Protein kinase signalling, which transduces external messages to mediate cellular growth and metabolism, is frequently deregulated in human disease, and specifically in cancer. As such, there are 77 kinase inhibitors currently approved for the treatment of human disease by the FDA. Due to their historical association as the receptors for the tumour-promoting phorbol esters, PKC isozymes were initially targeted as oncogenes in cancer. However, a meta-analysis of clinical trials with PKC inhibitors in combination with chemotherapy revealed that these treatments were not advantageous, and instead resulted in poorer outcomes and greater adverse effects. More recent studies suggest that instead of inhibiting PKC, therapies should aim to restore PKC function in cancer: cancer-associated PKC mutations are generally loss-of-function and high PKC protein is protective in many cancers, including most notably KRAS-driven cancers. These recent findings have reframed PKC as having a tumour suppressive function. This review focusses on a potential new mechanism of restoring PKC function in cancer — through targeting of its negative regulator, the Ser/Thr protein phosphatase PHLPP. This phosphatase regulates PKC steady-state levels by regulating the phosphorylation of a key site, the hydrophobic motif, whose phosphorylation is necessary for the stability of the enzyme. We also consider whether the phosphorylation of the potent oncogene KRAS provides a mechanism by which high PKC expression may be protective in KRAS-driven human cancers.
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January 2021
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High protein levels of protein kinase C confer a survival advantage in many cancers, including pancreatic cancer. In this issue, Tovell and Newton (pp. 341–355) review the mechanisms controlling the stability of protein kinase C, focusing on negative regulation by the phosphatase PHLPP as a potential strategy to restore protein levels of the kinase. Image provided by Hannah Tovell and was created with BioRender.com.
Review Article|
January 27 2021
PHLPPing the balance: restoration of protein kinase C in cancer
Hannah Tovell
;
Hannah Tovell
Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, U.S.A
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Alexandra C. Newton
Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, U.S.A
Correspondence: Alexandra C. Newton (anewton@health.ucsd.edu)
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Publisher: Portland Press Ltd
Received:
October 25 2020
Revision Received:
December 22 2020
Accepted:
January 04 2021
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2021 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2021
Biochem J (2021) 478 (2): 341–355.
Article history
Received:
October 25 2020
Revision Received:
December 22 2020
Accepted:
January 04 2021
Citation
Hannah Tovell, Alexandra C. Newton; PHLPPing the balance: restoration of protein kinase C in cancer. Biochem J 29 January 2021; 478 (2): 341–355. doi: https://doi.org/10.1042/BCJ20190765
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