Disease relevance of PPP2R4

• We provide here biochemical and functional evidence demonstrating that human immunodeficiency virus type 1 (HIV-1) Vpr mediates G(2) arrest by forming a complex with protein phosphatase 2A (PP2A), an upstream regulator of cdc25 [1].
• Recent studies with DNA viruses have contributed to our understanding of critical tumor targets (such as EGFR, PP2A, Rb and p53) and have an impact on the development of novel therapies, including oncolytic viral agents, for the treatment of cancer [2].
• Using baculovirus recombinants expressing individual PP2A subunits, we show that the dephosphorylation of furin in vitro requires heterotrimeric phosphatase containing B family regulatory subunits [3].
• The glycine 90 to aspartate alteration in the Abeta subunit of PP2A (PPP2R1B) associates with breast cancer and causes a deficit in protein function [4].
• Adenovirus E4orf4 protein induces PP2A-dependent growth arrest in Saccharomyces cerevisiae and interacts with the anaphase-promoting complex/cyclosome [5].

Psychiatry related information on PPP2R4

• The activity of protein phosphatase-2A (PP2A) is compromised and is believed to be a cause of the abnormal hyperphosphorylation of tau in Alzheimer's disease (AD) brain [6].
• We have attempted to determine the effects of electroconvulsive shock (ECS) on protein phosphatase 2A (PP2A) in the frontal cortices of rats [7].

High impact information on PPP2R4

• Because the only known targets of okadaic acid are the catalytic subunits PP1 and PP2A, these enzymes are crucial components of two basic functions carried out by cells: growth and division [8].
• We show here that DNA-responsive checkpoints also activate PP2A/B56delta phosphatase complexes to dephosphorylate Cdc25 at a site distinct from Ser287 (T138), the phosphorylation of which is required for 14-3-3 release [9].
• The serine/threonine phosphatase protein phosphatase 2A (PP2A) plays an essential role in many aspects of cellular functions and has been shown to be an important tumor suppressor [10].
• Here we report the crystal structures of the PP2A core enzyme bound to two of its inhibitors, the tumor-inducing agents okadaic acid and microcystin-LR, at 2.6 and 2.8 A resolution, respectively [10].
• Role for the PP2A/B56delta Phosphatase in Regulating 14-3-3 Release from Cdc25 to Control Mitosis [9].

Chemical compound and disease context of PPP2R4

• Caveolin-1 maintains activated Akt in prostate cancer cells through scaffolding domain binding site interactions with and inhibition of serine/threonine protein phosphatases PP1 and PP2A [11].
• We report that the small tumor (small-t) antigen of simian virus 40 (SV40) forms complexes with nuclear protein phosphatase 2A (PP2A) and regulates the phosphorylation and transcriptional transactivation function of the cyclic AMP (cAMP)-regulatory element binding protein (CREB) [12].
• Thus, endothall inhibits preferentially HCC growth and these new rat hepatocellular carcinoma lines may be useful for further biochemical and pharmacological studies on PP2A inhibitors, and for testing new forms of treatment of hepatic cell carcinomas [13].
• First, cell treatment with two phosphatase inhibitors, okadaic acid and calyculin A, prevented the hypophosphorylation of the retinoblastoma family proteins, at concentrations that specifically inhibit PP2A [14].
• Fostriecin, a PP2A inhibitor which has been used as an antineoplastic agent in clinical trials, is also able to inhibit PMA-stimulated HIV-1 proviral activation [15].

Biological context of PPP2R4

• Protein phosphatase 2A (PP2A) is a ubiquitously expressed member of the serine-threonine phosphatase family that is involved in regulation of many cellular processes including transcription, translation, cellular metabolism, and apoptosis [16].
• Carboxymethylation affects PP2A activity and varies during the cell cycle [17].
• Here, we report that substitution of glutamine for either of two putative active site histidines in the PP2A C subunit results in inactivation of PP2A and formation of stable complexes between PP2A and several cellular proteins [17].
• ER promoter studies showed that regulation of ER through the PP2A pathway did not occur through transcriptional activation [16].
• By testing OA for human cancer cell lines that express different types of ErbB receptors, we found that ErbB4 receptor expression was accompanied with positive regulation of PP2A for phosphorylation of Shc Tyr317 and its downstream ERK phosphorylation in MCF-7 and SK-OV-3 cell lines, but not in LNCaP and PC-3 cells [18].

Anatomical context of PPP2R4

• Accordingly, basal PP2A contributed to the phosphorylation of Shc Tyr317 in ErbB4 expressing CHO cells, nevertheless it had been reported that PP2A negatively regulates Shc tyrosine phosphorylation in the EGF- or IGF-I-induced signalling pathways [18].
• High levels of PTPA mRNA were detected in testis, which contrasted with the low levels present in skeletal muscle [19].
• In contrast, antibodies directed against bacterially expressed PP2A were not specifically localized to centrosomes [20].
• Regulation of endosome sorting by a specific PP2A isoform [3].
• We now show that cyclin G2 and PP2A colocalize at MTOCs in transfected cells and that the endogenous proteins copurify with isolated centrosomes [21].

Associations of PPP2R4 with chemical compounds

• Earlier, we demonstrated that okadaic acid (OA), an inhibitor of a serine/threonine phosphatase PP2A, stimulated the growth hormone-induced ERK phosphorylation in the wild type Chinese hamster ovary (CHO) cells and the cells expressing ErbB1 receptor, but suppressed ERK activation in CHO cells that express ErbB4 receptor [18].
• Using pNPP as substrate, PP6 and PP2A gave the same IC(50) with active site inhibitors okadaic acid, microcystin-LR, calyculin A, and cantharidin [22].
• Protein Ser/Thr phosphatases compose a PPP family that includes type-2 PP2A, PP4, and PP6, each with essential functions [23].
• Counteracting the promodulatory actions of HDL and estrogen, C-reactive protein (CRP) antagonizes eNOS through FcgammaRIIB and PP2A, which dephosphorylates and inactivates the enzyme [24].
• Protein phosphatase 2A (PP2A) is one kind of serine/ threonine protein phosphatase regulating mainly cell growth and division [25].

Physical interactions of PPP2R4

• The ability of cyclin G2 to inhibit cell cycle progression correlates with its ability to bind PP2A/B' and C subunits [26].
• The increased PP2A activity was accompanied by decreased phosphorylation of eukaryotic initiation factor 4E-binding protein (4E-BP1) but had no effect on Stat phosphorylation [27].

Enzymatic interactions of PPP2R4

• Our data suggest that Vpr mediates G(2) arrest by enhancing the nuclear import of PP2A and by positively modulating its catalytic activity towards active phosphorylated nuclear cdc25 [1].

Co-localisations of PPP2R4

• Notably, cyclin G2 colocalizes with both PP2A/C and B' subunits in detergent-resistant cellular compartments, suggesting that these complexes form in living cells [26].

Regulatory relationships of PPP2R4

• Thus, PP2A regulates the ERK activity in a cell-specific manner, and it is speculated that distinct regulation of PP2A in the ErbB4 receptor signalling pathway may cause a difference in progression of cancer phenotypes [18].
• These two genes may be part of the uncharacterized pathway for Vpr-induced G2 arrest in which Vpr upregulates PP2A to activate Wee1 and inhibit Cdc25 [28].

Other interactions of PPP2R4

• Together, our findings suggest that cyclin G2-PP2A complexes inhibit cell cycle progression [26].
• These data suggest a novel pathway controlling ER expression resulting from the activation of PP2A, potentially providing a novel therapeutic target [16].
• Mutations of the PPP2R1B gene, which encodes the Abeta scaffolding subunit of serine/threonine protein phosphatase 2A (PP2A), have been identified in several types of cancer including lung and breast carcinoma [4].
• SCA12 is associated with an expansion of a CAG repeat in the 5' region of the gene PPP2R2B which encodes a brain-specific regulatory subunit of the protein phosphatase PP2A [29].
• However, PPX did not bind the 65 kDa regulatory subunit of PP2A [20].

Analytical, diagnostic and therapeutic context of PPP2R4

• Molecular cloning, expression, and characterization of PTPA, a protein that activates the tyrosyl phosphatase activity of protein phosphatase 2A [19].
• By fluorescence in situ hybridization and G-banding, the PTPA gene was localized to the 9q34 region [30].
• As revealed by nested PCR, all these PTPA transcripts are expressed in various human cDNA libraries and cell lines [31].
• RT-PCR and Northern blotting revealed that all isoforms of PP1 and PP2A presently known are expressed in the human heart [32].
• PP2A multiple forms (2A0, 2A1, 2A2), separated by DEAE-cellulose chromatography and immunoblot analysis of PP2A catalytic subunit, also showed similar differences in these two HBC cell types [33].

References