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)

We detected an autoantibody which activated normal platelets in a patient with immune thrombocytopenic purpura and investigated the mechanism by which this autoantibody mediated platelet activation. The patient's IgG induced platelet aggregation and ATP secretion in normal platelet-rich plasma (PRP). IgG-induced aggregation was inhibited by aspirin (ASA), apyrase, a protein kinase C (PKC) inhibitor and two anti-platelet glycoprotein (GP) IIb/IIIa monoclonal antibodies. The increase of aequorin-detected intraplatelet Ca2+ induced by the patient's IgG was extremely slight. Phosphorylation of a 40 kDa protein was induced by the patient's IgG without any obvious phosphorylation of a 20 kDa protein, and was inhibited by a PKC inhibitor but not by ASA. With ASA-treated normal PRP, the patient's IgG failed to induce aggregation itself, but enhanced ADP- or STA2-induced aggregation. Western blotting and immunoprecipitation experiments showed that the patient's IgG reacted to a protein of 36 kDa. These results suggest that the platelet activation induced by this autoantibody depended on both the selective activation of PKC and the slight Ca2+ mobilization induced by thromboxane A2 synthesis, while the aggregation depended on secretion induced by the synergistic action of the above two mechanisms and was mediated through GP IIb/IIIa.
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PMID:Synergistic action in platelet activation induced by an antiplatelet autoantibody in ITP. 204 86

In a patient with immune thrombocytopenic purpura (ITP), we found a novel platelet-activating IgG (act-IgG) and an inhibitory IgG (inhi-IgG) that prevented activation induced by both CD9 monoclonal antibody (mAb) and the act-IgG. Purified IgG from the patient plasma caused a rise in [Ca2+]i and the aggregation of normal platelets, and bound to a 24 kD membrane protein. This aggregation was inhibited by aspirin, staurosporine, an inhibitor of protein kinase C, and F(ab')2 fragments of MALL13, a CD9 mAb. When the platelet count of this patient rose to normal range, the act-IgG disappeared. About 2 weeks later, the relapse of thrombocytopenia was observed. The purified IgG obtained in this period did not activate platelets but inhibited both the rise in [Ca2+]i and platelet aggregation stimulated by NNKY 1-19, a CD9 mAb, as well as the act-IgG, and bound to a 40 kD membrane protein. The inhi-IgG prevented the binding of IV-3, a mAb against Fc gamma receptor II (Fc gamma RII), but did not prevent the binding of NNKY 1-19 to its antigen. We suggest that the activating autoantibody recognized CD9 antigen and activated both the thromboxane- and phospholipase C-dependent pathways, while the inhibitory autoantibody recognized the Fc gamma RII and inhibited CD9 antibody-induced platelet activation mediated via this receptor.
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PMID:Platelet activation induced by an antiplatelet autoantibody against CD9 antigen and its inhibition by another autoantibody in immune thrombocytopenic purpura. 821 30

T lymphocyte activation and proliferation are complex cellular processes involving membrane and cytoplasmatic molecules as well as the secretion and response to cytokines, mainly interleukin 2. There is increasing evidence that autoimmune thrombocytopenic purpura (ATP) is associated with an alteration of the regulation of the immune system. The blastogenic response of purified T lymphocytes to mitogens that interact with membrane molecules (phytohemaglutinin, anti-CD3 monoclonal antibody) and with intracytoplasmic protein kinase C (phorbol myristate acetate) has been investigated in 22 ATP patients and 18 healthy controls. After the signal given by the three different mitogens [3H]-thymidine uptake in T lymphocytes from ATP patients was found to be significantly decreased with respect to that found in healthy controls under similar experimental conditions (P < 0.05). Analysis of the cell cycle progression in these T lymphocytes from ATP patients, showed a significantly diminished percentage of cells in S-phase after PHA stimulation (P < 0.05). The percentage of CD3+ cells in the CD2+ lymphocyte preparations was significantly decreased in ATP patients relative to healthy controls (P < 0.05). But there was no significant correlation between this percentage and the blastogenic response to PHA in the CD2+ cellular preparations from both groups of subjects. No significant differences were found in the percentages of CD4+ and CD8+ cells. These data indicate that the impaired blastogenic response of T lymphocytes from ATP patients may be ascribed to an intrinsic defect in these T cells. This defective proliferative response of T lymphocytes from ATP patients cannot be ascribed to either defective interleukin 2 production or receptor expression which were both similar to those of healthy controls (P > 0.05). And, the presence of saturating amounts of exogenous interleukin 2 did not normalize the defective proliferative response the mitogenic signals on the part of T lymphocytes from ATP patients. We conclude that T lymphocytes from ATP patients have a defective proliferative response to membrane and intracytoplasmatic mitogenic signals.
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PMID:T lymphocytes from autoimmune thrombocytopenic purpura show a defective activation and proliferation after cytoplasmic membrane and intracytoplasmic mitogenic signals. 819 58

The interaction between von Willebrand factor (VWF) and glycoprotein (GP) Ib results in platelet agglutination and activation of many signaling intermediates. To determine if VWF-dependent platelet activation requires the participation of pivotal transmembrane signaling pathways, we analyzed VWF-dependent platelet activation profiles following inhibition of several transmembrane signaling intermediates. This was accomplished using porcine VWF, which has been shown to interact with human GPIb independently of shear stress or ristocetin. Platelet alpha (CD62) and lysozomal granule release (CD63), microparticle formation, and platelet agglutination/aggregation were evaluated. The ability of signaling inhibitors to prevent VWF-dependent platelet activation was compared to their ability to inhibit thrombin-dependent activation. The results demonstrate that VWF-dependent platelet activation can occur independently of the activities of protein kinase C (PKC), wortmannin-sensitive phosphatidylinositide 3-kinase, and phospholipase C, as well as independently of elevations in the concentration of intracellular calcium. In sharp contrast, these transmembrane signaling intermediates are required for thrombin-dependent platelet activation. In addition, thrombin-dependent but not VWF-dependent platelet activation was associated with elevations in the concentration of intracellular calcium under the conditions used. The family of signaling intermediates which appeared to be pivotal for both thrombin- and VWF-dependent platelet activation were the protein tyrosine phosphatases and the serine/threonine phosphatases. It is concluded that thrombin-dependent platelet activation relies on the activation of several transmembrane signaling pathways, whereas VWF-dependent platelet activation is dependent upon the activity of protein phosphatases. Inhibition of these phosphatases in vivo may provide a novel therapeutic approach for treating VWF-dependent platelet disorders such as thrombotic thrombocytopenic purpura or arterial thrombosis.
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PMID:von Willebrand factor (VWF)-dependent human platelet activation: porcine VWF utilizes different transmembrane signaling pathways than does thrombin to activate platelets, but both require protein phosphatase function. 1287 9