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)

Both keratohyalin granules (KHG) and cornified envelopes were stained histochemically in an indirect immunofluorescent study by antiphosphorylated cystatin alpha antibody, indicating that phosphorylated cystatin alpha is a component of the cornified envelope proteins. When phosphorylated cystatin alpha (P-cystatin alpha) was incubated with epidermal transglutaminase (TGase) and Ca2+ ions, polymerized protein was produced by formation of epsilon-(gamma-glutamyl)lysine cross-linking peptide bonds between lysine residues of cystatin alpha and glutamine residues of suitable protein(s) in the enzyme preparation. However, phosphorylated and non-phosphorylated cystatins were polymerized to similar extents by the TGase. Immunofluorescent and immunoelectron microscopic observations revealed that P-cystatin alpha could be detected in vivo in the KHG and cornified envelopes. Treatment of sphingosine, a specific inhibitor of protein kinase C, markedly suppressed the incorporation of cystatin alpha into KHG. Thus phosphorylation of cystatin alpha by protein kinase C may play an important role in targeting cystatin alpha into KHG.
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PMID:Phosphorylated cystatin alpha is a natural substrate of epidermal transglutaminase for formation of skin cornified envelope. 135 32

Investigations were undertaken to see whether mouse keratinocyte differentiation was elicited by gangliosides. Among the gangliosides tested only GQ1b, a tetrasialoganglioside containing two disialosyl residues, induced keratinocyte differentiation, as indicated by the formation of cornified envelopes, enhancement of transglutaminase activity and suppression of DNA synthesis. Upon stimulation with GQ1b the mass content of Ins(1,4,5)P3 and the intracellular Ca2+ levels were markedly enhanced in a time- and dose-dependent manner, whereas no significant changes were observed with other gangliosides, thereby indicating activation of phospholipase C for the onset of keratinocyte differentiation. Furthermore, only GQ1b promoted the translocation of protein kinase C (PKC) from cytosol to membrane. Inhibition of PKC with H-7 or down-regulation of the enzyme by prolonged pre-treatment with phorbol 12,13-dibutyrate greatly suppressed transglutaminase activity and formation of cornified envelopes induced by GQ1b. These results demonstrate that the tetrasialoganglioside GQ1b generates the initial differentiation signal in mouse keratinocytes through phosphoinositide turnover, and also suggest that PKC activation may act at certain, as yet unidentified, stages of differentiation processes.
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PMID:Ganglioside GQ1b-induced terminal differentiation in cultured mouse keratinocytes. Phosphoinositide turnover forms the onset signal. 168 30

The membrane-bound transglutaminase of cultured keratinocytes became radioactively labelled upon addition of [32P]Pi to the medium. Transglutaminase phosphorylation was also demonstrable using particulate material isolated from cell homogenates. Compatible with mediation of the labelling by protein kinase C, the degree of phosphorylation in intact cells was stimulated approx. 5-fold in 4 h on treatment with the tumour-promoting phorbol ester phorbol 12-myristate 13-acetate, but not by phorbol. The extent of labelling was virtually unaffected by cycloheximide inhibition of protein synthesis, indicating that it arose primarily through turnover of phosphate in the membrane-bound enzyme. Phosphoamino acid analysis detected labelling only of serine residues. Most of the label was removed by trypsin release of the enzyme from the particulate fraction of cell homogenates, which deletes a membrane anchorage region of approximately 10 kDa. Upon trypsin treatment of the enzyme after immunoprecipitation, the phosphate label was recovered in soluble peptide material with a size of several thousand Da or less. Indicative of fragmentation of the membrane anchorage region, this material was separable by h.p.l.c. into two equally labelled peptides. Moreover, when the enzyme was labelled with [3H]palmitate or [3H]myristate, the fatty-acid-labelled peptide material required non-ionic detergent for solubilization and was separable from the phosphate-labelled material by gel filtration. Phorbol ester treatment of cultured keratinocytes in high- or low- Ca2(+)-containing medium was not accompanied by an appreciable protein-synthesis-independent change in transglutaminase activity. Independent of possible alteration of the intrinsic catalytic activity of the enzyme, phosphorylation may well modulate its interaction with substrate proteins, a potential site for physiological regulation.
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PMID:Phorbol ester-stimulated phosphorylation of keratinocyte transglutaminase in the membrane anchorage region. 197 83

Receptor-mediated endocytosis is a well recognized process by which many cells internalize and intracellularly process important biological molecules including viruses. The present hypothesis, addressing receptor-mediated cellular entry of viruses including HIV, describes a perspective of further basic studies seen through the current knowledge about pharmacological control of various steps of receptor-mediated endocytosis of different ligands and viruses as well. It proposes a list of more than 20 chemicals, targeted at inhibition of viral internalization and viral release into the cytoplasm, via their action(s) on transglutaminase, calmodulin, protein kinase C, and intraendosomal pH. It is cautiously suggested that a proper study of these chemicals may reveal some therapeutic values of their own in some viral diseases including AIDS.
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PMID:Inhibition of receptor-mediated cellular entry of viruses including HIV: a perspective on further researches on chemotherapy in viral diseases including AIDS. 209 Sep 29

Calpain is a Ca2(+)-dependent cysteine endopeptidase and calpastatin is a calpain-specific endogenous inhibitor protein. Both calpain and calpastatin are very widely distributed in various animal tissues and cells. Low (microM) Ca2(+)-requiring calpain I and high (mM) Ca2(+)-requiring calpain II are known to exist. Calpain consists of one heavy (80 kDa) and one light (30 kDa) subunit. The heavy subunits of calpains I and II are different genetic products, whereas the light subunits are the same for both calpains I and II. Molecular cloning as well as protein sequencing revealed that the heavy subunit has four domains, while the light subunit has two domains. The carboxyl terminal domain of each subunit is a calmodulin-like domain, whereas the catalytic site is located in domain 2 of the heavy subunit. Calpastatin has four internally repetitive inhibitory domains. A single domain, or even a truncated 27-mer fragment thereof, possesses inhibitory activity against calpains. Calpain shows a rather broad substrate specificity. It can cleave various enzymes, and cytoskeletal, membrane and receptor proteins. Calpain-catalyzed activation of protein kinase C and transglutaminase may represent a few of the physiological functions of calpain, but a great many other functions can be assigned as well to calpain. Immunohistochemical studies revealed very wide but quite diverse distribution of calpains I and II and calpastatin among various tissues and cells. The expression of the genes for calpain and calpastatin is found to be modulated by retrovirus (HTLV-I) infection to T-lymphocytes. The physiological significance of the calpain and calpastatin system is yet to be elucidated, and accumulating information definitely suggested the role of calpain/calpastatin in health and disease.
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PMID:[Calpain and calpastatin]. 219 87

Kinetic analysis of transferrin receptor properties in 6-8 day rat reticulocytes showed the existence of a single class of high-affinity receptors (Kd 3-10 nM), of which 20-25% were located at the cell surface and the remainder within an intracellular pool. Total transferrin receptor cycling time was 3.9 min. These studies examined the effects of various inhibitors on receptor-mediated transferrin iron delivery in order to define critical steps and events necessary to maintain the functional integrity of the pathway. Dansylcadaverine inhibited iron uptake by blocking exocytic release of transferrin and return of receptors to the cell surface, but did not affect transferrin endocytosis; this action served to deplete the surface pool of transferrin receptors, leading to shutdown of iron uptake. Calmidazolium and other putative calmodulin antagonists exerted an identical action on iron uptake and receptor recycling. The inhibitory effects of these agents on receptor recycling were overcome by the timely addition of Ca2+/ionomycin. From correlative analyses of the effects of these and other inhibitors, it was concluded that: (1) dansylcadaverine and calmodulin antagonists inhibit iron uptake by suppression of receptor recycling and exocytic transferrin release, (2) protein kinase C, transglutaminase, protein synthesis and release of transferrin-bound iron are not necessary for the functional integrity of the iron delivery pathway, (3) exocytic transferrin release and concomitant receptor recycling in rat reticulocytes is dependent upon Ca2+/calmodulin, (4) dansylcadaverine, dimethyldansylcadaverine and calmidazolium act on iron uptake by interfering with calmodulin function, and (5) the endocytotic and exocytotic arms of the iron delivery pathway are under separate regulatory control.
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PMID:Calmodulin dependence of transferrin receptor recycling in rat reticulocytes. 231 Mar 76

The macrocyclic lactone bryostatin 1 activates protein kinase C as effectively as the phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate (TPA). Nevertheless, there are only certain TPA-effects that can be induced by bryostatin 1. These include stimulation of epidermal DNA synthesis and alkaline phosphatase activity in vivo as well as activation of the Ca2+-independent, phospholipid-requiring phosphorylation of an epidermal protein in a cell-free system. Various other TPA-effects in vivo and in vitro, which are not mimicked by bryostatin 1 can be inhibited by applying bryostatin 1 30 min prior to TPA. TPA-effects suppressible by bryostatin 1 include the Ca2+-dependent stimulation of arachidonic acid and prostaglandin E2 release, of ornithine decarboxylase (ODC) activity and ODC-mRNA expression and of transglutaminase activity in keratinocytes in vivo and/or in vitro and, in addition, Epstein-Barr virus induction in Raji cells. The same is true for the conversion step (first stage of promotion) of multistage carcinogenesis. In contrast to the TPA induction of arachidonic acid and prostaglandin E2 release and of transglutaminase activity, induction by the Ca2+-ionophore and by high Ca2+-shift, respectively, are not significantly inhibited by bryostatin 1. We suggest that bryostatin 1 might inhibit a specific 'Ca2+-component' of TPA action.
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PMID:Bryostatin 1, an activator of protein kinase C, mimics as well as inhibits biological effects of the phorbol ester TPA in vivo and in vitro. 245 75

We have characterized a 68 kDa lipocortin from human placenta that was identified as a covalently linked homodimer of lipocortin-1 by peptide mapping and sequence analysis. The site of cross-linking was localized within the 3 kDa N-terminal tail region, an exposed domain that contains the phosphorylation sites for protein tyrosine kinase and protein kinase C and is sensitive to proteolysis. Sequence analysis of the corresponding peptide revealed that glutamine-18 was modified, suggesting that the cross-link may be generated by a transglutaminase. By incubating lipocortin-1 with placental membranes and with labelled glycine ethyl ester we observed a Ca2+-dependent labelling of lipocortin-1 within the tail region, supporting this notion. Like lipocortin-1, the dimer inhibits phospholipase Ad2 activity, is a substrate for the epidermal-growth-factor (EGF) receptor/kinase, and display Ca2+-dependent binding to phosphatidylserine-containing vesicles. In preparations from human placenta the dimer is particularly abundant, accounting for approx. 20% of the lipocortin-1.
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PMID:A dimeric form of lipocortin-1 in human placenta. 253 4

The effects of activators and inhibitors of protein kinase C (phorbol esters and H-7) and antagonist to calmodulin (TFP) on polyamine transport in murine leukemia (L1210) cells are investigated. Phorbol esters and H-7 are found to enhance and curtail the uptake of 14C-Spermidine (Spd) respectively in L1210 cells. TFP also inhibits the uptake process. After desialation of cells with neuraminidase, phorbol esters are found to further increase the uptake of 14C-Spd by 35% compared to untreated cells. The sialic acid contents of the cells are regenerated by incubation with 14C-glucosamine for 18 hours. The regenerated cells mimic like untreated cells for the uptake of 14C-Spd i.e. after regeneration of sialic acids, the Spd uptake is curtailed significantly in comparison with desialated cells. Phorbol esters are found to enhance the activity of transglutaminase present in L1210 cells while H-7 and TFP exhibit reverse effects. The possible role of phorbol esters, H-7 and TFP and their effects on transglutaminase activity in relation with Spd transport process are discussed.
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PMID:Role of protein kinase C activators and inhibitors, calmodulin antagonists and membrane sialic acids in polyamine transport in murine leukemia cells. 256 12

Previous studies have shown that normal human tracheobronchial epithelial (HBE) cells undergo squamous differentiation upon treatment with phorbol 12-myristate 13-acetate (PMA). In this study, we report that induction of this differentiation program is accompanied by an increase in the accumulation of cholesterol sulfate and in transglutaminase type I activity, two markers of squamous differentiation. Several carcinoma cell lines did not exhibit an increase in these differentiation markers after PMA-treatment and appear to have acquired a defect in the mechanism that triggers differentiation. The diacylglycerol analogue, didecanoylglycerol (diC10), was also able to induce squamous differentiation. Bryostatin 1, another activator of protein kinase C, did not induce terminal cell division or increase cholesterol sulfate accumulation or transglutaminase type I activity. Bryostatin 1 not only failed to inhibit cell proliferation and to induce differentiation but antagonized the PMA- and diC10-induced commitment to terminal differentiation. The bryostatin blocked both the PMA-induced terminal cell division as well as the expression of the two differentiation markers. Retinoids were found not to affect the PMA-induced commitment to terminal cell division but did inhibit the expression of the differentiated phenotype. Our results indicate that the bryostatins and retinoids affect the multistep process of squamous differentiation in tracheobronchial epithelial cells at two different stages.
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PMID:Effects of bryostatins and retinoic acid on phorbol ester- and diacylglycerol-induced squamous differentiation in human tracheobronchial epithelial cells. 256 23


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