Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The CD45 protein is a transmembrane tyrosine phosphatase that is required for normal T and B cell receptor-mediated signaling. In order to study the function of this phosphatase in mast cells, we have isolated a CD45-deficient variant from the rat basophilic leukemia cell line (RBL-2H3), a tumor analog of mucosal mast cells. The secretory response as well as the inositol 1,4,5-triphosphate (InsP3) formation to Fc epsilon RI and ionophore stimuli were similar in the RBL-2H3 cell line and its derived CD45-deficient subpopulation. However, pretreatment with the phorbol ester TPA, which directly activates protein kinase C (PKC), caused a marked increase in mediator release and InsP3 production in the CD45-deficient variant compared to the parental RBL-2H3 cells. These findings suggest that CD45 might directly or indirectly modify the activity of PKC or the InsP3-dephosphorylating phosphatase.
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PMID:CD45-deficient RBL-2H3 cells. Cellular response to Fc epsilon R- and ionophore-induced stimulation. 830 Jan 59

Resistance to FCE 24517 is not related to the emergence of any of the most frequently observed phenotypes. We have found that two resistant cell lines (L1210/24517 murine leukaemia and LoVo/24517 human colon adenocarcinoma) present congenital modifications in tyrosyl phosphatase and kinase activities. Moreover, the cytotoxic activity of FCE 24517 is increased in combination with a tyrosine phosphatase inhibitor and decreased in combination with protein kinase inhibitors, this being in agreement with the hypothesis that the activity of this drug is strictly dependent on the presence of tyrosine phosphorylated protein(s).
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PMID:Decreased tyrosine phosphorylation in tumour cells resistant to FCE 24517 (tallimustine). 851 67

Engagement of the T cell antigen receptor results in both its phosphorylation and its ubiquitination. T cell antigen receptor ubiquitination was evaluated in Jurkat, a well characterized human T leukemia cell line. Treatment of cells with the tyrosine kinase inhibitor herbimycin A resulted in an inhibition of receptor ubiquitination. Consistent with this, pervanadate, which increases cellular tyrosine phosphorylation, enhanced receptor ubiquitination. A requirement for receptor-mediated tyrosine kinase activity for ubiquitination was confirmed in cells lacking the tyrosine kinase p56lck and also in cells that are defective in expression of CD45, a tyrosine phosphatase that regulates the activity of p56lck. The need for tyrosine kinase activation for ubiquitination was not bypassed by directly activating protein kinase C and stimulating endocytosis of receptors. These observations establish ubiquitination of the T cell antigen receptor as a tyrosine kinase-dependent manifestation of transmembrane signaling and suggest a role for tyrosine phosphorylation in the ligand-dependent ubiquitination of mammalian transmembrane receptors.
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PMID:T cell antigen receptor ubiquitination is a consequence of receptor-mediated tyrosine kinase activation. 862 3

The family of cytokines signalling through the common receptor subunit gp130 comprises interleukin (IL)-6, IL-11, leukaemia inhibitory factor, oncostatin M, ciliary neurotrophic factor and cardiotrophin-1. These so-called IL-6-type cytokines play an important role in the regulation of complex cellular processes such as gene activation, proliferation and differentiation. The current knowledge on the signal-transduction mechanisms of these cytokines from the plasma membrane to the nucleus is reviewed. In particular, we focus on the assembly of receptor complexes after ligand binding, the activation of receptor-associated kinases of the Janus family, and the recruitment and phosphorylation of transcription factors of the STAT family, which dimerize, translocate to the nucleus, and bind to enhancer elements of respective target genes leading to transcriptional activation. The important players in the signalling pathway, namely the cytokines and the receptor components, the Janus kinases Jak1, Jak2 and Tyk2, the signal transducers and activators of transcription STAT1 and STAT3 and the tyrosine phosphatase SHP2 [SH2 (Src homology 2) domain-containing tyrosine phosphatase] are introduced and their structural/functional properties are discussed. Furthermore, we review various mechanisms involved in the termination of the IL-6-type cytokine signalling, namely the action of tyrosine phosphatases, proteasome, Jak kinase inhibitors SOCS (suppressor of cytokine signalling), protein inhibitors of activated STATs (PIAS), and internalization of the cytokine receptors via gp130. Although all IL-6-type cytokines signal through the gp130/Jak/STAT pathway, the comparison of their physiological properties shows that they elicit not only similar, but also distinct, biological responses. This is reflected in the different phenotypes of IL-6-type-cytokine knock-out animals.
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PMID:Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. 971 87

The transmembrane tyrosine phosphatase CD45 regulates the activity of src family protein tyrosine kinases (PTK) and thereby influences the signaling via such receptors as T and B cell antigen receptors associated with these PTK. However, its implication in signaling through the mast cell receptor with high affinity for IgE (FcepsilonRI) is less clear, although Lyn, a member of the src family, plays an important role in FcepsilonRI-mediated signaling. To define a role for CD45 in FcepsilonRI signal transduction, we established CD45 high expressing rat basophilic leukemia cell lines (RBL-CD45H) and cell lines expressing trace amounts of CD45 (RBL-CD45L). We demonstrate that although all RBL-CD45L cell lines degranulate following IgE- and antigen-induced FcepsilonRI aggregation, the response is significantly reduced at a low dose of antigen. The cells show a delayed and slowed Ca(2+) mobilization even though at a higher dose where the cells degranulate to a similar extent as RBL-CD45H. This diminished Ca(2+) response is restored by reconstitution of RBL-CD45L with a chimeric molecule containing the cytoplasmic phosphatase domains of rat CD45. Furthermore, tyrosine phosphorylation of FcepsilonRI, association of FcepsilonRI with Lyn and PTK activity associated with FcepsilonRI, all of which are enhanced upon FcepsilonRI aggregation in RBL-CD45H, are impaired in RBL-CD45L. Finally, we show that FcepsilonRI is physically associated with CD45 in RBL-CD45H prior to receptor aggregation. Thus, we propose that, although not indispensable in mast cell degranulation, CD45 positively regulates the signaling through FcepsilonRI by promoting the activation of FcepsilonRI-associated Lyn.
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PMID:Regulation of mast cell signaling through high-affinity IgE receptor by CD45 protein tyrosine phosphatase. 1065 52

Cellular transformation by the BCR/ABL oncogene depends on the ABL-encoded tyrosine kinase activity. To block BCR/ABL function, we created a unique tyrosine phosphatase by fusing the catalytic domain of SHP1 (SHP1c) to the ABL binding domain (ABD) of RIN1, an established binding partner and substrate for c-ABL and BCR/ABL. This fusion construct (ABD/SHP1c) binds to BCR/ABL in cells and functions as an active phosphatase. ABD/SHP1c effectively suppressed BCR/ABL function as judged by reductions in transformation of fibroblast cells, growth factor independence of hematopoietic cell lines, and proliferation of primary bone marrow cells. In addition, the leukemogenic properties of BCR/ABL in a murine model system were blocked by coexpression of ABD/SHP1c. Both the "escort" function provided by ABD and the inhibitor function provided by the phosphatase of SHP1c were necessary for effective BCR/ABL interference. Expression of ABD/SHP1c also reversed the transformed phenotype of K562, a human leukemia-derived cell line. These results have direct implications for leukemia therapeutics and suggest an approach to block aberrant signal transduction in other pathologies through the use of appropriately designed escort/inhibitors.
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PMID:BCR/ABL inhibition by an escort/phosphatase fusion protein. 1102

SHP-1 is a key tyrosine phosphatase that acts as a negative regulator of signal transduction in lymphocytes, which has been found down-regulated in several T cell lines derived from human T cell malignancies. The standardization of a sensitive ELISA for the quantification of SHP-1 protein in peripheral T and B lymphocytes has enabled us to quantify the SHP-1 content of freshly isolated T cells from patients with Sezary syndrome and in the Sezary T cell line HUT-78. In all cases, a dramatic decrease in the content of this protein, when compared with the content in healthy volunteer controls, was observed. These results were corroborated when the expression of SHP-1 mRNA was analyzed. In order to study whether there was any correlation between SHP-1 protein expression and tyrosine phosphorylated state of JAK3, the state of phosphorylation of JAK3 was studied in the T cell line HUT-78, and found to be highly phosphorylated. These results suggest that SHP-1 might be involved in maintaining the IL-2R/JAK3 signaling pathway under control and point towards a role of SHP-1 in the pathogenesis of the disease.
Leukemia 2002 Aug
PMID:SHP-1 expression in peripheral T cells from patients with Sezary syndrome and in the T cell line HUT-78: implications in JAK3-mediated signaling. 1214 87

The human NKG2A chain of the CD94/NKG2A receptor contains two immunoreceptor Tyr-based inhibitory motifs (ITIMs) in its cytoplasmic tail. To determine the relative importance of membrane-distal (residues 6-11) and membrane-proximal (residues 38-43) ITIMs in mediating the inhibitory signal, we made site-directed mutants of NKG2A at the Y (Y8F, Y40F, Y8F/Y40F) and the residues two positions N-terminal (Y-2) of Y (V6A, I38A, V6A/I38A) in each motif. Wild-type (wt) and mutated NKG2A were then cotransfected with CD94 into rat basophilic leukemia 2H3 cells. Immunochemical analyses after pervanadate treatment showed that each of the mutant molecules could be phosphorylated to expected levels relative to wt NKG2A and that all the mutations significantly reduced the avidity of SH2 domain-bearing tyrosine phosphatase-1 for NKG2A. Confocal microscopy was used to determine whether SH2 domain-bearing tyrosine phosphatase-1 and CD94/NKG2A colocalized intracellularly after receptor ligation. Only the Y8F/Y40F and Y8F mutant NKG2A molecules failed to show a dramatic colocalization. In agreement with this result, the Y8F/Y40F mutant was unable to inhibit FcepsilonRI-mediated serotonin release and the Y8F mutant was relatively ineffective compared with wt NKG2A. In contrast, the Y40F mutant was 70% as effective as wt in mediating inhibition, and the Y-2 mutations did not remarkably affect inhibitory function. These results show that, like KIR, both NKG2A ITIMs are required for mediating the maximal inhibitory signal, but opposite to KIR, the membrane-distal ITIM is of primary importance rather than the membrane-proximal ITIM. This probably reflects the opposite orientation of the ITIMs in type II vs type I proteins.
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PMID:Role that each NKG2A immunoreceptor tyrosine-based inhibitory motif plays in mediating the human CD94/NKG2A inhibitory signal. 1216 20

Patients with T-cell large granular lymphocyte (T-LGL) leukaemia and autoimmune lymphoproliferative syndrome (ALPS) share many features, including autoimmunity and an expansion of (cytotoxic) T cells, which in ALPS patients express an unusual (B220) isoform of CD45, corresponding to an altered O-glycosylation profile. Here we showed that T-LGL leukaemia cells also expressed this B220 isoform. We hypothesize that B220+ T cells constitute proliferating T cells that have become competent to undergo apoptosis, but that constitutive (ALPS) or functional (T-LGL) defects prevent this process. Altered O-glycosylation of the extracellular domains of CD45 may have consequences for this tyrosine phosphatase as a regulator of cell proliferation and survival.
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PMID:Common expression of an unusual CD45 isoform on T cells from patients with large granular lymphocyte leukaemia and autoimmune lymphoproliferative syndrome. 1249 82

In response to PMA treatment K562 myelogenous leukemia cells undergo megakaryocytic differentiation, which is dependent on prolonged ERK activation and is characterized by growth arrest, upregulation of CD41 and IL-6, and, finally, by characteristic changes in cell morphology. The tyrosine phosphatase HePTP was recently demonstrated to regulate ERK activity and changes in HePTP expression have been associated with hematopoietic malignancies. Here, we have studied the function of HePTP during PMA-induced megakaryocytic differentiation of K562 cells. Overexpression of HePTP or inhibition of HePTP expression with antisense cDNA had no effect on PMA-induced cell cycle arrest or upregulation of cyclin D in K562 cells. The expression of megakaryocytic markers such as CD41 and IL6, however, were highly reduced in cells overexpressing HePTP, due to reduced ERK activation, and the cells were impaired in their ability to differentiate. Compared to control cells, HePTP antisense expressing cells did not show increased basal or PMA-induced ERK activity. However, antisense inhibition of HePTP enhanced nuclear translocation of ERK and the expression of the megakaryocytic markers CD41 and IL-6. Interestingly, like cells overexpressing HePTP, morphological differentiation was also impaired in HePTP antisense expressing cells. The results for the first time demonstrate that different aspects of megakaryocytic differentiation have distinct requirements for ERK activity. They further show that HePTP is involved in the regulation of nuclear translocation of ERK2 and that HePTP protein levels can modulate K562 cell differentiation.
Leukemia 2003 Feb
PMID:The protein tyrosine phosphatase HePTP regulates nuclear translocation of ERK2 and can modulate megakaryocytic differentiation of K562 cells. 1259 37


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