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)

Transmembrane signals generated following mAb binding to CD19, CD20, CD39, CD40, CD43, Leu-13 Ag, and HLA-D region gene products induced rapid and strong homotypic adhesion in a panel of human B cell lines. Lower levels of adhesion were also observed after engagement of CD21, CD22, and CD23. Adhesion induced by mAb binding to these Ag was identical with respect to the kinetics of adhesion and the morphology of the resulting cellular aggregates, and was distinct from PMA-induced adhesion in both of these properties. Adhesion was not observed in response to mAb binding to MHC class I, CD24, CD38, CD44, CD45RA, or CD72. In contrast to B cell lines, homotypic adhesion was not induced in two pre-B cell lines, in spite of their high level expression of CD19 and HLA-D. Adhesion induced by suboptimal stimulation through these surface Ag or by PMA was mediated primarily through LFA-1 and ICAM-1. However, optimal stimulation through CD19, CD20, CD39, CD40, and HLA-D induced strong homotypic adhesion that was not blocked by anti-LFA-1 mAb. This alternate pathway of adhesion was also observed in LFA-1-deficient cell lines and in the presence of EDTA, suggesting that adhesion was not mediated by integrins. Adhesion in response to engagement of cell-surface Ag was unaffected by H7 or genestein, but was significantly inhibited by staurosporine, and was completely ablated by sphingosine and herbimycin. These studies indicate that engagement of multiple B cell-surface molecules initiates a signal transduction cascade that involves tyrosine kinases but not protein kinase C, and which leads to homotypic adhesion. Furthermore, adhesion was mediated by at least two distinct cell-surface adhesion receptors: LFA-1/ICAM-1 and a heretofore unknown adhesion receptor.
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PMID:Transmembrane signals generated through MHC class II, CD19, CD20, CD39, and CD40 antigens induce LFA-1-dependent and independent adhesion in human B cells through a tyrosine kinase-dependent pathway. 172 39

The human leukocyte surface Ag CD38 was recently identified as a nicotinamide adenine dinucleotide (NAD)(+)-glycohydrolase ecto-enzyme, degrading NAD into nicotinamide and ADP-ribose. We show here that expression of CD38 is increased in the Jurkat T cell line after treatment with agents that augment intracellular cAMP, with the permeant cAMP analogue dibutyryl-cAMP (db-cAMP), and also with PMA, which activates protein kinase C. Treatment of human PBL T cells with db-cAMP or submitogenic doses of PMA also increased CD38 expression. Two other nucleotide-hydrolyzing activities were induced on the T cell surface concomitantly with CD38: the human PC-1 molecule, a nucleotide phosphodiesterase/pyrophosphatase that produces AMP from NAD or ADP-ribose, and a nucleotidase that produces adenosine from AMP, but which may be distinct from the CD73 5'-nucleotidase. All three enzymes were up-regulated after stimulation of human peripheral blood T cells with PHA. The coordinated regulation of these ecto-enzymes suggested that, besides a possible signaling function, they may recycle extracellular NAD by degrading it to adenosine and nicotinamide, which can be taken up by cells. In support of this hypothesis, db-cAMP-treated Jurkat cells could degrade extracellular NAD for de novo synthesis of purines, while untreated cells could not. Activated lymphocytes are often located in tissues in which cell death is common. It is suggested that the coordinated expression of these enzymes may allow activated T cells to re-use NAD and nucleotides from dead cells.
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PMID:Coordinated regulation in human T cells of nucleotide-hydrolyzing ecto-enzymatic activities, including CD38 and PC-1. Possible role in the recycling of nicotinamide adenine dinucleotide metabolites. 875 17

Exposure of Farage, a human B-cell line, to interleukin 4 (IL4) reduced the amount of CD38 antigen on the surface of the cells and in cell lysates. No evidence was obtained for accelerated breakdown, shedding, or internalization of CD38 molecules following IL4 treatment, nor the accumulation of CD38 molecules in the cell interior. The inhibition of protein synthesis with cycloheximide (CXM) diminished the down-regulation of CD38 induced by IL4. CXM decreased the expression of CD38 in Farage cells with arrested mitosis, and IL4 failed to further reduce CD38 expression. Staurosporine, an inhibitor of serine/threonine protein kinases, and H7 (1-(5-isoquinolinylsulfonyl)-2-methylpiperazine), a preferential inhibitor of protein kinase C (PKC), abrogated the effect of IL4 on CD38, while inhibitors of other serine protein kinases W7 (N-(aminohexyl)-5-chloro-1-naphthalenesulfoamide) and H8 (N-(2-[methylamino]ethyl)-5-isoquinolinesulfonamide) failed to interfere with the effect of IL4. Phorbol 12-myristate 13-acetate (PMA), an activator of PKC, resembled IL4 in decreasing the expression of CD38, and either staurosporine or H7 abolished this effect. Genistein, an inhibitor of tyrosine kinases, increased the expression of CD38, but failed to abrogate the inhibitory effect of IL4 on CD38. It is concluded that serine/threonine protein kinases mediated the IL4-induced down-regulation of the expression of CD38 molecules in B cells.
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PMID:The mechanism of interleukin 4-induced down-regulation of CD38 on human B cells. 887 4

Two types of ADP-ribosyl cyclase activity were distinguished in dog and rat cardiac muscles by measuring the enzymatic conversion of NGD (as an NAD analog) into the fluorescent product cyclic GDP-ribose in cardiac muscle subcellular fractions. Both types of activity were confined to membrane fractions isolated from microsomes by sucrose gradient centrifugation. One of the activities co-purified with fractions that were enriched in sarcolemma (SLM), as evidenced by immunodetection of the dihydropyridine receptor, while the other activity was found to co-precipitate with the sarcoplasmic reticulum (SR), that was identified on the basis of its immuno-staining with a ryanodine receptor monoclonal antibody. In certain aspects, the plasma membrane-bound ADP-ribosyl cyclase activity resembled the characteristics of CD38 or CD38-like proteins: it was sensitive to thiols and lectins and was recognized by a monoclonal anti CD38 antibody. The SR enzyme had apparently distinct properties, as it was insensitive to both thiols and lectins and was not recognized by the CD38 antibody. In addition, the SR-associated ADP-ribosyl cyclase was inhibited by endogenous protein kinase C (PKC)-dependent phosphorylation in both dog and rat cardiac SR. The PKC-modulated SR ADP-ribosyl cyclase we describe here might be a principal component of the signal transduction machinery that is responsible for regulation of the intracellular levels of cADPR.
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PMID:Sarcoplasmic reticulum-associated and protein kinase C-regulated ADP-ribosyl cyclase in cardiac muscle. 916 98

CD38 ligation with the specific mAb IB4 induced early and late signaling events in Jurkat T cells, as judged by the transient induction of tyrosine phosphorylation of phospholipase C-gamma1, c-Cbl, zeta-associated protein (ZAP)-70, Shc, extracellular signal-regulated protein kinase-2 (Erk-2) as mitogen-activated protein (MAP) kinase, and increased expression of the activation Ag CD69. In addition, CD38 ligation induced Ras-dependent events such as Erk-2 mobility shift and increased Erk-2 kinase activity. Further evidence that Erk-2 activation is regulated by CD38 ligation was obtained indirectly with the observed induction of Raf-1, Lck, and Sos-1 mobility shifts, processes that are believed to be dependent, at least in part, on MAP kinase activation. Using a protein tyrosine kinase inhibitor, herbimycin A, or a protein kinase C inhibitor, Ro-31-8220, we found that the anti-CD38-induced Erk-2 activation is both protein tyrosine kinase and protein kinase C dependent. CD38 ligation also resulted in increased CD3-zeta tyrosine phosphorylation and its association with ZAP-70. CD38 ligation in a Jurkat Lck-deficient mutant, JCam1, failed to induce substrate tyrosine phosphorylation and activation of Erk-2. These data indicated that in Jurkat T cells, CD38 receptor triggering results in Lck-regulated activation of both Raf-1/MAP kinase and CD3-zeta/ZAP-70/phospholipase C-gamma1 signaling pathways.
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PMID:CD38 ligation results in activation of the Raf-1/mitogen-activated protein kinase and the CD3-zeta/zeta-associated protein-70 signaling pathways in Jurkat T lymphocytes. 920 Apr 55

Thrombopoietin (Tpo), the ligand for c-mpl and a principal regulator of megakaryocytopoiesis and platelet production, has been demonstrated to stimulate the growth and differentiation of megakaryocyte as well as multipotent hemopoietic progenitor cells. In the present study we demonstrate that Tpo can stimulate the adhesion of the Mo7e progenitor cell line to fibronectin (Fn) as well as vascular cell adhesion molecule-1 through activation of very late antigen (VLA)-4 and VLA-5, adhesion molecules previously demonstrated to be involved in regulation of steady state hemopoiesis. Tpo-induced adhesion was concentration dependent, reached a maximum following 30 min, and appeared to be dependent on adenylate cyclase, and tyrosine kinase activity. Furthermore, second messenger inhibitors implicated essential and complimentary roles of phosphatidylinositol-3-kinase and protein kinase C in mediating Tpo-induced adhesion. The ability of Tpo to promote adhesion to fibronectin was comparable to that of IL-3, but less than that of stem cell factor. Unlike the ability of these cytokines to synergistically enhance growth of Mo7e as well as normal progenitor cells, no synergy was observed with regard to their ability to enhance adhesion. Finally, Tpo stimulated adhesion of primitive (CD34+ CD38-) human bone marrow cells to fibronectin, predominantly through activation of VLA-5, whereas no such effect could be observed on CD34+ CD38+ bone marrow cells. Thus, Tpo might play an important role in early hemopoiesis, at least in part through its ability to promote adhesion through activation of adhesion molecules on hemopoietic progenitor cells.
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PMID:Thrombopoietin promotes adhesion of primitive human hemopoietic cells to fibronectin and vascular cell adhesion molecule-1: role of activation of very late antigen (VLA)-4 and VLA-5. 925 62

CD38 is a multifunctional membrane surface glycoprotein expressed by different cells and tissues, including T cells at certain stages of their development. Besides its involvement in transmembrane signaling, CD38 play a role in cell adhesion processes. Structurally, membrane CD38 was reported as presenting lateral associations with molecules involved in recognition and signaling, namely with the TCR/CD3 complex in T cells. Here we report that ligation of CD38 by agonistic and non-agonistic monoclonal antibodies exerts different effects on T cells, the former inducing down-modulation of the associated molecules, probably through a protein kinase C-dependent mechanism. This observation supports the view that the reduced expression of TCR/CD3 is secondary to interplay with CD38-mediated signaling, which partially overlaps with the CD3-mediated pathway. CD3 ligation by monoclonal antibodies leads not only to the expected internalization of the TCR/CD3 complex but also to down-modulation of surface CD38. The results obtained indicate that CD38 is closely associated with the CD3/TCR complex and that co-modulation of CD38 with TCR/CD3 is a critical step in signaling processes on T lymphocytes.
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PMID:Functional associations of CD38 with CD3 on the T-cell membrane. 958 13

Stem cell homing into the bone microenvironment is the first step in the initiation of marrow-derived blood cells. It is reported that human severe combined immunodeficient (SCID) repopulating cells home and accumulate rapidly, within a few hours, in the bone marrow and spleen of immunodeficient mice previously conditioned with total body irradiation. Primitive CD34(+)CD38(-/low)CXCR4(+) cells capable of engrafting primary and secondary recipient mice selectively homed to the bone marrow and spleen, whereas CD34(-)CD38(-/low)Lin(-) cells were not detected. Moreover, whereas freshly isolated CD34(+)CD38(+/high) cells did not home, in vivo stimulation with granulocyte colony-stimulating factor as part of the mobilization process, or in vitro stem cell factor stimulation for 2 to 4 days, potentiated the homing capabilities of cytokine-stimulated CD34(+)CD38(+) cells. Homing of enriched human CD34(+) cells was inhibited by pretreatment with anti-CXCR4 antibodies. Moreover, primitive CD34(+)CD38(-/low)CXCR4(+) cells also homed in response to a gradient of human stromal cell-derived factor 1 (SDF-1), directly injected into the bone marrow or spleen of nonirradiated NOD/SCID mice. Homing was also inhibited by pretreatment of CD34(+) cells with antibodies for the major integrins VLA-4, VLA-5, and LFA-1. Pertussis toxin, an inhibitor of signals mediated by Galpha(i) proteins, inhibited SDF-1-mediated in vitro transwell migration but not adhesion or in vivo homing of CD34(+) cells. Homing of human CD34(+) cells was also blocked by chelerythrine chloride, a broad-range protein kinase C inhibitor. This study reveals rapid and efficient homing to the murine bone marrow by primitive human CD34(+)CD38(-/low)CXCR4(+) cells that is integrin mediated and depends on activation of the protein kinase C signal transduction pathway by SDF-1.
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PMID:Rapid and efficient homing of human CD34(+)CD38(-/low)CXCR4(+) stem and progenitor cells to the bone marrow and spleen of NOD/SCID and NOD/SCID/B2m(null) mice. 1134 60

Connexin 43 (Cx43) hexameric hemichannels, recently demonstrated to mediate NAD(+) transport, functionally interact in the plasma membrane of several cells with the ectoenzyme CD38 that converts NAD(+) to the universal calcium mobilizer cyclic ADP-ribose (cADPR). Here we demonstrate that functional uncoupling between CD38 and Cx43 in CD38-transfected 3T3 murine fibroblasts is paralleled by decreased [Ca(2+)](i) levels as a result of reduced intracellular conversion of NAD(+) to cADPR. A sharp inverse correlation emerged between [Ca(2+)](i) levels and NAD(+) transport (measured as influx into cells and as efflux therefrom), both in the CD38(+) cells (high [Ca(2+)](i), low transport) and in the CD38(-) fibroblasts (low [Ca(2+)](i), high transport). These differences were correlated with distinctive extents of Cx43 phosphorylation in the two cell populations, a lower phosphorylation with high NAD(+) transport (CD38(-) cells) and vice versa (CD38(+) cells). Conversion of NAD(+)-permeable Cx43 to the phosphorylated, NAD(+)-impermeable form occurs via Ca(2+)-stimulated protein kinase C (PKC). Thus, a self-regulatory loop emerged in CD38(+) fibroblasts whereby high [Ca(2+)](i) restricts further Ca(2+) mobilization by cADPR via PKC-mediated disruption of the Cx43-CD38 cross-talk. This mechanism may avoid: (i) leakage of NAD(+) from cells; (ii) depletion of intracellular NAD(+) by CD38; (iii) overproduction of intracellular cADPR resulting in potentially cytotoxic [Ca(2+)](i).
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PMID:A self-restricted CD38-connexin 43 cross-talk affects NAD+ and cyclic ADP-ribose metabolism and regulates intracellular calcium in 3T3 fibroblasts. 1160 97

Leukemic CD34(+) immature acute myeloid leukemia (AML) cells express Fas receptor but are frequently resistant to Fas agonistic reagents. Fas plays an important role in T-cell-mediated cytotoxicity, and recently it has been suggested that altered Fas signaling may contribute to drug resistance. Therefore, Fas resistance could be one of the mechanisms by which AML progenitors escape chemotherapy or T-cell-based immune intervention. However, the molecular mechanism of Fas resistance in AML cells has not been identified. Fas signaling can be interrupted at 3 mains levels: Fas clustering, alteration of death-inducing-signaling-complex (DISC) formation, and effector caspase inhibition of downstream caspase-8. This study shows that in the Fas-resistant CD34(+)CD38(-) KG1a cells, Fas agonists resulted in Fas aggregation but not in caspase-8 activation, related to a defect in DISC formation. However, pretreatment with chelerythrin, but not with calphostin C, resulted in the restoration of Fas-induced caspase-8 activation and cytotoxicity, suggesting that some atypical protein kinase C (PKC) isoforms contributed to the lack of DISC formation. Indeed, treatment with antisense oligonucleotides directed against PKC zeta and enforced expression of Par-4, a negative regulator of PKC zeta activity, restored Fas-induced caspase-8 activity and apoptosis. Moreover, it was found that PKC zeta interacts with FADD and that PKC zeta immunoextracts prepared from KG1a cells are able to phosphorylate FADD in vitro, whereas this phosphorylation is dramatically reduced in Par-4 transfectant cells. In conclusion, it is suggested that in AML cells, PKC zeta plays an important role in Fas resistance by inhibiting DISC formation, possibly by phosphorylating FADD.
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PMID:Role of protein kinase C zeta isoform in Fas resistance of immature myeloid KG1a leukemic cells. 1173 85


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