hyperactivating AKT in human malignancies

25 26 The PP2A phosphatase is often inactivated in cancer and is considered as a tumour suppressor. A new 27 pathway controlling PP2A activity in mitosis has been recently described. This pathway includes the 28 Greatwall (GWL) kinase and its substrates endosulfines. At mitotic entry, GWL is activated and 29 phosphorylates endosulfines that then bind and inhibit PP2A. We analysed whether GWL 30 overexpression could participate in cancer development. We show that GWL overexpression promotes 31 cell transformation and increases invasive capacities of cells through hyperphosphorylation of the 32 oncogenic kinase AKT. Interestingly, AKT hyperphosphorylation induced by GWL is independent of 33 endosulfines. Rather, GWL induces GSK3 kinase dephosphorylation in its inhibitory sites and 34 subsequent SCF-dependent degradation of the PHLPP phosphatase responsible for AKT 35 dephosphorylation. In line with its oncogenic activity, we find that GWL is often overexpressed in 36 human colorectal tumoral tissues. Thus, GWL is a human onocoprotein that promotes the 37 hyperactivation of AKT via the degradation of its phosphatase, PHLPP, in human malignancies.