Select Stabilization of a Tumor-Suppressive PP2A Heterotrimer

Abstract

In cancer, suppression of protein phosphatases, such as protein phosphatase 2A (PP2A), that normally counteract kinases, contributes to aberrant signaling. Leonard et al. recently demonstrated that a novel small-molecule activator of PP2A, DT-061, selectively stabilizes a specific PP2A holoenzyme responsible for dephosphorylating critical oncogenic targets, including MYC. The 3.6-Å cryo-electron microscopy map of the heterotrimer assembly provides insight into the druggable structure of PP2A, guiding future phosphatase therapeutics.

Keywords: MYC; SMAP; cancer; phosphatase.

Figure 1.. Schematic Depicting Effects of DT-061 on Protein Phosphatase 2A (PP2A) and Its Regulation of c-MYC.

PP2A is a diverse family of heterotrimeric serine/threonine phosphatases containing distinct B subunits from one of four families, where a specific holoenzyme, PP2A-B56α, has an important role in regulating the MYC oncoprotein family. Depicted here, c-MYC is phosphorylated by enzymes, such as extracellular signal-regulated kinase (ERK), at the serine 62 position (pS62; black sphere), which in turn increases MYC protein stability and target gene activation. In cancer, downregulation of PP2A supports increased MYC activity (A). Leonard et al. [11] now show that DT-061, a small-molecule activator of PP2A (SMAP), selectively binds and stabilizes the PP2A-B56α holoenzyme (B). With DT-061, PP2A-B56α dephosphorylates S62-phosphorylated c-MYC to facilitate its inactivation via both immediate S62 dephosphorylation and S62 dephosphorylation subsequent to glycogen synthase kinase 3β (GSK3β)-mediated Threonine 58 phosphorylation (pT58; orange sphere). These regulated phosphorylation events trigger ubiquitin (pink spheres)-mediated degradation of MYC, promoting cellular homeostasis. Dotted lines denote that pathways are suppressed or inactivated, whereas thicker lines indicate increased activity. Figure created using BioRender (https://biorender.com/). Abbreviation: c-MYC, cellular MYC.