Title

Phosphatase: PP2A structural importance, regulation and its aberrant expression in cancer.

Journal

Cancer letters

Volume

335

Issue

None

Pages

9-18

Date

2013-07-10

Authors

Batra SK | Datta K | Pandey P | Seshacharyulu P

Potent tumor promoter, Okadaic acid (a microbial toxin), inhibits the enzymatic activity of PP2Ac and thereby has facilitated various studies to understand the functional aspects of PP2A and other phosphatases [12]. Other than Okadaic acid, calyculin A, microcystin, cantharidin, nodularm, fostriecin and tautomycin are able to inhibit PP2A activity at different IC50 values [48].

Recently, a major indirect activation of PP2A by inhibiting CIP2A at both the transcriptional and translational levels through the drug bortezomib was shown in triple negative breast cancer cells [50].

The isoform C α is predominantly expressed in the plasma membrane and C β in the cytoplasm and nucleus.

Intracellular localization of B56 isoforms vary, as B56 γ is expressed in the nucleus while B56 α , B56 β , and B56 ε are expressed in the cytoplasm, and PR61 δ appears to be expressed in both the nucleus and cytoplasm [20].

In neurons, B55 α and B55 β are localized in the cytoplasm, whereas B55 γ is localized in the cytoskeletal fraction.

In addition to microbial toxin, viral protein SV40 (potent oncogene) also inactivates PP2A action by binding to the AC dimer and displacing the PR56 (PP2A-B’ γ ) subunit [35].

PP2A also plays a major role in the Wnt signaling pathway.

In mammals, B55 is associated with cytoskeletal dynamics and nuclear translocation.

It is observed that the expression of B55 γ increases and B55 β decreases gradually after birth and are developmentally regulated [28].

In a typical cell, the functions of nearly one-third of the proteins are regulated via phosphorylation and it controls various biological functions like cell division, growth and development, survival, proliferation, and apoptosis.

During meiosis I, Shugoshins binds to PP2A and dephosphorylates cohesion, which prevents spindle microtubules disassembly [37]. PP2APR55 also dephosphorylates vimentin (intermediate filament) and protects cytoskeleton disassembly [38].

Methylation [52] and phosphorylation [53] are two major modifications that have been shown to modulate PP2A catalytic efficiency.

PP2A is an important player in many cellular functions. It controls cell metabolism by regulating the activity of the enzymes involved in glycolysis, lipid metabolism and catecholamine synthesis [8]. It also regulates various biological processes such as the cell cycle (by mediating cdc2 kinase activation), DNA replication, transcription and translation, signal transduction, cell proliferation, cytoskeleton dynamics and cell mobility and apoptosis. It has also been shown to play a role in cell transformation and cancer [9-12].

Co-immunoprecipitation and in-vitro pull down assay using pro-lymphoid FL5.12 cells showed a direct association of the PP2A-B55 holoenzyme with Akt, which selectively regulates phosphorylation of Akt at Thr-308 and regulates cell proliferation and survival [58].

PP2A is considered as a tumor suppressor and is thought to be functionally inactivated in cancer.

In Alzheimer's disease, inhibition of PP2A activity by SET leads to hyper phosphorylation of the Tau protein [47].

In Xenopus, PP2A- B56 is involved in β -catenin dephosphorylation and degradation and its phosphorylation directs activation of the Wnt pathway [43].

Phosphorylation of BAD suppresses, and its dephosphorylation by PP2A promotes pro-apoptotic activity [59]. Additionally, phosphorylation of Bcl-2 activates, and its dephosphorylation by PP2A suppresses anti- apoptotic activity.

This group also requires ATP and Mg2+ to activate its own activity.

Akt plays an important role in cell growth, proliferation and apoptosis.

Phosphorylation at Thr-308 and Ser-473 leads to activation of Akt and it was found that deregulation of Akt is associated with various human malignancies.

The addition of a methyl group by LCMT1 at L309 enhances the binding affinity of the core dimer (A&C subunit) toward distinct regulatory subunits and provides specific activity to the holoenzyme [56].

Phosphorylation of Y307 by receptor associated tyrosine kinases effectively decreases the PP2A activity by inhibiting the interaction of PP2Ac with the PP2A-PR55/PR61 subunit [54].

Endogenous CIP2A (cancerous inhibitor of PP2A) inhibits PP2Ac activity via interacting with c-Myc (Ser62) and stabilizes it from proteolytic degradation [49].

It has been shown in yeast that CDC55 (B55 in human) is essential for cytokinesis.

The phosphoprotein SET is a potent inhibitor of PP2A activity [45].

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