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Phosphoproteomic Characterization of Systems-Wide Differential Signaling Induced by Small Molecule PP2A Activation

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, Doctor of Philosophy, Case Western Reserve University, Systems Biology and Bioinformatics.
Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase that downregulates numerous biological processes implicated in anti-apoptotic and pro-proliferative signaling. Considering that it is frequently inhibited in cancers, PP2A is believed to be a tumor suppressor whose reactivation can potentially suppress oncogenic pathways and drive an anti-cancer response. We have developed and tested a novel series of small molecule activators of PP2A (SMAPs) that not only bind to and activate this phosphatase but also inhibit cell growth and promote apoptosis in non-small cell lung cancer (NSCLC) models. Given PP2A’s breadth of cellular targets, comprehensive characterization of the net signaling changes induced by this treatment requires a systems-level approach. Mass spectrometry-based phosphoproteomics is a high-throughput system capable of quantifying thousands of phosphopeptides in a single experiment. Consequently, this dissertation project aims to explore the global differential signaling fluxes induced by phosphatase activation using this platform, coupled to downstream bioinformatics analyses. To accomplish this, I first generated a new computational tool that performs kinase-level activity inferences from phosphoproteomics data. The resulting KSEA App was then applied, in conjunction with other pathway and network-level bioinformatic methods, to estimate relative changes in signaling pathway regulation and identify the major targets affected by SMAP treatment. Finally, proteome-wide analysis of the time-dependent phosphorylation changes with the PP2A activator versus dual kinase inhibitors revealed some striking differences in the internal rewiring between phosphatase activation and kinase inhibition. These findings, in turn, guided us to design a new drug combination featuring SMAP + AZD-6244 (a MEK inhibitor), which displayed enhanced anti-tumor activity in vivo. Altogether, this project features a unique bioinformatics workflow for phosphoproteomics data analysis that helped uncover the global signaling implications of phosphatase activation.
Mark Chance (Advisor)
Goutham Narla (Advisor)

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Citations

  • Wiredja, D. (n.d.). Phosphoproteomic Characterization of Systems-Wide Differential Signaling Induced by Small Molecule PP2A Activation [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1511288772792226

    APA Style (7th edition)

  • Wiredja, Danica. Phosphoproteomic Characterization of Systems-Wide Differential Signaling Induced by Small Molecule PP2A Activation. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1511288772792226.

    MLA Style (8th edition)

  • Wiredja, Danica. "Phosphoproteomic Characterization of Systems-Wide Differential Signaling Induced by Small Molecule PP2A Activation." Doctoral dissertation, Case Western Reserve University. Accessed JULY 23, 2025. http://rave.ohiolink.edu/etdc/view?acc_num=case1511288772792226

    Chicago Manual of Style (17th edition)