Protein phosphatase 2A B56α holoenzyme (PP2A-B56α) (PP2A-B56α)

The Protein phosphatase 2A (PP2A) B56α holoenzyme is a heterotrimeric serine/threonine phosphatase complex consisting of a catalytic C subunit, a structural A subunit, and the specific B56α (PPP2R5A) regulatory subunit (O'Connor et al., 2020, J. Biol. Chem., PMID: 32694153). This specific holoenzyme acts as a critical tumor suppressor by dephosphorylating and inactivating key oncogenic drivers, most notably the transcription factor c-Myc at the Ser62 position, as well as components of the PI3K/Akt and MAPK/ERK pathways (Sangodkar et al., 2017, J. Clin. Invest., PMID: 28414302). In many cancers, PP2A activity is suppressed through the overexpression of endogenous inhibitors like SET or CIP2A, or through the downregulation of the B56α subunit itself (Westermarck & Hahn, 2008, Trends Mol. Med., PMID: 18929509). Therapeutic strategies focus on Small Molecule Activators of PP2A (SMAPs), such as DT-061, which selectively stabilize the B56α-containing holoenzyme to restore its phosphatase activity against oncogenic substrates (Leonard et al., 2020, Cell, PMID: 32302571). Beyond oncology, PP2A-B56α plays roles in regulating tau phosphorylation in Alzheimer's disease and maintaining cardiac homeostasis (Sontag & Sontag, 2014, World J. Biol. Chem., PMID: 25110551). However, the ubiquity of PP2A and the complexity of its subunit compositions present significant challenges for achieving high selectivity and avoiding systemic toxicity in drug development.

Other names

PPP2R5A-containing PP2A complexPP2A-B'alphaProtein phosphatase 2 regulatory subunit B' alpha holoenzymePP2A-B56-alpha

Allosteric activation and stabilization of the heterotrimeric PP2A-B56α complex to promote the dephosphorylation of specific oncogenic substrates such as c-Myc, Akt, and ERK.