cell lung cancer (NSCLC) cell lines (A549 and H358) treated with a novel Small Molecule Activator of PP2A (SMAP). Overall, this permitted quantification of differential signaling across over 1,600 phosphoproteins and 3,000 phosphosites. Kinase activity assessment and pathway enrichment implicated collective downregulation of RAS and cell cycle kinases in the case of both cell lines upon PP2A activation. However, the effects on RAS-related signaling was attenuated for A549 compared to H358, while the effects on cell cycle related kinases were noticeably more prominent in A549. Network-based analyses and validation experiments confirmed these detailed differences in signaling. These studies reveal the power of phosphoproteomics studies, coupled to computational systems biology, to elucidate global patterns of phosphatase activation and understand the variations in response to PP2A activation across genetically similar NSCLC cell lines.


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