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Mechanisms Governing the Tumor Suppressive Functions of the A-alpha Subunit of Protein Phosphatase 2A

O'Connor, Caitlin M
http://rave.ohiolink.edu/etdc/view?acc_num=case1560175638682868

Abstract Details

2019, Doctor of Philosophy, Case Western Reserve University, Pharmacology.
Cellular signaling through reversible phosphorylation is an essential process of communication which allows cells to identify and respond to their microenvironment and is coordinated in a manner regulated both in time and space. This process is balanced by the opposing actions of phosphatases and kinases. Highlighting the importance of maintaining balanced cellular signaling, altered cellular signaling is dysregulated is multiple disease contexts. In particular, one of the hallmarks of cancer is sustained proliferative signaling, often through the dysregulation of phosphorylation. Work completed over the past several years has shown an important role for phosphatases in cellular transformation and disease progression. In particular, Protein Phosphatase 2A (PP2A) functions as a tumor suppressor by negatively regulating multiple oncogenic signaling pathways responsible for driving cancer progression. The canonical PP2A holoenzyme is comprised of a scaffolding subunit (PP2A A-alpha/beta), which serves as the platform for the binding of both the catalytic C subunit and one regulatory B subunit. While it has been established the PP2A holoenzyme and the A-alpha scaffold have tumor suppressive functions, the mechanisms responsible for these activities had not been well explored. The research presented in this dissertation sought to provide insight into the mechanisms of the tumor suppressive functions of the PP2A A-alpha scaffolding subunit by studying how mutations and deletions of this protein affect function. We showed how the most recurrent PP2A A-alpha mutation, R183W, altered holoenzyme formation, the downstream consequences on cellular signaling and decreased response to MEK inhibitors. Additionally, we investigated the functional consequences of homozygous deletion of the A-alpha subunit and identified that complete deletion of A-alpha is not tumor suppressive due to a compensatory upregulation of the A-beta scaffolding subunit. Collectively, these studies offer unique insight into the mechanisms inactivating PP2A A-alpha in patient tumors and provide an understanding of the essential nature of PP2A signaling in cellular homeostasis.
Goutham Narla (Advisor)
Jason Mears (Committee Chair)
Ruth Keri (Committee Member)
Mark Jackson (Committee Member)
Derek Taylor (Committee Member)
186 p.
Oncology; Pharmacology
cancer biology, phosphatase, protein phosphatase 2A, cellular signaling

Recommended Citations

Citations

  • O'Connor, C. M. (2019). Mechanisms Governing the Tumor Suppressive Functions of the A-alpha Subunit of Protein Phosphatase 2A [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1560175638682868

    APA Style (7th edition)

  • O'Connor, Caitlin. Mechanisms Governing the Tumor Suppressive Functions of the A-alpha Subunit of Protein Phosphatase 2A. 2019. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1560175638682868.

    MLA Style (8th edition)

  • O'Connor, Caitlin. "Mechanisms Governing the Tumor Suppressive Functions of the A-alpha Subunit of Protein Phosphatase 2A." Doctoral dissertation, Case Western Reserve University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=case1560175638682868

    Chicago Manual of Style (17th edition)

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© 2019, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.