Abstract
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.
Highlights
Protein phosphorylation plays a regulatory role in most biological processes and dysregulation of protein phosphorylation contributes to many diseases
Through mass spectrometry analysis of the phosphopeptides altered across these conditions, we identified 6025 phosphopeptides corresponding to 2428 individual proteins reproducibly detected in two replicate experiments
In consonance with previous studies (Ratcliffe et al, 2000; Kuo et al, 2008), we observed an increase in phosphorylation of direct or indirect targets of PP2A, including AKT1S and b-catenin (CTNNB1) in cells which were transformed by either expressing Small T antigen (ST) or partial knockdown of PP2A Ca subunit in Human embryonic kidney (HEK) TER cells (Figure 1B) (Sablina et al, 2010)
Summary
Protein phosphorylation plays a regulatory role in most biological processes and dysregulation of protein phosphorylation contributes to many diseases. Both kinases and phosphatases have been implicated in the pathogenesis of specific cancers, and several small molecule kinase inhibitors are. Two sets of enzymes – called kinases and phosphatases – contribute to this balance. Kinases “switch on” other proteins by tagging them with a phosphate molecule. Phosphatases, on the other hand, dephosphorylate these proteins, switching them off. Cancer cells often have mutations that activate kinases to drive cancer growth. One major hurdle in this research is that it is not always clear how they recognize the proteins they dephosphorylate
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