PubMed: 23454242

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

Evidence b148d81a96

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].

Evidence 2039ac73ed

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].

Evidence f9aa901d57

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

Evidence 9331280c98

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].

Evidence 59dae17ec5

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

Evidence 4b16780de3

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].

Evidence d1d297bc88

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

Evidence 9a3bf042b7

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

Evidence 87c7375bf6

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

Evidence 0e26f05c1c

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.

Evidence bf6a6e7c23

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].

Evidence 33f51678d7

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

Evidence 382e17ebb4

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].

Evidence 381c831f5b

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].

Evidence 3e3a8f755e

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

Evidence 888de6e065

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

Evidence a610030573

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

Evidence c94aff9cfe

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.

Evidence b55908081f

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

Evidence bf6254de8f

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

Evidence d7104b9831

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.

Evidence a14543e718

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].

Evidence 1f6f66718a

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].

Evidence 6e266b8bfd

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

Evidence a847e717d8

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

Evidence 5c6b132ee5

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

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