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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rapid increases in the membrane expression of C3 receptors on granulocytes and monocytes in response to the anaphylatoxin C5a have previously been described. In this study we demonstrate increases in the membrane expression of neutral endopeptidase (NEP, CD10, CALLA), aminopeptidase N (APN, CD13), tyrosine phosphatase (CD45/CD45Ro) and the Fc R Fc gamma-RIII (CD16) on granulocytes within minutes of treatment with human C5a. Monocytes responded to C5a with increases in CD13 and CD45/CD45Ro. These membrane modulations could be prevented by preincubating the C5a preparations with anti-C5a mAb C17/5 but not by pretreating the cells with cycloheximide. Increases of CD10, CD13, and CD11b but not CD11a (LFA-1) were also observed in leukocytes from patients undergoing hemodialysis with cuprophan membranes. The increase of CD16 on granulocytes was dependent on the presence of plasma during in vitro activation with C5a indicating that plasma contains inhibitors which prevent the previously described loss of Fc gamma-RIII upon stimulation of the cells.
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PMID:Rapid increases in the membrane expression of neutral endopeptidase (CD10), aminopeptidase N (CD13), tyrosine phosphatase (CD45), and Fc gamma-RIII (CD16) upon stimulation of human peripheral leukocytes with human C5a. 168 87

Autologous monocytes irreversibly suppressed functions of human natural killer (NK) cells including baseline and lymphokine-induced cytotoxicity, antibody-dependent cellular cytotoxicity (ADCC), and interleukin-2 (IL-2)-induced proliferation. The suppression of these NK-cell functions was cell contact-dependent and could be evoked only by purified monocytes, recovered directly from peripheral blood by countercurrent centrifugal elutriation (CCE). The presence of monocytes also induced the disappearance of CD16 and CD56 antigen on CD3- NK cells (CD3-/16+/56+-->CD3-/16-/56-). By contrast, T-cell proliferation and the expression of CD3 on CD56- T cells were not susceptible to cell contact-mediated suppression by monocytes. The biogenic amine serotonin abrogated monocyte-induced suppression of NK-cell functions as well as down-modulation of CD16/56 NK-cell antigen. Serotonin thus markedly augmented baseline and lymphokine-induced NK-cell cytotoxicity, ADCC, and NK-cell proliferation, and maintained the expression of NK-cell surface antigens in the presence of elutriated monocytes. The effect of serotonin was mediated by 5-HT1A-type serotonin receptors (5-HT1AR) as indicated by mimicry exerted by 5-HT1AR agonists such as 8-OH-DPAT and (+)-ALK, partial antagonism by the 5-HT1AR antagonists pindolol and cyproheptadine, and lack of antagonism by the 5-HT2R antagonist ketanserin or the 5-HT3R antagonist ondansetron. Our data are suggestive of a cell-to-cell-mediated mechanism by which monocytes down-modulate NK-cell function and phenotype and its serotonergic regulation.
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PMID:Serotonergic 5-HT1A receptors regulate a cell contact-mediated interaction between natural killer cells and monocytes. 767 81

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

Bispecific monoclonal antibodies (BsmAb) with specificity for tumor Ag and effector cell trigger molecules have been shown to redirect the cytotoxicity of several peripheral blood mononuclear cell populations against relevant tumor. The BsmAb, 2B1, binds to the extracellular domain of the c-erbB-2 gene product of the HER2/neu proto-oncogene and to CD16. In this report, the binding and cytotoxic characteristics of 2B1 are presented. Maximal saturation binding of 2B1 to PBL and c-erbB-2 expressing SK-OV-3 cells occurred in the 1 microgram/ml concentration range. However, substantial lysis potentiation was observed at 1000-fold lower BsmAb concentrations. Optimal tumor lysis was obtained when the BsmAb, PBL, and target cells were continuously coincubated. When PBL were franked with 2B1, washed, and added to labeled targets, substantially less lysis was observed. These results suggest that the best way to therapeutically exploit the cytotoxic attributes of 2B1 may be to obtain continuous BsmAb exposure to tumor. Approaches based on franking of this BsmAb to PBL may not be warranted.
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PMID:Binding and cytotoxicity characteristics of the bispecific murine monoclonal antibody 2B1. 810 70

Expression of the CD4 antigen was observed on human fetal liver, fetal bone marrow (BM), and umbilical cord blood progenitors expressing high levels of CD34. Using clonal and liquid-culture assays, CD4+ CD34++ Lin- (lineage = CD3, CD8, CD10, CD14, CD15, CD16, CD19, CD20, and glycophorin A) fetal liver progenitors were found to have a greater proliferative potential than CD4- CD34++ Lin- progenitors, whereas the CD4- fraction was more enriched for erythroid progenitors. Both the CD4+ and the CD4- progenitor subpopulations also gave rise to multilineage engraftment upon transplantation into human fetal bone fragments, supportive of B-lymphoid and myeloid growth, or into human fetal thymic fragments, supportive of T-cell growth, implanted in scid/scid (SCID) mice. However, in SCID-hu mice transplanted with graded doses of donor cells ranging from 2.0 x 10(2) to 2.0 x 10(4) cells, BM reconstitution by the CD4+ fraction of CD34++ Lin- cells was more frequent than by the CD4- fraction when low numbers of cells were injected. These functional data strongly suggest that stem cells reside among CD4+ CD34++ Lin- fetal liver cells. This hypothesis was further supported by the observations that CD4+ CD34++ Lin- fetal liver cells were enriched for CDw90+ (Thy-1), CD117+ (kit), CD123+, HLA-DR+, CD7-, CD38-, CD45RA-, CD71-, CD115- (fms), and rhodamine 123(dull) cells, a phenotypic profile believed to represent fetal stem cells. Furthermore, all CD4+ CD34++ Lin- fetal liver cells also expressed CD13 and CD33.
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PMID:Phenotypic and functional evidence for the expression of CD4 by hematopoietic stem cells isolated from human fetal liver. 902 60

LCK is a non-receptor protein tyrosine kinase required for signal transduction via the T-cell antigen receptor (TCR). LCK N-terminus is S-acylated on Cys3 and Cys5, in addition to its myristoylation on Gly2. Here the role of S-acylation in LCK function was examined. Transient transfection of COS-18 cells, which express a CD8-zeta chimera on their surface, revealed that LCK mutants that were singly S-acylated were able to target to the plasma membrane and to phosphorylate CD8-zeta. A non-S-acylated LCK mutant did not target to the plasma membrane and failed to phosphorylate CD8-zeta, although it was catalytically active. Fusion of non-S-acylated LCK to a transmembrane protein, CD16:7, allowed its plasma membrane targeting and also phosphorylation of CD8-zeta when expressed in COS-18 cells. Thus S-acylation targets LCK to the plasma membrane where it can interact with the TCR. When expressed in LCK-negative JCam-1.6 T cells, delocalized, non-S-acylated LCK was completely non-functional. Singly S-acylated LCK mutants, which were expressed in part at the plasma membrane, efficiently reconstituted the induced association of phospho-zeta with ZAP-70 and intracellular Ca2+ fluxes triggered by the TCR. Induction of the late signalling proteins, CD69 and NFAT, was also reconstituted, although at reduced levels. The transmembrane LCK chimera also supported the induction of tyrosine phosphorylation and Ca2+ flux by the TCR in JCam-1.6 cells. However, induction of ERK MAP kinase was reduced and the chimera was incapable of reconstituting induced CD69 or NFAT expression. These data indicate that LCK must be attached to the plasma membrane via dual acylation of its N-terminus to function properly in TCR signalling.
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PMID:S-acylation of LCK protein tyrosine kinase is essential for its signalling function in T lymphocytes. 930 40

Extracellular signal-regulated kinases (ERK, also known as mitogen-activated protein kinases) are serine-threonine kinases transducing signals elicited upon ligand binding to several tyrosine kinase-associated receptors. We have reported that ERK2 phosphorylation and activation follows engagement of the low affinity receptor for the Fc portion of IgG (CD16) on NK cells, and is necessary for CD16-induced TNF-alpha mRNA expression. Here, we analyzed the involvement of ERK in NK cell-mediated cytotoxicity and IFN-gamma expression induced upon stimulation with targets cells, coated or not with Abs. Our data indicate that, as with immune complexes, ERK2 phosphorylation occurs in human primary NK cells upon interaction with target cells sensitive to granule exocytosis-mediated spontaneous cytotoxicity, and that this regulates both target cell- and immune complex-induced cytotoxicity and IFN-gamma mRNA expression. A specific inhibitor of mitogen-activated protein kinase kinase reduced both spontaneous and Ab-dependent cytotoxicity in a dose-dependent manner involving, at least in part, inhibition of granule exocytosis without affecting effector/target cell interaction and rearrangement of the cytoskeleton proteins actin and tubulin. Involvement of ERK in the regulation of Ca2+-dependent cell-mediated cytotoxicity was confirmed, using a genetic approach, in primary NK cells infected with a recombinant vaccinia virus encoding an ERK inactive mutant. These data indicate that the biochemical pathways elicited in NK cells upon engagement of receptors responsible for either spontaneous or Ab-dependent recognition of target cells, although distinct, utilize ERK as one of their downstream molecules to regulate effector functions.
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PMID:Dependence of both spontaneous and antibody-dependent, granule exocytosis-mediated NK cell cytotoxicity on extracellular signal-regulated kinases. 986 93

We report on a series of 26 patients diagnosed with primary (de novo) plasma cell (PC) leukemia (PCL) in whom we analyzed the clinicobiologic characteristics of the disease together with the immunophenotype, DNA cell content, proliferative index, and numeric chromosomal aberrations of the neoplastic PC, and compared them with 664 multiple myeloma (MM) patients at diagnosis. The median age, sex ratio, and bone lesion extension were similar, but PCL cases displayed a higher prevalence of clinical stage III, extramedullary involvement, and Bence Jones cases, with fewer IgA cases than for MM patients. In addition, according to several prognostic indicators (beta2-microglobulin serum level, proportion of S-phase PCs, proteinuria, calcium serum level, lactate dehydrogenase [LDH] and renal function), the incidence of adverse prognostic factors was significantly higher in PCL versus MM. Immunophenotypic expression was similar for CD38, CD138, CD2, CD3, CD16, CD10, CD13, and CD15, but PCL differed from MM in the expression of CD56, CD9 HLA-DR, CD117, and CD20 antigens. Twenty-two PCL cases were diploid and one was hypodiploid, while most MM cases (57%) showed DNA hyperdiploidy. With the fluorescent in situ hydridization (FISH) technique, 12 of 13 PCL cases displayed the numeric aberrations, -13 (86%), +/-1 (57%), +18 (43%), and -X in women (25%), but they lacked several numeric aberrations usually found in MM such as +3, +6, +9, +11, and +15. PCL cases had a lower overall response to therapy than MM cases (38% v 63%, P =.01332). Among PCL patients, a trend for a worse response was observed in cases treated with melphalan and prednisone (MP) versus polychemotherapy. Overall survival was significantly worse in PCL versus MM patients (8 v 36 months, P <.0001), but it was significantly better in PCL patients treated with polychemotherapy versus MP (18 v 3 months, P =.0137). By contrast, MM patients did not show significant differences in overall survival according to the treatment used, MP or polychemotherapy. Ten variables seemed to predict survival in PCL patients, but only the beta2-microglobulin level and S-phase PCs retained an independent value in multivariate analysis. In summary, our study illustrates that PCs from PCL display singular phenotypic, DNA cell content, and cytogenetic characteristics that lead to a different disease evolution versus MM.
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PMID:Primary plasma cell leukemia: clinical, immunophenotypic, DNA ploidy, and cytogenetic characteristics. 1061 Jan 15

The CD94/NKG2-A complex is the inhibitory receptor for the nonclassical MHC class I molecule HLA-E on human NK cells. Here we studied the molecular mechanisms underlying the inhibitory activity of CD94/NKG2-A on NK cell functions by analyzing its interference on CD16-initiated signaling pathways involved in the control of cytolytic activity. Both tyrosine phosphorylation and activation of Syk kinase together with tyrosine phosphorylation of CD16 receptor zeta subunit are markedly inhibited by the coengagement of CD94/NKG2-A complex. As a downstream consequence, CD94/NKG2-A cross-linking impairs the CD16-induced activation of extracellular regulated kinases (ERKs), a pathway involved in NK cytotoxic function. The block of ERK activation is exerted at an early, PTK-dependent stage in the events leading to p21ras activation, as the CD16-induced tyrosine phosphorylation of Shc adaptor protein and the formation of Shc/Grb-2 complex are abrogated by CD94/NKG2-A simultaneous engagement. Our observations indicate that CD94/NKG2-A inhibits the CD16-triggered activation of two signaling pathways involved in the cytotoxic activity of NK cells. They thus provide molecular evidence to explain the inhibitory function of CD94/NKG2-A receptor on NK effector functions.
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PMID:CD94/NKG2-A inhibitory complex blocks CD16-triggered Syk and extracellular regulated kinase activation, leading to cytotoxic function of human NK cells. 1035 64

Bispecific antibody (bsAb)-based clinical trials of cancer have been conducted primarily using intact murine monoclonal antibody (mAb)-derived molecules. In some of these trials, toxicity resulting from the interactions of antibody Fc domains with cellular Fc receptors has limited the doses of antibody (Ab) that can be employed. Furthermore, human anti-mouse Ab responses prohibit multiple therapy courses. These factors have decreased the efficacy of the bsAb 2B1, which targets the extracellular domains (ECD) of the HER2/neu protooncogene product and the human FcgammaRIII (CD16). To address these obstacles, we have constructed and characterized a fully human gene-fused bsAb from single-chain Fv (scFv) molecules specific for HER2/neu and CD16. The human anti-CD16 scFv component, NM3E2, was isolated from a human scFv phage display library. As binding of NM3E2 to human neutrophil-associated CD16 decreased in the presence of plasma IgG, we have concluded that NM3E2 recognizes an epitope in the vicinity of the Fc binding pocket. Furthermore, the NM3E2 scFv was found by surface plasmon resonance-based epitope mapping to share an overlapping epitope with the Leu-11c mAb. The human anti-HER2/neu scFv component, C6.5, which was previously isolated from a human scFv phage display library, was employed as fusion partner for the creation of a bispecific scFv (bs-scFv). In the presence of the C6.5 x NM3E2 bs-scFv, peripheral blood lymphocytes promoted significant lysis of human SK-OV-3 ovarian cancer cells overexpressing HER2/neu. Biodistribution studies performed in SK-OV-3 tumor-bearing scid mice revealed that 1% ID/g of 125I-labeled C6.5 x NM3E2 bs-scFv was specifically retained in tumor at 23 h following injection. These results indicated that both scFv components of the bs-scFv retained their function in the fusion protein. This bsAb should overcome some of the problems associated with the 2B1 bsAb. C6.5 x NM3E2 bs-scFv offers promise as a platform for multifunctional binding proteins with potential clinical applications as a result of its human origin, lack of an Fc domain, ease of production, high level of in vitro tumor cell cytotoxicity and highly selective tumor targeting.
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PMID:Isolation and characterization of an anti-CD16 single-chain Fv fragment and construction of an anti-HER2/neu/anti-CD16 bispecific scFv that triggers CD16-dependent tumor cytolysis. 1044 96


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