Keywords
PTOV1, oncoprotein, prostate cancer, 14-3-3 protein, SGK2 phosphorylation, protein-protein interactions, cell proliferation, cancer progression, proteasomal degradation, E3 ubiquitin ligase (HUWE1), cytosolic sequestration, cJun expression, cell-cycle regulation
Abstract
PTOV1 is an oncogenic protein, initially identified in prostate cancer, that promotes proliferation, cell motility, and invasiveness. However, the mechanisms that regulate PTOV1 remain unclear. Here, we identify 14-3-3 as a PTOV1 interactor and show that high levels of 14-3-3 expression, like PTOV1, correlate with prostate cancer progression. We discover an SGK2-mediated phosphorylation of PTOV1 at S36, which is required for 14-3-3 binding. Disruption of the PTOV1–14–3-3 interaction results in an accumulation of PTOV1 in the nucleus and a proteasome-dependent reduction in PTOV1 protein levels. We find that loss of 14-3-3 binding leads to an increase in PTOV1 binding to the E3 ubiquitin ligase HUWE1, which promotes proteasomal degradation of PTOV1. Conversely, our data suggest that 14-3-3 stabilizes PTOV1 protein by sequestering PTOV1 in the cytosol and inhibiting its interaction with HUWE1. Finally, our data suggest that stabilization of the 14-3-3–bound form of PTOV1 promotes PTOV1-mediated expression of cJun, which drives cell-cycle progression in cancer. Together, these data provide a mechanism to understand the regulation of the oncoprotein PTOV1.
Original Publication Citation
Pennington KL, McEwan CM, Woods J, Muir CM, Pramoda Sahankumari AG, Eastmond R, Balasooriya ER, Egbert CM, Kaur S, Heaton T†, McCormack KK, Piccolo SR, Kurokawa M, Andersen J. SGK2, 14-3-3, and HUWE1 Cooperate to Control the Localization, Stability, and Function of the Oncoprotein PTOV1. Molecular Cancer Research, 2021
BYU ScholarsArchive Citation
Pennington, Katie L.; McEwan, Colten M.; Woods, James; Muir, Colin M.; Sahankumari, A.G. Pramoda; Eastmond, Riley; Balasooriya, Eranga R.; Egbert, Christina M.; Kaur, Sandeep; Heaton, Tyler; McCormack, Katherine K.; Piccolo, Stephen R.; Kurokawa, Manabu; and Andersen, Joshua L., "SGK2, 14-3-3, and HUWE1 Cooperate to Control the Localization, Stability, and Function of the Oncoprotein PTOV1" (2022). Faculty Publications. 7485.
https://scholarsarchive.byu.edu/facpub/7485
Document Type
Peer-Reviewed Article
Publication Date
2022-02-01
Publisher
American Association for Cancer Research
Language
English
College
Life Sciences
Department
Biology
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