Figure 9.

Proposed model for the negative regulation of anchorage-independent growth and survival by methylation-sensitive PP2A heterotrimers and the protransformation effects of reducing these heterotrimers by SVST expression, LCMT-1 knockdown, or PME-1 overexpression. Methylation of PP2Ac through LCMT-1 promotes incorporation of methylation-sensitive B-type subunits (B*) into heterotrimers that dephosphorylate and thereby inactivate Akt and S6K. PP2A methylation-sensitive heterotrimers can act on S6K in both an Akt-dependent and independent manner to block downstream survival and translation signals and thus transformation. PP2A methylation-sensitive heterotrimers also promote the dephosphorylation of rpS6 independently of S6K to block translation, although it is not known if this is a direct or indirect effect. Methylation-insensitive SVST (or PyST and PyMT) oncoprotein replaces methylation-sensitive B-type subunits, promoting transformation by preventing the dephosphorylation and inactivation of Akt and S6K. Transformation is also enhanced by reducing methylation-sensitive PP2A heterotrimers by inhibition of LCMT-1 (e.g., through shRNA or mutation) or PME-1 overexpression (PME-OE). For simplicity, only the targets of methylation-sensitive PP2A heterotrimers examined in this study are shown in this schematic.