Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The secretory and aggregation responses of stirred platelets exposed to complement proteins C5b-9 was investigated. C5b-9 assembly on the platelet surface resulted in the release of dense granule adenosine triphosphate (ATP) accompanied by a decrease in sample turbidity, but no detectable cell lysis. Inhibition of cellular protein kinase C completely blocked the C5b-9 initiated release of ATP, confirming the secretory nature of this response. Addition of fibrinogen (up to 1 mg/mL) had no effect on either the release of ATP or the decreased turbidity observed for C5b-9 cells. Addition of the peptides Arg-Gly-Asp-Ser (RGDS) and fibrinogen gamma-chain carboxyl-terminal (gamma 397-411) at concentrations sufficient to completely block fibrinogen binding to GP IIb-IIIa had no effect on either C5b-9 induced dense granule secretion or the associated turbidity change. Microscopic examination and electronic particle counting of the stirred platelet suspensions confirmed that no aggregation of C5b-9 platelets occurred even when these cells were stirred in the presence of fibrinogen. The capacity of the C5b-9 proteins to initiate platelet secretion without activation of cell surface glycoprotein (GP) IIb-IIIa suggests a mechanism for intravascular dissemination of activated platelets during complement activation in vivo.
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PMID:The secretory release reaction initiated by complement proteins C5b-9 occurs without platelet aggregation through glycoprotein IIb-IIIa. 291 85

Tumor-promoting phorbol esters are believed to affect cell functions by activating a Ca+2- and lipid-dependent protein kinase (protein kinase C). Since such protein kinases may be involved in ovarian granulosa cell metabolism, the effects of phorbol esters on prostaglandin (PG) and progesterone (P) accumulation were investigated. Cells were obtained from immature (28-29 days old) rats 48 h after injection of 20 IU PMSG and incubated for up to 5 h. A tumor-promoting phorbol ester, 12-O-tetradecanoyl-phorbol 13-acetate (TPA), at a concentration of 25 ng/ml, caused 4-fold increases in PGE and 6-keto-PGF1 alpha accumulation at 5 h. LH (10 ng/ml) caused 7- and 4-fold increases in PGE and 6-keto-PGF1 alpha accumulation, respectively. When tested in combination, the increases in PGE and 6-keto PGF1 alpha due to TPA and LH were additive. Like the effect of LH, the TPA stimulation of PG synthesis occurred after a delay of 2-3 h. By 5 h of incubation, cells exposed to TPA exhibited increased PG synthase activity in whole homogenates. TPA caused a smaller (2-fold) increase in P accumulation than was observed with LH (10-fold). When tested in combination, however, TPA decreased the P response to LH by approximately 25%. These effects of TPA on basal and LH-stimulated PG and P accumulation were very similar to the actions of GnRH. We, therefore, investigated the effect of exposure to the combination of GnRH and TPA. A GnRH agonist, [D-Ala6,des-Gly-NH2(10)] GnRH ethylamide (GnRHa; 10 ng/ml) caused a 4-fold increase in PGE accumulation. The effect of TPA on PGE accumulation was also additive to that of GnRHa. TPA, on the other hand, did not affect the 2.5-fold P response to GnRHa. Neither stimulation or inhibition of PGE or P accumulation was observed in the presence of a nontumor-promoting phorbol ester. Furthermore, TPA did not affect basal or LH-stimulated cAMP accumulation or basal or LH-stimulated protein kinase A activity. These data indicate that protein kinase C activation can influence granulosa cell PG and P accumulation.
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PMID:Phorbol ester regulation of rat granulosa cell prostaglandin and progesterone accumulation. 298 45

A peptide, Ala-Ser-Gly-Ser-Phe-Lys-Leu, which corresponds to Ala103-Leu109 of Hl histone, was synthesized and tested as substrate for protein kinase C. The serine residue at position 4 was phosphorylated specifically. Another peptide lacking the lysine at position 6 was not phosphorylated by the same enzyme, indicating the importance of that basic residue as the recognition site for protein kinase C.
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PMID:Phosphorylation by protein kinase C of a synthetic heptapeptide bearing a lysine residue on the C terminal side of serine. 310 85

In Chinese hamster ovary (CHO) fibroblast cells the protein kinase C activating phorbol ester, phorbol myristate acetate (PMA), stimulates an increase in cell surface transferrin receptor (TR) expression by increasing the exocytic rate of the recycling pathway. The human TR expressed in CHO cells is similarly affected by PMA treatment. A mutant human TR in which the major protein kinase C phosphorylation site, serine 24, has been replaced with the non-phosphorylatable amino acid glycine has been constructed to investigate the role of receptor phosphorylation in the PMA induced up-regulation. The Gly-24-substituted receptor binds, internalizes, and recycles Tf. Furthermore, the altered receptor mediates cellular Fe accumulation from diferric-Tf, thereby fulfilling the receptor's major biological role. The Gly-24 TR behaves identically to the wild-type TR when cells are treated with PMA. Therefore, Ser-24 phosphorylation is not required for the PMA-induced redistribution of the human TR expressed in CHO cells. The increased TR expression on the cell surface after PMA treatment results from an increase in the rate of exocytosis of the recycling receptors. No change in the endocytic rate or the size of the recycling receptor pool was observed. These results indicate that the PMA effect on the TR surface expression may result from a more general perturbation of membrane trafficking rather than a specific modulation of the TR.
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PMID:Phorbol ester treatment increases the exocytic rate of the transferrin receptor recycling pathway independent of serine-24 phosphorylation. 312 37

The site-specific phosphorylation of bovine histone H1 by protein kinase C was investigated in order to further elucidate the substrate specificity of protein kinase C. Protein kinase C was found to phosphorylate histone H1 to 1 mol per mol. Using N-bromosuccinimide and thrombin digestions, the phosphorylation site was localized to the globular region of the protein, containing residues 71-122. A tryptic peptide containing the phosphorylation site was purified. Modification of the phosphoserine followed by amino acid sequence analysis demonstrated that protein kinase C phosphorylated histone H1 on serine 103. This sequence, Gly97-Thr-Gly-Ala-Ser-Gly-Ser(PO4)-Phe-Lys105, supports the contention that basic amino acid residues C-terminal to the phosphorylation site are sufficient determinants for phosphorylation by protein kinase C.
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PMID:Identification of the phosphoserine residue in histone H1 phosphorylated by protein kinase C. 313 56

This study examined the effect of the calcium- and phospholipid-dependent protein kinase C (PKC) activator, 12-O-tetradecanoyl-phorbol-13-acetate (TPA) on the plasma glucose responses to central thyrotropin-releasing hormone (TRH) injection in mice in order to evaluate the involvement of PKC in the mechanism of TRH action in the central nervous system (CNS). TRH (0.1-10 micrograms), as well as the neuroactive TRH analogs, CG 3509, CG 3703, DN 1417, RX 77368, [Nva2]-TRH, KPC-TRH, and TRH-Gly (0.1-10 micrograms), injected centrally in normoglycemic mice reduced the circulating glucose levels in a dose-dependent manner. TPA (0.1-1 microgram), administered centrally together with TRH (1 microgram) or the TRH analogs strongly enhanced the hypoglycemic response. Similar doses of TPA had no effect on plasma glucose when administered alone or together with TRH analogs devoid of central hypoglycemic action, i.e. [Glu1]-TRH, [Phe2]-TRH, and [Gly3]-TRH (1 microgram). Central injection of a TPA analog lacking PKC-stimulating activity, 4-alpha-phorbol (0.1-1 microgram) had no effect on the hypoglycemic response to coadministered TRH. These results, demonstrating a specific effect of TPA in enhancing the hypoglycemic response to central TRH or its neuroactive, though not inactive, analogs are consistent with a possible role for PKC in the mechanism of TRH action in the CNS.
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PMID:TPA (12-O-tetradecanoylphorbol-13-acetate) enhances the central hypoglycemic action of thyrotropin-releasing hormone in mice. 313 16

Protein kinase C, purified to near homogeneity from the brain, has been tested toward a variety of synthetic peptide substrates including different phosphorylatable residues. While it proved totally inactive toward the tyrosyl peptide Asp-Ala-Glu-Tyr-Ala-Ala-Arg-Arg-Arg-Gly, as well as toward several more or less acidic seryl peptides, it phosphorylates with a Ca2+/phospholipid-dependent mechanism, at seryl and/or threonyl residues, many basic peptides, some of which are also good substrates for cAMP-dependent protein kinase (A-kinase). Among the peptides tested, however, the best substrate for protein kinase C, with kinetic constants comparable to those of histones, is the nonapeptide Gly-Ser-Arg6-Tyr, which is not a substrate for A-kinase. Moreover, although the peptide Pro-Arg5-Ser-Ser-Arg-Pro-Val-Arg is a good substrate for both kinases, its derivative with ornitines replacing arginines is phosphorylated only by protein kinase C. Some typical substrates of A-kinase on the other hand, like the peptides Phe-Arg2-Leu-Ser-Ile-Ser-Thr-Glu-Ser and Arg2-Ala-Ser-Val-Ala, are phosphorylated by protein kinase C rather slowly and with unfavourable kinetic constants. It is concluded that, while both protein kinase C and A-kinase need basic groups close to the phosphorylatable residues, their primary structure determinants are quite distinct.
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PMID:Distinct structural requirements of Ca2+/phospholipid-dependent protein kinase (protein kinase C) and cAMP-dependent protein kinase as evidenced by synthetic peptide substrates. 315 99

The regulatory domain of protein kinase C contains an amino acid sequence between residues 19 and 36 that resembles a substrate phosphorylation site in its distribution of basic residue recognition determinants. The corresponding synthetic peptide (Arg19-Phe-Ala-Arg-Lys-Gly-Ala25-Leu-Arg-Gln-Lys-Asn-Val-His -Glu-Val-Lys-Asn36) acts as a potent substrate antagonist with an inhibitory constant of 147 +/- 9 nM. It is a specific inhibitor of protein kinase C and inhibits both autophosphorylation and protein substrate phosphorylation. Substitution of Ala25 with serine transforms the pseudosubstrate into a potent substrate. These results demonstrate that the conserved region of the regulatory domain (residues 19 to 36) of protein kinase C has the secondary structural features of a pseudosubstrate and may be responsible for maintaining the enzyme in the inactive form in the absence of allosteric activators such as phospholipids.
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PMID:Protein kinase C contains a pseudosubstrate prototope in its regulatory domain. 368 12

Several synthetic peptides reproducing fragments of protamines have been used as model substrates for Ca2+/phospholipid-dependent protein kinase C, tested both in the absence of any effector (basal conditions) and upon activation by either Ca2+ and phosphatidylserine (or diacylglycerol) or limited proteolysis. Only the peptide Arg4-Tyr-Gly-Ser-Arg6-Tyr [Ga(52-65)] shares the unique property of protamines of being readily phosphorylated even under basal conditions. Optimal activity in the absence of effectors is observed with Tris/HCl buffer pH 7.5; Pipes and Hepes are less effective at pH 7.5, and at pH 6.5 basal phosphorylation is reduced. Under the best conditions for basal phosphorylation of Ga(52-65), its derivative with ornithine replaced for arginine and those corresponding to its C-terminal fragments Gly-Ser-Arg6-Tyr [Ga(57-65)] and Gly-Ser-Arg3 [Ga(57-61)], as well as the peptides Pro-Arg5-Ser2-Arg-Pro-Val-Arg [Th(1-12)], Arg4-Tyr-Arg2-Ser-Thr-Val-Ala [Th(13-23)] and Arg2-Leu-Ser2-Leu-Arg-Ala are not significantly affected though all of them, like histones, are more or less readily phosphorylated upon activation of protein kinase C by Ca2+/phosphatidylserine. The peptide Ser2-Arg-Pro-Val-Arg [Th(7-12)] however, corresponding to the C-terminal part of Th(1-12), is not phosphorylated even in the presence of activators. Limited proteolysis can roughly mimic the Ca2+/phosphatidylserine effect inducing however different extents of activation depending on the nature of the peptide substrates. Our results support the following two conclusions. Basal phosphorylation by protein kinase C in the absence of any effector requires peptide substrates whose target residue(s) are included between two extended arginyl blocks and is also dependent on pH and nature of the buffer. Peptides having extended clusters of either arginyl or ornithyl residues on the C-terminal side of serine are also readily phosphorylated, but they need activation of protein kinase by either Ca2+/phosphatidylserine or limited proteolysis. The same is true of peptides having basic residues only on the N-terminal side, or even on both sides but in limited number.
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PMID:Ca2+ phospholipid-dependent and independent phosphorylation of synthetic peptide substrates by protein kinase C. 383 Jan 67

The synthetic nonapeptide Arg-Arg-Lys-Ala-Ser-Gly-Pro-Pro-Val is a substrate for in vitro phosphorylation by a partially purified preparation of rat brain protein kinase C, with Kmapp of about 130 microM. The closely related peptide kemptide was a much weaker substrate, bovine serum albumin was not a substrate and the peptide Arg-Arg-Lys-Ala-Ala-Gly-Pro-Pro-Val was a weak inhibitor of the enzyme. Protein kinase C-catalyzed phosphorylation of histone III-S and the nonapeptide are regulated by identical mechanisms since with both substrates the reaction required added phospholipid and either Ca2+ (1mM) or TPA (200 nM TPA). Our findings show that polypeptides containing multiple basic residues followed by the sequence Ala-Ser can be substrates for TPA-stimulated phosphorylation by protein kinase C.
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PMID:Protein kinase C phosphorylates the synthetic peptide Arg-Arg-Lys-Ala-Ser-Gly-Pro-Pro-Val in the presence of phospholipid plus either Ca2+ or a phorbol ester tumor promoter. 623 95


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