ORCID ID
Graduation Date
Spring 5-9-2026
Document Type
Thesis
Degree Name
Master of Science (MS)
Programs
Cancer Research
First Advisor
Ying Yan
Abstract
Pancreatic cancer (PC) is an aggressive malignancy marked by delayed detection and poor prognosis, driven by signaling pathways regulated by both kinases and phosphatases. While kinase signaling in PC is well characterized, the equally critical roles of phosphatases remain underexplored. Protein phosphatase 2A (PP2A) is a heterotrimeric serine/threonine phosphatase composed of the scaffolding, catalytic, and regulatory subunits. The regulatory subunit determines cellular localization and substrate specificity. The PR55α regulatory subunit has been implicated in cell proliferation, cell cycle control, and apoptosis, in which evading cell death contributes to both oncogenesis and resistance to therapeutics.
Myeloid cell leukemia-1 (MCL-1), an anti-apoptotic protein upregulated in PC, promotes tumor cell survival and therapy resistance. MCL-1 stability is strongly influenced by phosphorylation at serine 159 (S159) promoting degradation and phosphorylation at threonine 163 (T163) promoting MCL-1 stability. Prior work suggests PP2A complexes may regulate these events; however, the exact molecular mechanism remains a gap in knowledge. This study investigates the role of PR55α-directed PP2A in the positive regulation of MCL-1 protein stability by dephosphorylating S159, thereby enhancing its anti-apoptotic function. A complementary axis was investigated in which PR61α, another PP2A regulatory subunit, is hypothesized to dephosphorylate MCL-1 at T163, leading to proteasomal degradation.
These findings support a working model in which PR55α enhances MCL-1 protein stability, while PR61α may function in opposition to limit this effect, together revealing a novel phosphatase-mediated mechanism regulating cell survival. Identifying the specific MCL-1 phosphorylation sites regulated by PP2A complexes containing PR55α or PR61α will further clarify the role of phosphatases in apoptotic signaling and may identify new therapeutic targets for pancreatic cancer treatments.
Rights
The author holds the copyright to this work and any reuse or permissions must be obtained from the author directly.
Recommended Citation
Jegadish, Sharon Krithi, "Antagonistic Regulation of MCL-1 Protein Stability by PR55α- and PR61α-Directed PP2A in Pancreatic Cancer" (2026). Theses & Dissertations. 1073.
https://digitalcommons.unmc.edu/etd/1073