Disease relevance of Ppp1cc

• Thus HOX11 is a cellular oncogene that targets PP2A and PP1, both of which are targets for oncogenic viruses and chemical tumour promoters [1].
• Okadaic acid (70 nM), the inhibitor of protein phosphatases 1 and 2A (PP1/PP2A), and pertussis toxin (12.5 microg/ml), a G(i)-protein inhibitor, also showed similar effects [2].
• Their toxicity is associated with specific inhibition of intracellular protein phosphatases type-1 and type-2A (PP1 and PP2A, respectively) [3].
• In poorly differentiated hepatomas, however, only PP1 alpha mRNA was specifically increased, in contrast to PP2A and PP2C, which were at the control levels or below [4].
• To explore if protective effect of melatonin on oxidative stress induced by okadaic acid, an inhibitor of protein phosphatases PP1 and PP2A, is mediated by membrane receptors subtype mt1, we used an in vitro model with N1E-115 neuroblastoma cells [5].

High impact information on Ppp1cc

• HOX11 interacts with protein phosphatases PP2A and PP1 and disrupts a G2/M cell-cycle checkpoint [1].
• Protein dephosphorylation by phosphatase PP1 plays a central role in mediating the effects of insulin on glucose and lipid metabolism [6].
• Although phosphorylation is mediated by the kinase aurora, the dephosphorylation is due to the phosphatase PP1 [7].
• PP1 in cell lysates was separated by sequential affinity chromatography into at least two fractions, one bound specifically to thiophospho-CPI-17, and another bound specifically to inhibitor-2 [8].
• This binding was eliminated by addition of excess microcystin-LR to the lysate, showing that binding at the active site of PP1 is required [8].

Chemical compound and disease context of Ppp1cc

• The potency sequence of ETA > CA > endothall was established for the inhibition of PP1 and PP2A in vivo and shows close correlation with the sequence of relative toxicity [9].
• It is found that the replacement of the non-polar amino acid l-leucine at the second position of these heptacyclic peptide toxins by a polar l-arginine reduces their mouse toxicities and inhibitory activities against PP-1 and PP-2A to different extends [10].
• The loss of a methyl group on the common methylaspartic acid (MeAsp) at the third position of MC-FR, -WR, and -RR does not alter their toxicity levels, but dominantly reduces their activities in PP-1 inhibition compared to other substitutions or modifications [10].

Biological context of Ppp1cc

• Overexpression of the protein phosphatase 1 (PP1) subunit protein targeting to glycogen (PTG) markedly enhances cellular glycogen levels [11].
• Cumulatively, these data indicate that disruption of PTG expression resulted in the uncoupling of PP1 activity from glycogen metabolizing enzymes, the enhancement of glycogenolysis, and a dramatic decrease in cellular glycogen levels [11].
• Protein phosphatase-1 (PP1) catalytic subunit isoforms interact with diverse proteins, typically containing a canonical (R/K)(V/I)XF motif [12].
• Despite sharing approximately 90% amino acid sequence identity, PP1beta and PP1gamma1 have distinct subcellular localizations that may be determined by selective interactions with PP1-binding proteins [12].
• Type 1 protein phosphatases (PP1) are involved in diverse cellular activities, ranging from glycogen metabolism to chromatin structure modification, mitosis, and meiosis [13].

Anatomical context of Ppp1cc

• Identification of the spermatogenic zip protein Spz1 as a putative protein phosphatase-1 (PP1) regulatory protein that specifically binds the PP1cgamma2 splice variant in mouse testis [14].
• Here we demonstrate that fully grown germinal vesicle-intact (GVI) mouse oocytes contain mRNA corresponding to two isotypes of PP1, PP1alpha and PP1gamma [15].
• Finally, we found that SIPP1 is also a component of the spliceosomes and that a SIPP1-fragment inhibits splicing catalysis by nuclear extracts independent of its ability to interact with PP1 [16].
• We propose that CPI-17 binds at the PP1 active site where it is dephosphorylated, but association of MYPT1 with PP1C allosterically retards this hydrolysis, resulting in formation of a complex of MYPT1.PP1C.P-CPI-17, leading to an increase in smooth muscle contraction [8].
• PP1-R5/PTG, another glycogen targeted form of PP1, was not significantly stimulated by insulin in the skeletal muscle of WT mice but showed compensatory stimulation by insulin in G(M)(-/-) mice [17].

Associations of Ppp1cc with chemical compounds

• Okadaic acid (OA) enhances the resumption of meiosis in mouse oocytes, indicating that serine/threonine protein phosphatase-1 (PP1) and/or PP2A is involved [15].
• Calyculin A also caused a selective loss of Glu-MTs but was effective at 10 nM, consistent with its more potent inhibition of PP1 [18].
• Phosphorylation of CPI-17 in rabbit arteries was enhanced by calyculin A but not okadaic acid or fostriecin, consistent with PP1-mediated dephosphorylation [8].
• Conversely, BAD dephosphorylation was not inhibited by the PP1-selective inhibitor tautomycin [19].
• The phosphatase activity was inhibited by cyclosporin A (a calcineurin inhibitor) but not by okadaic acid (a PP1 and PP2A inhibitor) [20].

Enzymatic interactions of Ppp1cc

• These results suggest that the expressed PP2C alpha is phosphorylated by a casein kinase II-like protein kinase and dephosphorylated by PP1 and/or PP2A in COS7 cells [21].

Regulatory relationships of Ppp1cc

• Protein targeting to glycogen (PTG) enhances glycogen accumulation by increasing PP1 activity against glycogen-metabolizing enzymes [22].
• The expression and activity levels of protein phosphatase 2A (PP2A) and 2B (PP2B) but not protein phosphatase 1 (PP1) in P19 cells increased in accordance with the enhanced NF-L gene expression [23].
• The PP1-binding activity appears to be specific to cells that express the POMC gene because it was detected in nuclear extracts prepared from AtT20 corticotroph cells and mouse melanotroph tumours but not from GH4 pituitary tumour cells, HeLa cells or liver [24].
• Finally, PTG decreased the ability of DARPP-32 to inhibit PP1 activity from 3T3-L1 adipocyte lysates [25].

Other interactions of Ppp1cc

• In spleen and liver from MRL/lpr mice, potential activities of PP1 and PP2A were distinctly elevated over those of the control mice [26].
• However, specific identification of PP1 and/or PP2A in mouse oocytes has not been reported [15].
• We conclude that PP1 is a transcriptional activator for pituitary-specific POMC gene expression [24].
• However, tautomycin (PP1 inhibitor) and cyclosporin A (PP2B inhibitor) failed to alter CHT-mediated choline uptake [27].
• CPD1, affinity-purified using a chemically synthesized oligobody inhibits the activity of protein phosphatase PP2A but not protein phosphatase PP1 [28].

Analytical, diagnostic and therapeutic context of Ppp1cc

• Site-directed mutagenesis indicated that this isoform selectivity was not due to sequence differences between the canonical PP1-binding motifs (neurabin, (457)KIKF(460); G(M)/R(GL), (65)RVSF(68)) [12].
• This PP1 isoform selectivity was confirmed by immunoprecipitation of neurabin I and II from brain extracts from wild type and mutant PP1gamma null mice [29].
• In contrast, all compounds induced contraction and led to enhanced MLC(20)-phosphorylation in nominally Ca(2+)-free solution in fibers of mouse aorta permeabilised (skinned) with Triton X-100.In addition, Western blot analysis revealed that skinning of mouse aorta did not result in a loss of PP1 and PP2A compared to intact rings [30].
• Potential PP1 activity, which was measured after treatment of cell extract with Co(2+)-trypsin, was much higher in T lymphocytes than B lymphocytes [31].
• While PP1 activity in the non-nuclear fraction of partially hepatectomized livers was nearly constant, the activity in nuclei was increased about 2.5-fold over control levels at 12 h after partial hepatectomy, the time that corresponds to the G1 to S transition in the cell cycle of hepatocytes [4].

References