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 human CD7 antigen is a glycoprotein, M(r) 40,000, expressed on the surface of peripheral blood T-lymphocytes and thymocytes, and is the earliest surface antigen to appear on T-cell lineage cells. In this study, putative mouse CD7 cDNA was identified based on its similarities with human CD7. Five independent clones originating from the same mRNA species were isolated (designated as mCD7) by screening a mouse thymocyte cDNA library with human CD7 cDNA, J61, under moderate stringency. The longest insert of a 995 base pair had an open reading frame of 210 amino acids. Northern blot analysis using the mouse CD7 cDNA probe demonstrated a single 1.2 kilobase mRNA in the thymus, spleen, bone marrow, and small intestine. The protein deduced from mCD7 cDNA consisted of the leader, extracellular, transmembrane, and cytoplasmic domains of 24, 126, 21, and 39 amino acids, respectively, based on the hydrophobicity plot and the structure of human CD7. The extracellular domain contained three potential N-glycosilation sites, while the cytoplasmic domain contained one potential protein kinase C phosphorylation site. The amino acid sequence had 45.5% similarity with human CD7, while the similarities for the individual domains ranged from 49.2% to 63.2%. The six highly conserved regions, which may possibly be involved with still unknown CD7-mediated functions, were located in the extracellular and cytoplasmic domains.
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PMID:Isolation and characterization of mouse CD7 cDNA. 767 79

4-1BB is an inducible receptor-like protein expressed in both cytolytic and Th cells. Optimal induction of 4-1BB mRNA in T cells required both PMA and ionomycin stimulation, indicating that protein kinase C activation and increases in intracellular Ca2+ were required for its expression. 4-1BB was categorized as an early activation gene since the protein synthesis inhibitor, cycloheximide, blocked the induction of 4-1BB mRNA. A rat mAb, 53A2, was generated against recombinant soluble 4-1BB and was used to characterize this molecule. 4-1BB is a 30-kDa glycoprotein and appears to exist as both a monomer and a 55-kDa dimer on the cell surface of a T cell clone. The 4-1BB protein may be post-translationally modified since its predicted backbone is 25 kDa. FACS analysis indicated that 4-1BB was inducible and expressed on the cell surface of activated splenic T cells and thymocytes. Cross-linking of 4-1BB on anti-CD3-stimulated T cells with 53A2 resulted in a dramatic enhancement of T cell proliferation. This suggests that 4-1BB may function as an accessory signaling molecule during T cell activation.
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PMID:Inducible T cell antigen 4-1BB. Analysis of expression and function. 767 21

Transient transfection studies using gonadotrope-derived, alpha T3-1 cells were used to determine the DNA sequences of the mouse glycoprotein hormone alpha-subunit gene that mediate the transcriptional response to gonadotropin releasing hormone (GnRH). The roles of phorbol esters and cyclic AMP in mediating the GnRH response were also investigated. The initial studies demonstrated that a construct containing approximately 500 base pairs of alpha-subunit flanking sequence was sufficient to mediate responses to a GnRH agonist (GnRHa), phorbol myristate acetate (PMA) and a cAMP analog. Responses to combinations of cAMP and GnRHa or cAMP and PMA were approximately additive, whereas the response to the combination of GnRHa and PMA was similar to that seen with either of the agents alone. Cotransfection studies with an expression vector for the heat-stable inhibitor of the cAMP-dependent protein kinase demonstrated that GnRHa and PMA responses are not dependent on the cAMP-dependent kinase. Deletion analysis indicated that sequences between -507 and -205 were involved in mediating responses to GnRHa and PMA. To determine if this region alone could support responses to these agents, the -507 to -205 region was linked to a minimal promoter and tested in transient transfections. The results demonstrated that this region supports responses to GnRHa, PMA, and cAMP. Clustered point mutations of this region were used to further characterize sequences involved in the GnRH response. Mutations in two regions, one at positions -406 to -399 and one at positions -337 to -330, resulted in decreased responses to GnRH and PMA. There is no obvious sequence similarity between the two regions that are required for the GnRH response. An enhancer test demonstrated that multimers of the -416 to -385 region were able to function as a GnRH-responsive element when linked to a minimal promoter, although a single copy of this region was not sufficient to permit a response to GnRH. In contrast, multimers of the -344 to -300 region did not permit a response to GnRH, but enhanced basal transcription. These findings are consistent with the identification of a two-component GnRH response unit, which probably involves the functional cooperation of two different transcription factors. The observation that GnRH responsiveness appears to co-localize with PMA responsiveness suggests that GnRH effects on the alpha-subunit transcription are likely mediated by the protein kinase C pathway.
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PMID:Two different DNA elements mediate gonadotropin releasing hormone effects on expression of the glycoprotein hormone alpha-subunit gene. 768 35

Through physiologic interactions with its ligands CD58 (lymphocyte function-associated Ag-3, LFA-3) and CD59, the T cell glycoprotein CD2 plays a role in T cell signaling and promotes lymphocyte adhesion. We have recently demonstrated that the interaction of CD2 with CD58 is dynamic: TCR stimulation or treatment with the phorbol ester PMA rapidly up-regulates CD2 ligand avidity, and this regulation requires the carboxyl-terminal asparagine residue of the CD2 cytoplasmic domain. Here we have analyzed the regulation of CD2 avidity for CD58, as assessed by the binding of CD2+ cells to purified CD58 and by the formation of rosettes between CD2+ cells and SRBC. In murine T cell hybridomas transfected with human CD2, we show that, unlike CD2-mediated IL-2 production, cell surface expression of the TCR-CD3 structure is not required for up-regulation of CD2 ligand avidity. TCR-initiated up-regulation of CD2 avidity requires the activity of both protein tyrosine kinases and protein kinase C. Agents which elevate intracellular levels of cAMP also up-regulate CD2 ligand avidity and act either distal to or independently of protein kinase C and protein tyrosine kinases. Cell lines expressing single amino acid substitutions of the carboxyl-terminal asparagine of CD2 are incapable of avidity regulation by TCR signaling, PMA treatment, or elevation of intracellular cAMP levels, demonstrating that each of these stimuli utilizes a common structural element for regulating CD2 avidity. The response to both cAMP and phorbol ester treatment distinguishes the regulation of CD2 avidity from that of a second major adhesion pathway, LFA-1 (CD11a/CD18)/ICAM-1 (CD54) and from that of the TCR coreceptor CD8. These observations identify the signaling events involved in the regulation of CD2 avidity and help to define the signal transduction processes that participate in "inside-out" signaling.
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PMID:Signal transduction pathways involved in T cell receptor-induced regulation of CD2 avidity for CD58. 768 Oct 75

The CD6 glycoprotein is expressed primarily on lymphocytes and conveys co-activating signals to T cells, but its exact function and ligand(s) are unknown. A novel mAb, termed UMCD6, was demonstrated to recognize CD6 by immunoprecipitation, Western blotting, and reactivity with COS cells transfected with CD6 cDNA. UMCD6 was mitogenic for T cells and was strongly synergistic with phorbol ester in inducing T cell activation. UMCD6 enhanced the autologous mixed lymphocyte reaction as previously observed with another anti-CD6 mAb, anti-T12. The activating effects of UMCD6 were more striking than those of other anti-CD6 mAbs and encompassed all of the diverse stimulatory properties previously reported for other anti-CD6 reagents. However, neither UMCD6 nor other anti-CD6 antibodies alone or in combination with phorbol ester or IL-2 were able to induce thymocytes to proliferate. Stimulation by UMCD6 is dependent on accessory cell function in a manner not accounted for simply by antibody cross-linking. UMCD6 did not induce an increase in cytoplasmic free Ca2+, but the CD6 activation pathway appears to involve protein kinase C. UMCD6 and a panel of seven other anti-CD6 mAbs were used in a series of experiments to define four discrete epitopes of CD6 using the criteria of antibody cross-blocking, reactivity on reduced Western blots, and resistance to controlled V8 protease digestion. The functional mAbs UMCD6, 2H1, and anti-T12 each recognized a different epitope. Taken together, the results of these studies strongly reinforce the hypothesis that CD6 plays a significant and distinct role in T cell activation, and suggest that multiple regions of CD6 may be functionally active.
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PMID:Activation of human T cells through CD6: functional effects of a novel anti-CD6 monoclonal antibody and definition of four epitopes of the CD6 glycoprotein. 769 Feb 43

Aplysiatoxin and debromoaplysiatoxin, a debrominated form of aplysiatoxin, have both been shown to be potent tumor promoters in a two-stage carcinogenesis experiment on mouse skin. However, debromoaplysiatoxin did not behave like aplysiatoxin in most of the biological assay systems using cultured cells. The discrepancy was supposed to be due to a factor in the bovine serum used for culture, a similar factor not being present in sera of eight other animal species examined. The factor was purified to homogeneity from bovine serum by ammonium sulfate fractionation and chromatographies on DEAE-cellulose, Sephadex G-150, hydroxyapatite, and a reversed-phase HPLC column. The factor was a 40-kDa protein, and partial amino-acid sequencing of its tryptic peptides indicated that the factor is alpha 1-acid glycoprotein. Both the purified factor and the commercially available bovine alpha 1-acid glycoprotein abolished in vitro the activation of protein kinase C by debromoaplysiatoxin but not that by aplysiatoxin. Debromoaplysiatoxin induced differentiation of HL-60 cells into macrophages at a comparable concentration to aplysiatoxin, when serum-free medium was used. These results suggest that alpha 1-acid glycoprotein, which interacts specifically with debromoaplysiatoxin, contained in bovine serum must have masked the in vitro properties of the tumor promoter in the biological assay systems.
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PMID:Specific protein interacting with a tumor promoter, debromoaplysiatoxin, in bovine serum is alpha 1-acid glycoprotein. 775 19

Mouse malignant T-lymphoma CS-21 cells grow in vitro in the presence of CA-12 stromal cells, but they undergo apoptotic cell death with DNA fragmentation when cultured alone. Because apoptosis of CS-21 cells was not inhibited by soluble factors secreted from CA-12 stromal cells, cell-cell interactions between the two seemed to be important to inhibit apoptosis. We found that CS-21 cell adhesion was mediated by M(r) 168,000 and M(r) 23,000 proteins and that apoptosis-inhibitory signals were transmitted through these proteins. In this study, we identified the M(r) 23,000 cell adhesion molecule as a glycosylphosphatidylinositol-anchored Thy-1 (CD90) glycoprotein. Cross-linking of M(r) 23,000 protein with anti-M(r) 23,000 mAb and a second antibody transiently raised the [Ca2+]i and activated calcineurin in CS-21 cells, as has been observed in normal T lymphocytes stimulated by cross-linking anti-Thy-1 mAbs. However, differing from normal T lymphocytes, CS-21 cells could grow either by the transient increase in [Ca2+]i or by the activation of protein kinase C. Furthermore, M(r) 23,000 protein-mediated cell survival of CS-21 cells was not accompanied by expression of the apoptosis-inhibiting protein bcl-2, although protein kinase C-activated cell survival was attended by bcl-2 expression. These results indicate that the M(r) 23,000 protein (Thy-1) of CS-21 lymphoma cells functions as a cell adhesion molecule capable of transducing signals of cell survival and growth that are not followed by bcl-2 expression.
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PMID:Apoptosis inhibition by anti-M(r) 23,000 (Thy-1) monoclonal antibodies without inducing bcl-2 expression. 779 3

The influenza virus hemagglutinin glycoprotein (HA) induces a vigorous B cell proliferation and Ig-synthesis by an unknown activation mechanism, which is susceptible to the inhibitory effects of anti-Ig and anti-class II mAbs. To gain further insight into the activation mode of this T cell-independent, B cell "superstimulatory" virus, we analyzed the sensitivity of H2-subtype virus-mediated B cell activation to the inhibitory effects of various signal transduction-blocking agents and compared it to the well characterized anti-mu-mediated and the LPS-employed pathway. Cyclic-AMP agonists (cAMP-analogues, pentoxifylline, cholera toxin, and forskolin) blocked HA-mediated activation of B cells only at concentrations at least 50-fold higher than required for blocking of anti-mu-induced activation. However, HA-treatment failed to induce an increase in intracellular cAMP levels in responding B cells. The B cell response to HA was highly resistant to calcineurin-inhibitory cyclosporin-A treatment and did not result in a measurable Ca2+ influx. Similarly, HA failed to induce an increase in tyrosine phosphorylations, including phosphorylation of phospholipase C gamma 2. HA-activated B cells showed an increase in membrane-associated protein kinase C activity, and depletion of protein kinase C by pretreatment of B cells with phorbol esters inhibited a subsequent activation by HA. Collectively, our results provide a new example of B cell stimulation by multivalent type-2 Ags, which seems to be mediated by a phosphatidylinositol- and Ca(2+)-independent signaling pathway.
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PMID:B cell superstimulatory influenza virus (H2-subtype) induces B cell proliferation by a PKC-activating, Ca(2+)-independent mechanism. 786 86

P-glycoprotein is phosphorylated in cells, and it has been suggested that phosphorylation may regulate the drug transport activity of P-glycoprotein. Domain mapping, utilizing a combination of cyanogen bromide digestion and immunoblot analysis, was used to reveal the major phosphorylation sites in murine mdr1b P-glycoprotein. After labeling of J7.V1-1 cells with [32P]Pi, or labeling membranes with [gamma-32P]ATP and either protein kinase A or protein kinase C, it was found that the majority of the label was contained within a single cyanogen bromide fragment (amino acid 627-682) that encompassed the majority of the linker region. The in vitro protein kinase C phosphorylation sites within this fragment were analyzed by a combination of fast atom bombardment mass spectrometry (FABMS) and two-dimensional phosphopeptide mapping. FABMS analysis of a protein kinase C-phosphorylated synthetic peptide, corresponding to a segment of the linker region of P-glycoprotein, identified serine 669 as the single site of phosphorylation. Comparison of two-dimensional tryptic phosphopeptide maps prepared from synthetic peptide and P-glycoprotein, both of which were phosphorylated in vitro with protein kinase C, revealed that serine 669 was also the major phosphorylation site in the intact glycoprotein. The in vitro protein kinase A phosphorylation site was identified as serine 681 by site-directed mutagenesis. Inspection of the gene organization and the deduced amino acid sequence of mdr1b P-glycoprotein revealed that the linker region, although shorter than the R domain (55 versus 241 amino acids), fits the operational definition of the R domain of cystic fibrosis conductance regulator. Like the R domain, the linker region is encoded by a single exon, is highly charged with alternating acidic and basic side chains, and contains several protein kinase A/protein kinase C consensus phosphorylation sites. Since the R domain is believed to be involved in the regulation of cystic fibrosis conductance regulator function by phosphorylation, it is possible that the linker region plays a similar regulatory role in P-glycoprotein function.
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PMID:Identification of the major phosphorylation domain of murine mdr1b P-glycoprotein. Analysis of the protein kinase A and protein kinase C phosphorylation sites. 790 Dec 20

An ATP-dependent transport system specific for non-bile acid organic anions such as S-(2,4-dinitrophenyl)-glutathione is present in the canalicular plasma membrane of hepatocytes. It has been shown recently that transport of these anions by isolated hepatocytes is modulated by the activity of cellular protein kinase C (Roelofsen, H., Ottenhoff, R., Oude Elferink, R. P., and Jansen, P.L. (1991) Biochem. J. 278, 637-641, 1991). Using a series of affinity chromatography steps, we have purified to apparent homogeneity a 90-kDa glycoprotein which has S-(2,4-dinitrophenyl)glutathione-dependent ATPase activity. As shown by binding to immobilized S-(2,4-dinitrophenyl)glutathione and by photoaffinity labeling with 8-azido-ATP, the binding sites for organic anions and for ATP of the 90-kDa protein are interdependent, a behavior that is consistent with an ATP-dependent transport function. The ATP binding site has been further characterized using a fluorescent ATP analog. The 90-kDa protein was phosphorylated by protein kinase C, and the Vmax (but not the Km) of the S-(2,4-dinitrophenyl)glutathione-dependent ATPase activity increased at least 2-fold upon phosphorylation. On the basis of its enzymatic properties, we propose that the 90-kDa protein is identical with the multispecific organic anion transporter (MOAT) of the hepatic canalicular plasma membrane. The size and oligosaccharide content of the 90-kDa protein indicate that it does not belong to the family of mammalian plasma membrane P-glycoproteins.
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PMID:Organic anion-transporting ATPase of rat liver. I. Purification, photoaffinity labeling, and regulation by phosphorylation. 796 73


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