Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Co-ligation of antigen receptors and type II Fcgamma receptors (FcgammaRIIb) on B cells interrupts signal transduction and ultimately inhibits antibody production. We have identified p52 Shc in the FcgammaRIIb1-specific immunoprecipitates isolated from the membrane fraction of BL41 Burkitt lymphoma cells following B cell receptor-FcgammaRIIb1 co-ligation. The insolubilized synthetic peptide representing the phosphorylated form of the tyrosine-based inhibitory motif of FcgammaRIIb also binds Shc from the lysates of activated but not from resting BL41 cells. This suggests that the binding does not depend on the interaction of FcgammaRIIb1-phosphotyrosine with the SH2 domain of Shc. Tyr phosphorylation of FcgammaRIIb1-associated Shc is low, indicating an impaired function. Shc is implicated in regulating p21(ras) activation; thus, we have compared p21(ras) activities in BL41 cells treated in different ways. p21(ras) activity is reduced when B cell receptor and FcgammaRIIb1 are co-ligated. p21(ras) couples protein-tyrosine kinase-dependent events to the Ser/Thr kinase-mediated signaling pathway leading to the activation of mitogen-activated protein kinases (MAPK). Our results show that B cell receptor-FcgammaRIIb1 co-cross-linking partially inhibits mitogen-activated protein kinase activity. We conclude that FcgammaRIIb1-dependent inhibition of human B cell activation may be based on interrupting signal transduction between protein-tyrosine kinases and the p21(ras)/mitogen-activated protein kinase-dependent activation pathway.
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PMID:Human type II Fcgamma receptors inhibit B cell activation by interacting with the p21(ras)-dependent pathway. 894 17

The glycosylphosphatidylinositol-anchored CD24 protein is a B cell differentiation Ag that is expressed on mature resting B cells but disappears upon Ag stimulation. We used Burkitt's lymphoma (BL) cells, which are thought to be related to germinal center B cells, to examine the biological effect of Ab-mediated CD24 cross-linking on human B cells and observed 1) induction of apoptosis in BL cells mediated by cross-linking of CD24; and 2) synergism between the cross-linking of CD24 and that of the B cell receptor for Ag in the effect on apoptosis induction. We also observed activation of mitogen-activated protein kinases following CD24 cross-linking, suggesting that CD24 mediates the intracellular signaling that leads to apoptosis in BL cells. Although CD24 has no cytoplasmic portion to transduce signals intracellularly, analysis of biochemically separated glycolipid-enriched membrane (GEM) fractions indicated enhanced association of CD24 and Lyn protein tyrosine kinase in GEM as well as increased Lyn kinase activity after CD24 cross-linking, suggesting that CD24 mediates intracellular signaling via a GEM-dependent mechanism. Specific microscopic cocapping of CD24 and Lyn, but not of other kinases, following CD24 cross-linking supported this idea. We further observed that apoptosis induction by cross-linking is a common feature shared by GEM-associated molecules expressed on BL cells, including GPI-anchored proteins and glycosphingolipids. CD24-mediated apoptosis in BL cells may provide a model for the cell death mechanism initiated by GEM-associated molecules, which is closely related to B cell receptor for Ag-mediated apoptosis.
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PMID:CD24 induces apoptosis in human B cells via the glycolipid-enriched membrane domains/rafts-mediated signaling system. 1131 96

We previously reported that the cross-linking of cluster of differentiation (CD)24 induces apoptosis in Burkitt's lymphoma cells and that this phenomenon can be enhanced by a B cell Ag receptor (BCR)-mediated signal. In this study, we extend our previous observation and report that CD24 also mediated apoptosis in human precursor-B acute lymphoblastic leukemia cell lines in the pro-B and pre-B stages accompanying activation of multiple caspases. Interestingly, simultaneous cross-linking of pre-BCR clearly inhibited CD24-mediated apoptosis in pre-B cells. We also observed that mitogen-activated protein kinases (MAPKs) were involved in the regulation of this apoptotic process. Pre-BCR cross-linking induced prompt and strong activation of extracellular signal-regulated kinase 1, whereas CD24 cross-linking induced the sustained activation of p38 MAPK, following weak extracellular signal-regulated kinase 1 activation. SC68376, a specific inhibitor of p38 MAPK, inhibited apoptosis induction by CD24 cross-linking, whereas anisomycin, an activator of p38 MAPK, enhanced the apoptosis. In addition, PD98059, a specific inhibitor of MEK-1, enhanced apoptosis induction by CD24 cross-linking and reduced the antiapoptotic effects of pre-BCR cross-linking. Collectively, whether pre-B cells survive or die may be determined by the magnitude of MAPK activation, which is regulated by cell surface molecules. Our findings should be important to understanding the role of CD24-mediated cell signaling in early B cell development.
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PMID:Pre-B cell antigen receptor-mediated signal inhibits CD24-induced apoptosis in human pre-B cells. 1249 7

Formation of an immunological synapse by T, B, or NK cells is associated with an intercellular transfer of some membrane fragments from their respective target cells. This capture is thought to require effector cell activation by surface recognition of stimulatory ligand(s). However, spontaneous synaptic transfers between homotypic lymphoid cells has never been described. In this study, we show that without adding Ag, resting healthy lymphoid cells and several tumor cell lines are inactive. Conversely, however, some leukemia cell lines including the Burkitt's lymphoma Daudi continuously uptake patches of autologous cell membranes. This intercellular transfer does not involve cytosol molecules or exosomes, but requires cell contact. In homotypic Daudi cell conjugates, this occurs through immunological synapses, involves constitutive protein kinase C and mitogen-activated protein/extracellular signal-regulated kinase kinase activity and strongly increases upon B cell receptor activation. Thus, spontaneous homosynaptic transfer may reflect the hitherto unsuspected autoreactivity of some leukemia cell lines.
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PMID:Spontaneous membrane transfer through homotypic synapses between lymphoma cells. 1292 1

Defects in apoptosis are frequently the cause of cancer emergence, as well as cellular resistance to chemotherapy. These phenotypes may be due to mutations of the tumor suppressor TP53 gene. In this study, we examined the effect of various mitotic spindle poisons, including the new isocombretastatin derivative isoNH2CA-4 (a tubulin-destabilizing molecule, considered to bind to the colchicine site by analogy with combretastatin A-4), on BL (Burkitt lymphoma) cells. We found that resistance to spindle poison-induced apoptosis could be reverted in tumor protein p53 (TP53)-mutated cells by EBV (Epstein Barr virus) infection. This reversion was due to restoration of the intrinsic apoptotic pathway, as assessed by relocation of the pro-apoptotic molecule Bax to mitochondria, loss of mitochondrial integrity and activation of the caspase cascade with PARP (poly ADP ribose polymerase) cleavage. EBV sensitized TP53-mutated BL cells to all spindle poisons tested, including vincristine and taxol, an effect that was systematically downmodulated by pretreatment of cells with inhibitors of p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinases. Exogenous activation of p38 and JNK pathways by dihydrosphingosine reverted resistance of TP53-mutated BL cells to spindle poisons. Dihydrosphingosine treatment of TP53-deficient Jurkat and K562 cell lines was also able to induce cell death. We conclude that activation of p38 and JNK pathways may revert resistance of TP53-mutated cells to spindle poisons. This opens new perspectives for developing alternative therapeutic strategies when the TP53 gene is inactivated.
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PMID:Reversion of apoptotic resistance of TP53-mutated Burkitt lymphoma B-cells to spindle poisons by exogenous activation of JNK and p38 MAP kinases. 2478 13