Biased holoenzyme assembly of protein phosphatase 2A (PP2A): From cancer to small molecules

Protein phosphatase 2A (PP2A) is a family of serine threonine phosphatases responsible for regulating protein phosphoryla-tion, thus opposing the activity of cellular kinases. PP2A is composed of a catalytic subunit (PP2A C alpha/beta) and scaffolding subunit (PP2A A alpha/beta) and various substrate-directing B regula-tory subunits. PP2A biogenesis is regulated at multiple levels. For example, the sequestration of the free catalytic subunit during the process of biogenesis avoids promiscuous phospha-tase activity. Posttranslational modifications of PP2A C direct PP2A heterotrimeric formation. Additionally, PP2A functions as a haploinsufficient tumor suppressor, where attenuated PP2A enzymatic activity creates a permissive environment for onco-genic transformation. Recent work studying PP2A in cancer showed that its role in tumorigenesis is more nuanced, with some holoenzymes being tumor suppressive, while others are required for oncogenic transformation. In cancer biology, PP2A function is modulated through various mechanisms including the displacement of specific B regulatory subunits by DNA tumor viral antigens, by recurrent mutations, and through loss of carboxymethyl-sensitive heterotrimeric complexes. In aggregate, these alterations bias PP2A activity away from its tumor suppressive functions and toward oncogenic ones. From a therapeutic perspective, molecular glues and disruptors present opportunities for both the selective stabilization of tumor -suppressive holoenzymes and disruption of holoenzymes that are pro-oncogenic. Collectively, these approaches represent an attractive cancer therapy for a wide range of tumor types. This review will discuss the mechanisms by which PP2A holoenzyme formation is dysregulated in cancer and the current therapies that are aimed at biasing heterotrimer formation of PP2A for the treatment of cancer.

Automated summary

Protein phosphatase 2A (PP2A) is an enzyme that regulates protein phosphorylation and has anti-cancer effects. In cancer, the activity and heterotrimer formation of PP2A are regulated by various mechanisms, which can bias its activity towards oncogenic functions. Therapeutic approaches such as molecular glues and disruptors can be used to treat cancer.