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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Expression of the CD45 tyrosine protein phosphatase is required for the response of functional lymphocytes to stimulation through the antigen receptor. One or more of its substrates may therefore be essential for signal transduction during lymphocyte activation. We have studied the phosphorylation of the closely related lck, fyn, and c-src tyrosine protein kinases in leukemic murine T-cell lines that have lost the expression of CD45. The phosphorylation of the lck kinase at an inhibitory site of tyrosine phosphorylation, Tyr-505, was increased by two-, six-, and eightfold in three different cell lines. Phosphorylation of the fyn kinase at the homologous site, Tyr-531, was unaltered in one of these cell lines, but increased by 2.5-fold in the two others. The phosphorylation of p60c-src at the homologous tyrosine was essentially unchanged in the one CD45-negative cell line in which it was examined. The expression of CD45 therefore regulates the phosphorylation and potentially the activity of the lck and fyn tyrosine protein kinases, but the effect on the lck kinase is much greater than on the fyn kinase. This finding and the observation that CD45 had no effect on the phosphorylation of p60c-src suggest that CD45 exhibits polypeptide substrate specificity in vivo. Additionally, these findings are consistent with the hypothesis that the unresponsiveness of CD45-negative lymphoid cells to antigenic stimulation is due largely to hyperphosphorylation of the lck kinase.
Mol Cell Biol 1993 Mar
PMID:Differential effects of expression of the CD45 tyrosine protein phosphatase on the tyrosine phosphorylation of the lck, fyn, and c-src tyrosine protein kinases. 844 3

Ligation of the B cell Ag receptor (BCR) activates a protein-tyrosine kinase (PTK) and CD45 protein-tyrosine phosphatase (PTPase)-dependent signaling cascade that results in the activation of Ras. This pathway of Ras activation can operate independently of protein kinase C (PKC) activity. Activation of Ras may lead to two distinct Ras-dependent pathways involving either a Raf1/MEK/MAPK module or a MEKK/SEK/SAPK module; however, it is unclear as to how Ras controls the independent activation of either of these pathways. We have used genistein and phenylarsine oxide (PAO) as inhibitors of PTK and PTPase, respectively, to investigate whether they regulate the BCR- and Ca2+/PKC-dependent activation of the Ras/Raf1/MEK/MAPK module. Assays of phosphotransferase activities conducted with Ag (TNP6-OVA)-specific 7.9 murine B lymphoma cells demonstrated that BCR-mediated stimulation of the Raf1/MEK/MAPK module is controlled by PTK and PTPase activities. An elevation in [Ca2+]i was required to optimally activate Raf1 and MEK through the BCR. However, when signaling through the BCR was bypassed by direct stimulation of the Raf1/MEK/MAPK module via a rise in [Ca2+]i and phorbol ester-induced PKC activation, the phosphotransferase activities of Raf1, MEK and MAPK were still regulated in a PTK-dependent manner that was also partially sensitive to the PTPase inhibitor PAO. Thus, at least two alternate routes, i.e. a BCR/PTK/Ras-dependent route and another PKC/Ca(2+)-dependent route, may converge at the level of Raf1 for activation of the Raf1/MEK/MAPK module in B cells.
Mol Immunol 1996 Feb
PMID:Regulation of BCR- and PKC/Ca(2+)-mediated activation of the Raf1/MEK/MAPK pathway by protein-tyrosine kinase and -tyrosine phosphatase activities. 864 50

Depending on their prior antigen recognition history, mature T cells respond with different functional outcomes to T cell receptor (TCR) stimulation. These functional outcomes include proliferation, anergy and cell death. The biochemical basis underlying differential responses by mature T cells at different stages of their developmental pathway to TCR stimulation remains to be determined. We have previously shown that proliferating but not naive T cells were susceptible to apoptosis after TCR stimulation and that the tyrosine phosphorylation of TCR zeta, CD3 gamma, and CD3 epsilon in proliferating T cells was decreased after TCR stimulation. In this study. We determined whether differences in phosphorylation between naive and proliferating T cells were due to altered regulation of p56lck (Lck) or p59fyn (Fyn) by their positive or negative regulators, CD45 or p5Ocsk (Csk), respectively. We found that Lck was expressed at the same level and had the same phosphotyrosine content in naive and proliferating T cells. However, its autophosphorylation activity was lower in proliferating cells, corresponding to a 2-fold decrease in its specific kinase activity. Similarly, the specific kinase activity of Fyn was also decreased by about 2-fold in proliferating T cells. In contrast, although Csk was expressed at the same level in both cell types its specific kinase activity was increased by 6-fold in proliferating T cells. The tyrosine phosphatase CD45, a positive regulator of src-family kinases, was overexpressed by 3- to 6-fold in proliferating cells. However, the specific activity of CD45 in naive and proliferating T cells was the same. Therefore, although the protein expression level of CD45 was increased in proliferating T cells it only partially compensated for the hyperactivity of Csk resulting in a 2-fold reduction in the specific activity of Lck and Fyn in proliferating T cells.
Mol Immunol 1996 Apr
PMID:Increase in the specific activity of p50csk in proliferating T cells correlates with decreased specific activity of p56lck and p59fyn and reduced phosphorylation of CD3 subunits. 870 Jan 69

The CD45 tyrosine phosphatase has been reported to activate the src family tyrosine kinases Lck and Fyn by dephosphorylating regulatory COOH-terminal tyrosine residues 505 and 528, respectively. However, recent studies with CD45- T-cell lines have found that despite the fact that Lck and Fyn were constitutively hyperphosphorylated, the tyrosine kinase activity of both enzymes was actually increased. In the present study, phosphoamino acid analysis revealed that the increased phosphorylation of Lck in CD45- YAC-1 T cells was restricted to tyrosine residues. To understand the relationship between tyrosine phosphorylation and Lck kinase activity, CD45- YAC-1 cells were transfected with forms of Lck in which tyrosines whose phosphorylation is thought to regulate enzyme activity (Tyr-192, Tyr-394, Tyr-505, or both Tyr-394 and Tyr-505) were replaced with phenylalanine. While the Y-to-F mutation at position 192 (192-Y-->F) had little effect, the 505-Y-->F mutation increased enzymatic activity. In contrast, the 394-Y-->F mutation decreased the kinase activity to very low levels, an effect that the double mutation, 394-Y-->F and 505Y-->F, could not reverse. Phosphopeptide analysis of tryptic digests of Lck from CD45- YAC-1 cells revealed that it is hyperphosphorylated on two tyrosine residues, Tyr-505 and, to a lesser extent, Tyr-394. The purified and enzymatically active intracellular portion of CD45 dephosphorylated Lck Tyr-394 in vitro. These results demonstrate that in addition to Tyr-505, CD45 can dephosphorylate Tyr-394, and that in the absence of CD45 the hyperphosphorylation of Tyr-394 can cause an increase in the kinase activity of Lck despite the inhibitory hyperphosphorylation of Tyr-505. Therefore, Lck kinase activity is determined by the balance of activating and inhibitory tyrosine phosphorylations that are, in turn, regulated by CD45.
Mol Cell Biol 1996 Sep
PMID:Mutational analysis of Lck in CD45-negative T cells: dominant role of tyrosine 394 phosphorylation in kinase activity. 875 58

B-cell non-Hodgkin's lymphomas with a marked preponderance of reactive T cells, so-called T-cell rich B-cell lymphomas (TCRBCLs), can be morphologically confused with Hodgkin's disease (HD). To establish helpful distinguishing features in paraffin sections, 10 cases of L26-positive, CD15-negative HD and 10 cases of TCRBCL were compared; 4 cases of HD had morphologic features of the nodular lymphocyte predominant (LP) type. Nine of 10 cases of HD contained fewer than 20 mitoses/20 high power fields (hpf) and only 1 had pericapsular involvement. In contrast, 9 of 10 TCRBCL had greater than 20 mitoses/20 hpf and 7 had perinodal infiltration. HDLP was easily distinguished from TCRBCL by the expanded dendritic meshworks outlining the L & H nodules and the high content of CD57-positive lymphocytes. The remaining 6 cases of non-LP L26-positive HD had a relatively distinctive immunostaining pattern, with absence of CD45 and discordant reactivity for L26 and Ki-B5 in Reed-Sternberg cells and variants. Only 3 cases of TCRBCL had a similar CD45 and L26/Ki-B5 immunostaining pattern, and these could be distinguished by demonstrable cytoplasmic light-chain restriction. These results show that evaluation of the mitotic count, pericapsular involvement, and immunohistochemical staining patterns for Ki-M4p, CD57, L26/Ki-B5, and CD45 can help to discriminate TCRBCL from L26-positive HD when only fixed material is available.
Hematopathol Mol Hematol 1996
PMID:Differential diagnosis of L26-positive, CD15-negative Hodgkin's disease and large B-cell lymphoma with a high content of reactive T-cells: a morphologic and immunohistochemical study. 887 32

We investigated the contribution of hemopoietic progenitors to the accumulation of inflammatory cells in allergic airways disease. Using a multiparameter flow-cytometric method, the detection of peripheral blood (PB) and bone marrow (BM) cells expressing CD34, a progenitor cell marker, was explored. True CD34+ blast cells were detected as a discrete cluster exhibiting low intensity CD45 expression, low granularity, and low to intermediate cell size. A significantly greater number of CD34+ cells was detected in the PB of atopic individuals (1,438 +/- 347/10(6) nonadherent mononuclear cells [NAMNC], n = 19) compared with nonatopics (236 +/- 77/10(6) NAMNC, n = 13; P = 0.006). Similarly, in BM samples, a significantly greater number of CD34+ cells was detected in atopic (17,537 +/- 4,986/10(6) NAMNC, n = 7) compared with nonatopic subjects (6,422 +/- 1,853/10(6) NAMNC, n = 13, P = 0.02). Greater numbers of total colony-forming units (CFU) (granulocyte/macrophage [GM] and Eo/Baso) were present in cultures of PB NAMNC from atopics (24 +/- 5 CFU/10(6) NAMNC) cultured with recombinant human interleukin 5 (rhIL-5) (1 ng/ml) compared with nonatopics (5 +/- 2 CFU/10(6) NAMNC; P = 0.003). Analyses of colony subtypes showed significantly greater numbers of IL-5-responsive Eo/Baso-CFU in cultures from atopics (15 +/- 2 CFU/10(6) NAMNC) compared with nonatopics (5 +/- 2 CFU/10(6) NAMNC; P = 0.011). In contrast, no significant differences in colony counts were found between the two subject groups in cultures with rhIL-3 (1 ng/ml) or rhGM-CSF (10 ng/ml). A positive correlation was observed between PB CD34+ cell numbers and total CFU in cultures with rhIL-5 (r = 0.43, n = 32, P = 0.01) and rhGM-CSF (r = 0.45, n = 32, P = 0.009). Purging BM NAMNC with an anti-CD34 monoclonal antibody completely abrogated in vitro colony growth, supporting the view that a subset of CD34+ cells represents the relevant population of progenitors growing in culture. These data indicate that flow cytometric estimation of CD34+ cells is predictive of the colony-forming capacity of the sample and may be a useful alternative tool to clonogenic assays for enumerating progenitors. In addition, raised levels of CD34+ cells and IL-5-responsive Eo/Baso-CFU in atopics, including patients with atopic asthma, indicate a role for progenitors in allergic airways disease.
Am J Respir Cell Mol Biol 1996 Nov
PMID:Increased levels of CD34+ hemopoietic progenitor cells in atopic subjects. 891 71

Autoantibodies to the i, I and Pr2 carbohydrate determinants bind red blood cells, preferentially at low temperature in vitro. Using multiparameter flow cytometric analyses, we demonstrate that each of these autoantibodies also react with human and mouse lymphocytes at physiologic temperatures. The anti-Pr2 autoantibody recognizes a glycoprotein determinant(s) expressed by a subset of both T and B lymphocytes. In contrast, the binding of anti-i and anti-I antibodies each is restricted to B-lymphocytes. The anti-i autoantibody binds to over 50% of all B cells, whereas the anti-I antibody reacts with less than 10% of either tonsillar or blood B cells. Prior studies identified that the B cell isoform of CD45 (B220) has the linear poly-N-acetyllactosamine that forms the "i" determinant. Because anti-B220 antibodies recently have been reported to influence T-dependent B-cell isotype switching, we tested each antibody for its ability to influence the production of secondary Ig isotypes by murine splenocytes co-cultured with a stimulator helper T cell clone. We find that addition of anti-i antibody increases the proportion of B cells secreting secondary Ig isotypes. In contrast, the anti-I antibody had no such effect. These findings imply that stimulation of B cells through the highly conserved carbohydrate determinant that forms the "i" antigen may be of physiologic importance in T-dependent B-cell differentiation.
Blood Cells Mol Dis 1996
PMID:The V4-34 encoded anti-i autoantibodies recognize a large subset of human and mouse B-cells. 893 53

MRL/Mp-lpr/lpr mice develop a spontaneous lupus syndrome, including hypergammaglobulinemia, autoantibodies, glomerulonephritis, and lymphadenopathy. To investigate the role of lymphocytes subsets in the pathogenesis of disease, lupus-prone MRL mice deficient in alpha beta T cells, gamma delta T cells, or both were generated. Mice deficient in alpha beta T cells developed a partially penetrant lupus syndrome, characterized by lymphadenopathy, elevated levels of class-switched immunoglobulins, an increased incidence of antinuclear antibodies, and immune deposits in kidneys which progressed to renal insufficiency over time. In comparison to wild type animals, gamma delta T cell-deficient animals developed an accelerated and exacerbated disease phenotype, characterized by accelerated hypergammaglobulinemia and enhanced autoantibody production and mortality. Repertoire analysis of these latter animals identified polyclonal expansion (V beta) of alpha beta CD4+ B220-cells. Mice lacking both alpha beta and gamma delta T cells failed to generate class-switched autoantibodies and immune complex renal disease. First, these findings demonstrate that murine lupus in the setting of Fas-deficiency does not absolutely require the presence of alpha beta T cells, and they also suggest that a significant basis for MRL/lpr disease, including renal disease, involves alpha beta T cell-independent, gamma delta T cell dependent, polyreactive B cell autoimmunity, upon which alpha beta T cell-dependent mechanisms aggravate specific autoimmune responses. Second, these data indicate that gamma delta T cells partake in the regulation of systemic autoimmunity, presumably via their effects on alpha beta CD4+ B220-T cells that provide B cell help. Finally, these results demonstrate that MRL/lpr B cells, despite their intrinsic abnormalities, cannot per se cause tissue injury without T cell help.
Mol Biol Rep 1996
PMID:T cells in murine lupus: propagation and regulation of disease. 911 36

During 15 days of treatment of K562 cells with sodium phenylacetate, we observed an increase in the cellular hemoglobin concentration with a similar increase in the expression of gamma-globin mRNA. Morphological studies demonstrated characteristic features of erythroid differentiation and maturation. At the same time there was no change in the level of expression of the cell surface antigenes CD33, CD34, CD45, CD71 and glycophorin A. Likewise, the level of expression of the erythroid transcription factors GATA-1, GATA-2, NF-E2, SCL and RBTN2, all expressed in untreated K562 cells, did not increase during sodium phenylacetate induced erythroid differentiation. The expression of the nuclear factors Evi-1 and c-myb, known to inhibit erythroid differentiation, did not decrease. We conclude that sodium phenylacetate treatment of K562 cells increases gamma-globin mRNA and induces cell maturation as judged by morphology without affecting the expression of the erythroid transcription factors, some of which are known to be involved in the regulation of beta-like globin genes.
Blood Cells Mol Dis 1997
PMID:Expression of transcription factors during sodium phenylacetate induced erythroid differentiation in K562 cells. 921 48

Rearrangement of the T cell antigen receptor genes is a complex, highly regulated process. To gain a better understanding of the extracellular factors involved in the regulation of TCR beta and gamma gene rearrangement in adult murine bone marrow-resident precursor T cells, several cytokines were tested for their ability to induce gene recombination. A selected population of C58/J bone marrow cells (Thy 1(low), CD3, CD8, B220) that is enriched for pre-T cell activity was propagated in vitro in medium supplemented with IL-3 and mast cell growth factor (MGF, also referred to as stem cell factor, Steele factor and c-kit ligand). These cytokines were required for the maintenance of pre-T cell activity in culture, but had no effect on TCR gene expression. Several additional cytokines were added to the culture medium. Of all those tested, only IL-7 induced complete rearrangement of the TCR gamma locus. Complete rearrangement of the TCR beta locus was not induced under any of the culture conditions analysed here. The bone marrow cells cultured in IL-3, MGF and IL-7 did not begin to express mature T cell proteins and maintained their in vivo progenitor potential. Furthermore, IL-7 cultured bone marrow cells were capable of differentiation in vivo into all phenotypic subpopulations of T cells, without an apparent bias toward the gammadelta lineage. The data presented here suggest that TCR gamma gene rearrangement in adult pre-T cells is regulated by IL-7, but that the TCR beta locus requires additional or alternative signals for the induction of complete rearrangement.
Mol Immunol 1997 Apr
PMID:Interleukin 7 induces TCR gene rearrangement in adult marrow-resident murine precursor T cells. 930 61


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