Disease relevance of PP2A

• When melanophores express the small t antigen of SV-40 virus, a specific inhibitor of protein phosphatase 2A (PP2A), aggregation is completely prevented [1].

High impact information on PP2A

• Therefore, melanosome aggregation is mediated by PP2A [1].
• Regulation of organelle movement in melanophores by protein kinase A (PKA), protein kinase C (PKC), and protein phosphatase 2A (PP2A) [1].
• Distinct roles of PP1 and PP2A-like phosphatases in control of microtubule dynamics during mitosis [2].
• The question as to whether chromosomal DNA replication also depends on PP2A was addressed by using a cell-free replication system derived from Xenopus laevis eggs [3].
• Importantly, the DSB-induced inhibition of Cdc45 loading is prevented by addition of the catalytic subunit of PP2A to the extract [4].

Chemical compound and disease context of PP2A

• Protein phosphatase 2A (PP2A) is an abundant, multifunctional serine/threonine-specific phosphatase that stimulates simian virus 40 DNA replication [3].

Biological context of PP2A

• We previously used a soluble cell-free system derived from Xenopus eggs to investigate the role of protein phosphatase 2A (PP2A) in chromosomal DNA replication [4].
• In the preactivation phase, PP2A inhibits the pathway leading to T161 phosphorylation, suggesting that this activity may be one of the rate-limiting events for transition [5].
• In contrast, small t antigen, an antagonist of PP2A-C, inhibited Dishevelled-mediated signal transduction, as did the regulatory PP2A-B'epsilon subunit, consistent with the requirement of PP2A function in this pathway [6].
• Protein phosphatase-2A (PP2A) is a multisubunit serine/threonine phosphatase involved in intracellular signaling, gene regulation, and cell cycle progression [6].
• INH, a type 2A protein phosphatase (PP2A), negatively regulates entry into M phase and the cyclin B-dependent activation of cdc2 in Xenopus extracts [5].

Anatomical context of PP2A

• The 65-kDa subunit of PP2A holoenzymes isolated from Xenopus skeletal muscle reacted with both anti-alpha and anti-beta PR65-specific antisera whereas the PP2A holoenzymes isolated from Xenopus oocytes reacted preferentially with the beta-specific antisera, indicating developmental changes in the expression of the 65-kDa subunit isoform [7].
• Using an oocyte cell-free system, we demonstrate that PP2A depletion is sufficient to lead to Cdc2 activation, whereas Aurora-A activation depends on Cdc2 activity [8].

Associations of PP2A with chemical compounds

• Remarkably, Aurora A that has been fully deactivated by Protein Phosphatase 2A (PP2A) becomes phosphorylated and reactivated by recombinant TPX2 in an ATP-dependent manner [9].
• Test of a PP2A-specific inhibitor, fostriecin, on cells arrested in G2/M via CRK depletion or a knockdown of the PP2A catalytic subunit from the CRK-depleted cells both showed a partial lift of the G2/M block without forming multinucleate cells [10].
• Altogether, our results show that the accumulation of inactive p34cdc2/cyclin B2 during the long-lasting prophase of the oocyte is positively controlled by PP2A through the tyrosine phosphorylation of p34cdc2 [11].
• Melatonin induces aggregation of the melanosomes to the cell centre through a G(i/o)-protein-coupled receptor, Mel1c, which leads to an inhibition of PKA and a stimulation of PP2A [12].
• When expressed ectopically in Xenopus oocytes, the B beta' isoform can augment the endogenous PP2A activity and inhibit oocyte maturation induced by progesterone [13].

Physical interactions of PP2A

• Different subunits of PP2A bind to Axin and Adenomatous Polyposis Coli, components of the Wnt signal transduction pathway [6].

Other interactions of PP2A

• Inhibition of cdc2 activation by INH/PP2A [5].
• Because previous work has suggested that PP2A can act upstream of beta-catenin, we propose that PP2A regulates the Wnt pathway at multiple levels [6].
• Our results suggest that although PP2A inhibits the switch in tyrosine kinase and tyrosine phosphatase activities accompanying mitosis, this switch is a consequence of the inhibition of some other rate-limiting event [5].
• Two major peaks of cdc25 dephosphorylating activities were detected during the sequential chromatography, one that copurified with the major peak of MPM-2 epitope phosphatase activity, and the other with the major peak of PP2A activity [14].

Analytical, diagnostic and therapeutic context of PP2A

• Although a role for PP2A in regulating G2/M has been suggested by studies in various systems, it is the relative simplicity of the in-vitro cell cycle extracts of Xenopus that has allowed the clearest dissection of the mechanism by which PP2A regulates this transition [15].
• Using a semi-quantitative immunological assay (Western blot), the in vivo concentration could be estimated to be micromolar, which is in the same range as the PP2A target [16].
• We therefore studied the effect of modulation of either PKC or protein phosphatases PP1alpha and PP2A on I(Cl(Ca)) stimulated either by lysophosphatidate (LPA) signaling or by microinjection of Ca [17].

References