Greatwall promotes cell transformation by hyperactivating AKT in human malignancies
- Université de Montpellier, France
- Université Bordeaux Segalen, France
- Institut de Recherche en Cancérologie de Montpellier, France
Abstract
The PP2A phosphatase is often inactivated in cancer and is considered as a tumour suppressor. A new pathway controlling PP2A activity in mitosis has been recently described. This pathway includes the Greatwall (GWL) kinase and its substrates endosulfines. At mitotic entry, GWL is activated and phosphorylates endosulfines that then bind and inhibit PP2A. We analysed whether GWL overexpression could participate in cancer development. We show that GWL overexpression promotes cell transformation and increases invasive capacities of cells through hyperphosphorylation of the oncogenic kinase AKT. Interestingly, AKT hyperphosphorylation induced by GWL is independent of endosulfines. Rather, GWL induces GSK3 kinase dephosphorylation in its inhibitory sites and subsequent SCF-dependent degradation of the PHLPP phosphatase responsible for AKT dephosphorylation. In line with its oncogenic activity, we find that GWL is often overexpressed in human colorectal tumoral tissues. Thus, GWL is a human onocoprotein that promotes the hyperactivation of AKT via the degradation of its phosphatase, PHLPP, in human malignancies.
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Animal experimentation: All animal experiments conformed to the relevant regulatory standards and were approved by the Ethics Local Committee of the IRCM (Institut de Recherche en Cancérologie de Montpellier) and by the Regional Ethic Commitée of the "Languedoc Roussillon"(France). Ref: 1137.
Human subjects: Human Samples for TMA:Cases were issued from the archives of the Department of Pathology of Bergonie Institute (Bordeaux, France). For all samples, ethical approval was obtained from the appropriate committees. Cases were then centralised in the Biological Resources Center of Bergonie Institute, which has received the agreement from the French authorities to deliver samples for scientific research (AC-2008-812)."The TMA used in this study has been moreover used in three other published studies (See: Soubeyran and al., Am J of Pathology 2011, Rey and al., Cell Cycle 2013 and Oncogene 2015).For colorectal tumour samples used for western blot:The study was approved by the ICM CORT (Translational Research Committee) ethical committee and all participating patients were informed of the study and provided their signed written informed consent before enrolment. This set of samples were already used in Del Rio et al., JCO 2007 and Del Rio et al, Plos one 2013.
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© 2015, Vera et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Greatwall promotes cell transformation by hyperactivating AKT in human malignancies
eLife 4:e10115.
https://doi.org/10.7554/eLife.10115
