Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.21.4 (trypsin)
42,187 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have examined the levels of gene expressions and activities of protein phosphatases, PP1 and PP2A, in rat regenerating livers. PP1 alpha mRNA started to increase from 6 h after partial hepatectomy (PH) and showed two peaks at 12 and 48 h. PP2A mRNA level showed two peaks at 6 and 10-12 h. Protein phosphatase activities were determined both in non-nuclear fraction and in nuclei. While spontaneous PP1 activity in non-nuclear fraction was nearly constant, potential PP1 activity revealed by Co(2+)-trypsin treatment showed a small peak between 7 and 12 h. In nuclei, both spontaneous and potential PP1 activity began to increase from 4-7 h after PH, reached a maximum (about 2.5-fold over control levels) at 12 h, the time which corresponds to the G1 to S transition in the cell cycle, and then declined back to control levels by 7 days. PP2A activity in non-nuclear fraction was nearly constant in both spontaneous and potential forms. PP2A activity in both forms in nuclei was very low throughout. These results suggest the possibility that PP1 in nuclei plays some role in the G1 to S transition in the cell cycle of hepatocyte proliferation.
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PMID:Gene expressions and activities of protein phosphatases PP1 and PP2A in rat liver regeneration after partial hepatectomy. 131 42

The differential assay conditions for protein phosphatases PP1, PP2A, and PP2C were extensively studied by using crude extracts from mouse lymphoid tissues as enzyme sources. Under these conditions, the protein phosphatase activities were measured in MRL/MpJ-lpr/lpr mice (MRL/lpr mice), autoimmune-prone mice, and MRL/MpJ(-)+/+ mice (MRL/+/+ mice) and C3H/HeJ mice as the controls. In MRL/lpr mice, significant alterations in protein phosphatase activities from those in the control mice were demonstrated. In spleen and liver from MRL/lpr mice, potential activities of PP1 and PP2A were distinctly elevated over those of the control mice. These elevations appeared to be due to accumulation of the abnormal lymphocytes that emerged in MRL/lpr mice. Although the PP1 activity in MRL/lpr lymph nodes was lower than those of normal spleen and thymus, it was greatly increased by Co(2+)-trypsin treatment so that the PP1 activity of MRL/lpr lymph nodes was the highest among those of all the tissues examined. In contrast, PP2C activity showed no remarkable alteration in the autoimmune disease model mice as compared with that in the control mice. These results demonstrated a specific elevation in potency of protein dephosphorylation in the tissues of MRL/lpr mice, suggesting a new explanation for the defect in signal transduction in this disease.
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PMID:Increase in potential activities of protein phosphatases PP1 and PP2A in lymphoid tissues of autoimmune MRL/MpJ-lpr/lpr mice. 131 90

Neoplastic alterations of type 1 alpha protein phosphatase (PP1 alpha) have been studied in rat ascites hepatoma cells, using regenerating liver after partial hepatectomy and normal rat liver as controls. In the particulate fraction of hepatomas, potential PP1 activity and the amount of PP1 alpha were remarkably increased compared with either regenerating or normal livers. In the nuclear fraction, PP1 activity and the amount of PP1 alpha were increased in hepatoma compared with the controls. The nuclear PP1 activity in hepatomas was activated by treatment with CO2+/trypsin, whereas that of normal or regenerating liver was not activated. These characteristic alterations of PP1 alpha in its amount and subcellular distribution may be implicated in malignant phenotype(s) such as uncontrolled cell growth.
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PMID:Neoplastic alterations in subcellular distribution of type 1 alpha protein phosphatase in rat ascites hepatoma cells. 763 44

In the IL-2-dependent murine cytotoxic T cell line CTLL-2, IL-2 induced a rapid and transient decrease in Co(2+)-trypsin-treated activity of protein phosphatase PP1. The PP1 activity declined to a minimum level, being 70% of control value, in 20 min after the addition of IL-2 but recovered to the control level within 45 min. The decrease of PP1 activity was dependent on IL-2 concentration and occurred specifically in cytosolic fraction. Similar alteration was observed in IL-2 sensitive murine T-lymphoblasts. Neither activity of protein phosphatase PP2A nor PP2C showed alteration during the IL-2 stimulation. These results suggest that PP1 plays an important role in early events of the intracellular growth signaling from the IL-2 receptor.
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PMID:IL-2 induces transient and specific decrease in cytosolic protein phosphatase PP1 activity in murine T cell lines. 839 34

Activities of protein phosphatases PP1 and PP2A were determined in T and B lymphocytes of autoimmune-prone MRL/MpJ-lpr/lpr mice (MRL/lpr mice) and two control strains, MRL/MpJ-(+)/+ mice (MRL/+/+ mice) and C3H/HeJ mice. Potential PP1 activity, which was measured after treatment of cell extract with Co(2+)-trypsin, was much higher in T lymphocytes than B lymphocytes. However, no difference in the activity was observed between MRL/lpr mice and the controls. Spontaneous PP2A activity showed similar levels in T and B lymphocytes from normal mice, but potential PP2A activity, which was measured after treatment with 2-mercaptoethanol, was significantly higher in T lymphocytes from MRL/lpr mice than those from controls. No differences were detected in PP1 or PP2A activities in B lymphocytes. From these results, our previous data [Matsuzawa, S. et al. (1992) J. Biochem. 111, 472-477] demonstrating increases in potential activities of PP1 and PP2A in lymphoid tissues from autoimmune MRL/lpr mice can be interpreted as follows. 1) The increase in potential PP1 activity of the lymphoid tissues from MRL/lpr mice is caused by replacement of B lymphocytes by abnormal T lymphocytes, which accumulate in enormous numbers. 2) The increase of potential PP2A activity in the lymphoid tissues from MRL/lpr mice is caused by the increase in this activity in their T lymphocytes.
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PMID:Alterations in activities of protein phosphatases PP1 and PP2A in T and B lymphocytes of autoimmune MRL/MpJ-lpr/lpr mice. 840 76

The protein phosphatase encoded by coliphage lambda (PPlambda) was found to be the equivalent of the minimal catalytic core of serine/threonine protein phosphatases (PP) by biochemical and mutational criteria. Bacterially expressed truncated versions of PP1 and PP5 phosphatases, representing the catalytic cores homologous to PPlambda, exhibited potent phosphatase activity. Unlike full-length PP1, but like PPlambda, the recombinant cores could use casein, p-nitrophenyl phosphate, and a wide variety of peptides as substrates and were resistant to okadaic acid, microcystin-LR, and trypsin. Mutations of His173, Asp208, or Arg221 had little effect on the activity of the PP1 core protein, indicating its closer identity with PPlambda than with full-length PP1. Terminal deletions of a few amino acids of the cores destroyed their activity, supporting their minimal nature. Analysis of PPlambda mutants suggested an influence of the substrate on metal ion binding. The minimal length of a phosphopeptide substrate of PPlambda appeared to be a phosphorylated serine/threonine flanked by 1 or 2 amino acid residues on either side, the N-terminal ones being more effective.
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PMID:Interactions between a minimal protein serine/threonine phosphatase and its phosphopeptide substrate sequence. 879 96

Type 1 protein phosphatase (PP1) is a negative regulator of cardiac function. However, studies on the status and regulation of sarcoplasmic reticulum (SR)-associated PP1 activity in failing hearts are limited. We studied PP1 activity and protein and mRNA expression of the catalytic subunit of PP1 (PP1C) and protein levels of PP1-specific inhibitors [inhibitor 1 (Inh-1) and inhibitor 2 (Inh-2)] in the left ventricular (LV) myocardium of 6 dogs with heart failure (HF; LV ejection fraction, 23 +/- 2%) and 6 normal dogs. In failing LV tissue, PP1 activity values (expressed as pmol 32P. min-1. mg of noncollagen protein-1) in the homogenate, crude membranes, cytosol, and purified SR were increased by 52, 54, 55, and 72%, respectively. Trypsin treatment released PP1 but not type 2A protein phosphatase from the SR. In the supernatant of trypsin-treated SR, PP1 activity was approximately 24% higher in failing hearts than in normal control hearts. A similar increase in protein expression of PP1C was observed in the nontrypsinized SR. Heat-denatured phosphorylated SR inhibited PP1 activity by 30%, which suggests the presence of Inh-1 or -2 or both in the SR. With the use of a specific antibody, both Inh-1 and -2 proteins were found in the SR; the former was decreased by 56% in the failing SR, whereas the latter did not change. These results suggest that protein phosphatase activity bound to the SR is increased and is predominantly type 1. Increased SR-associated PP1 activity in failing hearts appears to be due partly to increased expression of PP1C and partly to reduced levels of Inh-1 but not Inh-2 protein. Thus inhibition of PP1 activity in the SR appears to be a potential therapeutic target for improving LV function in failing hearts, because it may lead to increased SR Ca2+ uptake, which is impaired in failing hearts.
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PMID:Cardiac SR-coupled PP1 activity and expression are increased and inhibitor 1 protein expression is decreased in failing hearts. 1461 11

Many toxins from viperid venoms have been characterised as powerful activators of platelets. Here, the venom from the East African Lowland viper, Proatheris superciliaris, was investigated for its effect on platelets and the coagulation system. Whole P. superciliaris venom stimulated platelet shape change and aggregation; however, the stimulation of platelet activation was unaffected by the structurally distinct Src family kinase inhibitors PP1 and PD0173952, suggesting that platelet activation was mediated by a G protein-coupled receptor. A platelet reactive 34-kDa protein was isolated from P. superciliaris venom which we have designated proatherocytin. This protein induced Src kinase-independent aggregation of both human and mouse platelets that was inhibited by the serine protease inhibitor AEBSF. Proatherocytin did not clot bovine or human fibrinogen, degrade fibrinogen or hydrolyse the serine protease substrate benzoyl-FVR-pNA. It activated human PAR1 on stably transfected rat kidney epithelial cells, whereas no activation of the trypsin receptor PAR2 was shown. Surprisingly, Edman degradation of proatherocytin revealed sequence identity with existing disintegrin-like domains of snake venom metalloproteinases. These results suggest that proatherocytin is a highly selective PAR1 agonist that also causes mouse platelet aggregation, probably through cleavage of PAR4.
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PMID:Characterization of a novel protein from Proatheris superciliaris venom: proatherocytin, a 34-kDa platelet receptor PAR1 agonist. 1611

We evaluated the ability of different trypsin-revealed tethered ligand (TL) sequences of rat proteinase-activated receptor 2 (rPAR(2)) and the corresponding soluble TL-derived agonist peptides to trigger agonist-biased signaling. To do so, we mutated the proteolytically revealed TL sequence of rPAR(2) and examined the impact on stimulating intracellular calcium transients and mitogen-activated protein (MAP) kinase. The TL receptor mutants, rPAR(2)-Leu(37)Ser(38), rPAR(2)-Ala(37-38), and rPAR(2)-Ala(39-42) were compared with the trypsin-revealed wild-type rPAR(2) TL sequence, S(37)LIGRL(42)-. Upon trypsin activation, all constructs stimulated MAP kinase signaling, but only the wt-rPAR(2) and rPAR(2)-Ala(39-42) triggered calcium signaling. Furthermore, the TL-derived synthetic peptide SLAAAA-NH2 failed to cause PAR(2)-mediated calcium signaling but did activate MAP kinase, whereas SLIGRL-NH2 triggered both calcium and MAP kinase signaling by all receptors. The peptides AAIGRL-NH2 and LSIGRL-NH2 triggered neither calcium nor MAP kinase signals. Neither rPAR(2)-Ala(37-38) nor rPAR(2)-Leu(37)Ser(38) constructs recruited beta-arrestins-1 or -2 in response to trypsin stimulation, whereas both beta-arrestins were recruited to these mutants by SLIGRL-NH2. The lack of trypsin-triggered beta-arrestin interactions correlated with impaired trypsin-activated TL-mutant receptor internalization. Trypsin-stimulated MAP kinase activation by the TL-mutated receptors was not blocked by inhibitors of Galpha(i) (pertussis toxin), Galpha(q) [N-cyclohexyl-1-(2,4-dichlorophenyl)-1,4-dihydro-6-methylindeno[1,2-c]pyrazole-3-carboxamide (GP2A)], Src kinase [4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]-pyrimidine (PP1)], or the epidermal growth factor (EGF) receptor [4-(3'-chloroanilino)-6,7-dimethoxy-quinazoline (AG1478)], but was inhibited by the Rho-kinase inhibitor (R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide, 2HCl (Y27362). The data indicate that the proteolytically revealed TL sequence(s) and the mode of its presentation to the receptor (tethered versus soluble) can confer biased signaling by PAR(2), its arrestin recruitment, and its internalization. Thus, PAR(2) can signal to multiple pathways that are differentially triggered by distinct proteinase-revealed TLs or by synthetic signal-selective activating peptides.
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PMID:Agonist-biased signaling via proteinase activated receptor-2: differential activation of calcium and mitogen-activated protein kinase pathways. 1960 24

Microcystins (MCs) are cyanobacterial toxins that inhibit protein phosphatases 1 and 2A (PP1, PP2A) within an animal through both reversible and covalent interactions. Only MCs that have accumulated in animal tissue in reversible interactions are currently considered when estimating risk to higher trophic levels and humans through food web exposure. However, the majority of MCs is likely covalently bound to target proteins in tissues and these MCs are not quantified or included in these assessments. These covalently bound MCs may be made bioavailable in the digestive system of a consumer through the digestion of their attached protein phosphatase. Three common digestive enzymes, pepsin, chymotrypsin, and trypsin, did not digest cyclic MC-LR and MC-LY, but were very active against a control peptide with typical linkages and standard amino acids in "L" conformation, supporting the possibility for MC-peptide formation during gut passage. To test if digestion products could be biologically active in the consumer, four predicted MC-peptides were synthesized and assayed for activity against PP1 by the protein phosphatase inhibition assay (PPIA). All four MC-peptides were active against PP1 and comparably half (58%) as inhibitory as the parent toxin. This in vitro study demonstrated that MCs covalently bound to proteins may represent a reservoir of potential toxicity for consumers.
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PMID:Possible mechanism for the foodweb transfer of covalently bound microcystins. 2007 Oct 28


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