STRIPAK directs PP2A activity toward MAP4K4 to promote oncogenic transformation of human cells

Alterations involving serine-threonine phosphatase PP2A subunits occur in a range of human cancers, and partial loss of PP2A function contributes to cell transformation. Displacement of regulatory B subunits by the SV40 Small T antigen (ST) or mutation/deletion of PP2A subunits alters the abundance and types of PP2A complexes in cells, leading to transformation. Here, we show that ST not only displaces common PP2A B subunits but also promotes A-C subunit interactions with alternative B subunits (B’’’, striatins) that are components of the Striatin-interacting phosphatase and kinase (STRIPAK) complex. We found that STRN4, a member of STRIPAK, is associated with ST and is required for ST-PP2A-induced cell transformation. ST recruitment of STRIPAK facilitates PP2A-mediated dephosphorylation of MAP4K4 and induces cell transformation through the activation of the Hippo pathway effector YAP1. These observations identify an unanticipated role of MAP4K4 in transformation and show that the STRIPAK complex regulates PP2A specificity and activity.


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eLife Sciences Publications, Ltd is a limited liability non-profit non-stock corporation incorporated in the State of Delaware, USA, with company number 5030732, and is registered in the UK with company number FC030576 and branch number BR015634 at the address Westbrook Centre, Milton Road Cambridge CB4 1YG, UK | March 2019 2 All assays unless indicated were performed in triplicates. Soft agar experiments were performed in triplicates, and the graphs are plotted based on the mean and standard error of these experiments, as indicated in the figure legends. In vivo tumor, formation assays were performed across five individual mice injected in three sites. In vitro kinase assays were performed in three replicates, except Figure 6B, which was performed as biological replicates with two independent experiments carried out by different individuals at different time points. iTRAQ Phosphoproteomic experiments were performed as two independent biological and technical replicate experiments. SILAC was performed as two biological replicates. MudPIT was performed once, as indicated in the figure, and the results were subsequently validated using Co-IP assays. RNAseq experiments were performed in triplicates, and both raw and processed data are available on GEO accession GSE118272.

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