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:2.7.11.13 (protein kinase C)
49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ubenimex (Bestatin) is a potent inhibitor of aminopeptidases (APase) including APase N (EC 3.4.11.2), a widely distributed membrane-bound metalloprotease. Binding of Ubenimex (UBX) to cells has been implicated in a variety of its biological activities, while little evidence has yet been provided as to any subsequent mechanisms of intracellular signal transduction. We now examined the possible involvement of protein kinase C (PKC), a key regulator in transmembrane signaling. Human leukemia K562 cells were cultured in the presence or absence of UBX (1 to 50 micrograms.ml-1, 1 to 72 h), and the subcellular distribution as well as phorbol-12, 13-dibutyrate (PDBu)-induced redistribution of PKC activities were assessed. The membrane-bound enzymatic activity tended to increase in the presence of UBX, while a significant loss of the activity was demonstrable upon subsequent exposure to PDBu (100 nM, 10 min) in both the cytosolic and membrane fractions. Specific binding of [3H]PDBu to intact K562 cells was also down-modulated with UBX concentration- and time-dependently, suggesting loss of PKC enzyme protein on the cell surface. Western blot analysis of the total cell extracts disclosed no appreciable alteration in the amount of PKC protein. APase inhibition with UBX was observable independently of PKC modulation. The present findings were discussed with reference to the possible differential mechanisms of PKC-mediated regulation of cellular responses depending on cell types.
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PMID:Ubenimex (Bestatin), an aminopeptidase inhibitor, modulates protein kinase C in K562 cells. 129 52

Two genes encode the CD16 low affinity IgG FcR. CD16-I (Fc gamma RIII-1) is expressed on PMN as a phosphatidylinositol-glycan anchored glycoprotein. CD16-II (Fc gamma RIII-2) is expressed on NK cells and macrophages as a transmembrane glycoprotein associated with CD3 zeta or Fc epsilon RI-gamma. NK cells spontaneously release soluble CD16-II from the cell surface and this is enhanced by activation with phorbol ester. In this study, we demonstrate that a metalloprotease is involved in the spontaneous and PMA-induced release of CD16-II from NK cells. 1,10-phenanthroline, an inhibitor of Zn(2+)-dependent metalloproteases, efficiently inhibits CD16-II release. 1,7-phenanthroline, an inactive analogue that doesn't chelate Zn2+ or other divalent metal cations, and inhibitors of serine proteases do not affect spontaneous or PMA-induced release of CD16-II. Murine P815 mastocytoma cells transfected with human CD16-II cDNA shed membrane CD16, and 1,10-phenanthroline inhibits this process. P815 transfectants expressing CD16-II molecules with truncated cytoplasmic domains also release soluble receptors, indicating that the cytoplasmic segment of CD16-II is not required for interaction with the protease or the cytoskeleton. By contrast, 1,10-phenanthroline does not inhibit PMA-induced release of CD16-I glycoprotein from PMN, indicating a different mechanism of release for this phosphatidylinositol-glycan anchored molecule. Prior studies have demonstrated that NK cells are activated via the inositol phosphate pathway after engagement of CD16-II by immune complexes or Ig-coated tumor cell targets. A membrane metalloprotease with substrate specificity for CD16-II that is activated by PKC stimulation may provide a mechanism for releasing the immune complex or target from the effector cells and halting signal transduction.
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PMID:Involvement of a metalloprotease in spontaneous and phorbol ester-induced release of natural killer cell-associated Fc gamma RIII (CD16-II). 183 41

Stromelysin (transin) is a secreted metalloprotease that is transcriptionally induced by a variety of growth factors and oncogenes. We examined the necessity of specific secondary (protein kinase C) and tertiary (c-fos and c-jun protein products) messengers in the transactivation of stromelysin gene expression by epidermal growth factor (EGF). Rat-1 fibroblasts exposed to antisense c-fos DNA or RNA demonstrated that c-fos expression was necessary for complete EGF induction of stromelysin expression. Similar results demonstrating the necessity of c-jun protein in the EGF induction of stromelysin were obtained. We also demonstrated that protein kinase C activation is required for the EGF induction of stromelysin, since phorbol ester desensitization of C kinase proteins abolished the ability of EGF to induce stromelysin mRNA, protein, and promoter activity. In reconstitution experiments, neither c-fos, c-jun, nor C kinase activation alone induced significant stromelysin expression. Overexpression of c-fos and c-jun was able to induce stromelysin to a level similar to that of the growth factor, and stimulation of protein kinase C activity augmented this induction. The data suggest that the EGF induction of stromelysin in rat fibroblasts procedes through a pathway involving c-fos, c-jun, and protein kinase C.
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PMID:Epidermal growth factor stimulation of stromelysin mRNA in rat fibroblasts requires induction of proto-oncogenes c-fos and c-jun and activation of protein kinase C. 211 24

Downregulation of functionally relevant surface molecules has been shown to be a powerful regulatory mechanism of Ag surface expression that seems to be of general significance in vivo. CD16-II (Fc gamma RIIIA alpha) is the transmembrane form of the low-affinity receptor for IgG which is expressed on monocytes and NK cells. Occupancy of CD16-II receptor on NK cells induces expression of activation antigens, synthesis of cytokines, and lysis of antibody-coated target cells. Furthermore, after activation the receptor is downregulated from the cell surface. This downregulation could play a physiological role in the NK activation process via CD16 by releasing the antibody-coated target cell and halting signal transduction. The participation of PKC and PTKs in the activation of NK cells via CD16 is clearly established. Thus, we have considered of interest to study the mechanism of CD16-II downregulation in NK cells and the role played by these kinases in the process. The results show that 1,10-phenantroline, a specific inhibitor of Zn(2+)-dependent metalloproteases, inhibits CD16 downregulation induced by CD16 crosslinking, thus suggesting that this process requires the activation of a Zn2+ dependent metalloprotease as it occurs in PMA mediated CD16 downregulation by shedding. Our results also demonstrate that CD16-II downregulation induced by CD16 crosslinking is independent of PKC and PTK activation. In contrast other NK cell activities induced by CD16 crosslinking, such as the induction of activation markers or the production of TNF-alpha, were dependent of PTK activation. The fact that PKC inhibitor staurosporine blocks PMA- but not CD16-induced downregulation suggests that CD16 downregulation can be achieved via two different pathways: one that is PKC dependent and one that is not. The characterization of the Zn(2+)-dependent metalloproteases and the analysis of the regulatory mechanisms involved in its activation will be of interest in order to clarify the physiological relevance of CD16-II release from NK cells as part of the NK activation process.
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PMID:Downregulation of Fc gamma receptor IIIA alpha (CD16-II) on natural killer cells induced by anti-CD16 mAb is independent of protein tyrosine kinases and protein kinase C. 808 66

This study explores novel aspects of the interaction between inflammatory mediators and extracellular matrix degradation. Here we have evaluated the effects of a T-cell cytokine interleukin-4 (IL-4) on the expression and activity of a metalloprotease, stromelysin, and its tissue inhibitor (TIMP-1) in human skin fibroblasts. IL-4 strongly decreased stromelysin mRNA levels and stromelysin-producing activity induced by IL-1 beta-treated and untreated cells. Under the same experimental conditions, TIMP-1 mRNA expression was slightly modified. Phorbol ester (PMA), a PKC activator, induced stromelysin gene expression, an effect enhanced by the addition of IL-1 beta. IL-4 was not able to decrease the PMA and PMA + IL1 beta effects. Calphostin, a specific PKC inhibitor, inhibited stromelysin mRNA expression induced by IL-1 beta. Forskolin, a PKA activator, did not modify mRNA levels and was not able to reduce the effect of IL-4 on IL-1 beta-induced stromelysin expression. These data suggest that in human dermal fibroblasts, activation of PKC abolishes the observed IL-4 effect on both basal and IL-1 beta-induced stromelysin gene expression. It therefore appears that lack of PKC activation is a prerequisite for the inhibitory effect of IL-4 in the system.
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PMID:Inhibition by Interleukin-4 of stromelysin expression in human skin fibroblasts: role of PKC. 861 84

The extracellular domains of a diverse group of membrane proteins are shed in response to protein kinase C activators such as phorbol 12-myristate 13-acetate (PMA). The lack of sequence similarity in the cleavage sites suggests the involvement of many proteases of diverse specificity in this process. However, a mutant Chinese hamster ovary cell line recently isolated for being defective in PMA-activated shedding of the membrane-anchored growth factor transforming growth factor alpha precursor (proTGF-alpha) is concomitantly defective in the shedding of many other unrelated membrane proteins. Here we show that independent mutagenesis and selection experiments yield shedding mutants having the same recessive phenotype and belonging to the same genetic complementation group. Furthermore, two structurally distinct agents, TAPI-2 and 1,10-phenanthroline, which are known to inhibit metalloproteases, block PMA-activated shedding of proTGF-alpha, cell adhesion receptor L-selectin, interleukin 6 receptor alpha subunit, beta-amyloid precursor protein, and an entire set of anonymous Chinese hamster ovary cell surface proteins. Certain serine protease inhibitors prevent release of these proteins by interfering with their maturation and transport to the cell surface but do not inhibit ectodomain shedding from the cell surface. The results suggest the existence of a common system for membrane protein ectodomain shedding involving one or several proteolytic activities sensitive to metalloprotease inhibitors, whose ability to act can be disrupted by recessive mutations in a single gene.
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PMID:Diverse cell surface protein ectodomains are shed by a system sensitive to metalloprotease inhibitors. 862 92

HLA Class I molecules on activated T cells are expressed as mAb W6/32 reactive heterodimers associated with beta 2-microglobulin (beta 2-m) and also as mAb LA45 reactive beta 2-m free HLA Class I alpha-chains. However, the regulation of free alpha-chain expression remained enigmatic. Here we show, that the amount of cell surface expressed free heavy chains is influenced by two distinct mechanisms. Firstly, a proportion of expressed molecules are cleaved and give rise to a soluble pool of HLA Class I molecules. We provide evidence that, besides the previously described constitutive release of free alpha chains, a second phorbol ester inducible release mechanism involving activation of protein kinase C (PKC) does exist. We demonstrate that both the constitutive and the enhanced release of LA45 reactive HLA Class I alpha-chains are the consequence of a cell membrane bound proteolytic activity with the characteristics of a 1, 10 phenanthroline sensitive metalloprotease. Secondly, we report that a distinct fraction of mAb tagged free alpha-chains is internalized via an n-ethylmaleimide sensitive pathway. Together, this data suggests that the expression of free alpha-chains is regulated by pathways governing release and internalization.
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PMID:Expression of LA45 reactive beta 2-microglobulin free HLA class I alpha-chains on activated T-cells is regulated by internalization, constitutive and protein kinase C inducible release. 886 70

A hallmark of invasive tumors is their ability to effect degradation of the surrounding extracellular matrix (ECM) by the local production of proteolytic enzymes, such as the matrix metalloproteases (MMPs). In this paper, we demonstrate that the invasion of human gliomas is mediated by a 72 kDa MMP, referred to as MMP-2, and provide further evidence that the activity of MMP-2 is regulated by protein kinase C (PKC). The invasiveness of five human glioma cell lines (A172, U87, U118, U251, U563) was assessed in an in vitro invasion assay and was found to correlate with the level of MMP-2 activity (r2 = 0.95); in contrast, the activity of this 72 kDa metalloprotease was barely detectable in non-invasive control glial cells (non-transformed human astrocytes and oligodendrocytes). Treatment with 1,10-phenanthroline, a metalloprotease inhibitor, or with a synthetic dipeptide, containing a blocking sequence (ala-phe) specific for MMPs, resulted in a > 90% reduction in glioma invasion. Furthermore, this MMP-2 activity could be inhibited by the treatment of tumor cells with calphostin C, a specific inhibitor of PKC. Glioma cell lines treated with calphostin C demonstrated a dose-dependent decrease (IC50 = 30 nM) in tumor invasiveness with a concomitant reduction in the activity of the MMP-2. Conversely, treatment of non-invasive control astrocytes with a PKC activator (phorbol ester) led to a corresponding increase in their invasiveness and metalloprotease activity. These findings support the postulate that MMP-2 activity constitutes an important effector of human glioma invasion and that the regulation of this proteolytic activity can be modulated by PKC.
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PMID:Glioma invasion in vitro: regulation by matrix metalloprotease-2 and protein kinase C. 887 36

Neutral serine proteinases such as mast cell chymase, cathepsin G, and neutrophil elastase are far more potent secretagogues for airway gland serous cells than all other agonists studied (e.g., histamine and bradykinin). To determine the mechanism of proteinase-induced secretion, we investigated the stimulation-secretion coupling in cultured bovine serous cells. Histamine stimulates degranulation of serous cells via adenosine 3', 5'-cyclic monophosphate-, protein kinase C-, and intracellular Ca2+ concentration ([Ca2+]i)-dependent pathways. Similarly, bradykinin-induced secretion involves inositol phosphates, protein kinase C, and [Ca2+]i. Degranulation caused by both agonists also depends on the activity of an endogenous metalloprotease, which is required in a late step of stimulation-secretion coupling, i.e., after Ca2+ entry. On the basis of the effect of different inhibitors, this metalloprotease is a Zn(2+)- and Ca(2+)-dependent enzyme similar to a gelatinase A synthesized by serous cells. In marked contrast to other secretagogues, degranulation induced by chymase, cathepsin G, and neutrophil elastase neither involves the classical second messengers nor the activity of the endogenous metalloprotease. These observations suggest that exogenous proteinases such as chymase, cathepsin G, and elastase may substitute for or mimic the action of an endogenous metalloprotease and directly activate degranulation, bypassing the signal transduction mechanisms necessary for secretion caused by other agonists.
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PMID:Classical second messengers are not involved in proteinase-induced degranulation of airway gland cells. 894 23

Although regulated ectodomain shedding is a well known process that affects a large group of transmembrane molecules, it is not clear how the shedding system selects its substrates. Here we investigate the structural requirements for the regulated shedding of two substrates of the general shedding system, the transforming growth factor-alpha precursor, pro-TGF-alpha, and the beta-amyloid precursor protein, beta-APP. The ability of different regions of pro-TGF-alpha or beta-APP to confer susceptibility to the shedding system was tested using as a reporter a transmembrane molecule that is not a substrate of this shedding system. For this purpose we chose the TGF-beta accessory receptor, betaglycan, since genetic and biochemical evidence showed that betaglycan is not a substrate of the shedding system. We determined that replacement of the 14 extracellular amino acids adjacent to the transmembrane region of betaglycan with the corresponding regions of TGF-alpha or beta-APP rendered betaglycan susceptible to ectodomain shedding. These domain swap constructs were cleaved in response to protein kinase C stimulation, and cleavage was prevented by the metalloprotease inhibitor TAPI, both effects being characteristic of the general shedding system. Domain swap constructs containing the transmembrane and/or the cytoplasmic domains of pro-TGF-alpha did not undergo regulated ectodomain cleavage. We conclude that despite a lack of sequence similarity, the extracellular regions of pro-TGF-alpha and beta-APP immediately preceding their transmembrane domains are key determinants of ectodomain shedding.
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PMID:Role of the juxtamembrane domains of the transforming growth factor-alpha precursor and the beta-amyloid precursor protein in regulated ectodomain shedding. 920 36


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