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Статті в журналах з теми "Sphingosine kinase activator molecule"
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Brindley, David N., Abdelkarim Abousalham, Yutaka Kikuchi, Chuen-Neu Wang, and David W. Waggoner. ""Cross talk" between the bioactive glycerolipids and sphingolipids in signal transduction." Biochemistry and Cell Biology 74, no. 4 (July 1, 1996): 469–76. http://dx.doi.org/10.1139/o96-051.
Повний текст джерелаАнотація:
Hydrolysis of phosphatidylcholine via receptor-mediated stimulation of phospholipase D produces phosphatidate that can be converted to lysophosphatidate and diacylglycerol. Diacylglycerol is an activator of protein kinase C, whereas phosphatidate and lysophosphatidate stimulate tyrosine kinases and activate the Ras–Raf–mitogen-activated protein kinase pathway. These three lipids can stimulate cell division. Conversely, activation of sphingomyelinase by agonists (e.g., tumor necrosis factor-α) causes ceramide production that inhibits cell division and produces apoptosis. If ceramides are metabolized to sphingosine and sphingosine 1-phosphate, then these lipids can stimulate phospholipase D and are also mitogenic. By contrast, ceramides inhibit the activation of phospholipase D by decreasing its interaction with the G-proteins, ARF and Rho, which are necessary for its activation. In whole cells, ceramides also stimulate the degradation of phosphatidate, lysophosphatidate, ceramide 1-phosphate, and sphingosine 1-phosphate through a multifunctional phosphohydrolase (the Mg2+-independent phosphatidate phosphohydrolase), whereas sphingosine inhibits phosphatidate phosphohydrolase. Tumor necrosis factor-α causes insulin resistance, which may be partly explained by ceramide production. Cell-permeable ceramides decrease insulin-stimulated glucose uptake in 3T3-L1 adipocytes after 2–24 h, whereas they stimulate basal glucose uptake. These effects do not depend on decreased tyrosine phosphorylation of the insulin receptor and insulin receptor substrate-1 or the interaction of insulin receptor substrate-1 with phosphatidylinositol 3-kinase. They appear to rely on the differential effects of ceramides on the translocation of GLUT1- and GLUT4-containing vesicles. It is concluded that there is a significant interaction and "cross-talk" between the sphingolipid and glycerolipid pathways that modifies signal transduction to control vesicle movement, cell division, and cell death.Key words: ceramides, insulin resistance, phosphatidate, phospholipases, signal transduction.
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Allende, Maria L., Teiji Sasaki, Hiromichi Kawai, Ana Olivera, Yide Mi, Gerhild van Echten-Deckert, Richard Hajdu, et al. "Mice Deficient in Sphingosine Kinase 1 Are Rendered Lymphopenic by FTY720." Journal of Biological Chemistry 279, no. 50 (September 30, 2004): 52487–92. http://dx.doi.org/10.1074/jbc.m406512200.
Повний текст джерелаАнотація:
Sphingosine-1-phosphate (S1P), a lipid signaling molecule that regulates many cellular functions, is synthesized from sphingosine and ATP by the action of sphingosine kinase. Two such kinases have been identified, SPHK1 and SPHK2. To begin to investigate the physiological functions of sphingosine kinase and S1P signaling, we generated mice deficient in SPHK1.Sphk1null mice were viable, fertile, and without any obvious abnormalities. Total SPHK activity in mostSphk1-/-tissues was substantially, but not completely, reduced indicating the presence of multiple sphingosine kinases. S1P levels in most tissues from theSphk1-/- mice were not markedly decreased. In serum, however, there was a significant decrease in the S1P level. Although S1P signaling regulates lymphocyte trafficking, lymphocyte distribution was unaffected in lymphoid organs ofSphk1-/- mice. The immunosuppressant FTY720 was phosphorylated and elicited lymphopenia in theSphk1null mice showing that SPHK1 is not required for the functional activation of this sphingosine analogue prodrug. The results with theseSphk1null mice reveal that some key physiologic processes that require S1P receptor signaling, such as vascular development and proper lymphocyte distribution, can occur in the absence of SPHK1.
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Urtz, Nicole, Ana Olivera, Elisa Bofill-Cardona, Robert Csonga, Andreas Billich, Diana Mechtcheriakova, Frederic Bornancin, Max Woisetschläger, Juan Rivera та Thomas Baumruker. "Early Activation of Sphingosine Kinase in Mast Cells and Recruitment to FcεRI Are Mediated by Its Interaction with Lyn Kinase". Molecular and Cellular Biology 24, № 19 (1 жовтня 2004): 8765–77. http://dx.doi.org/10.1128/mcb.24.19.8765-8777.2004.
Повний текст джерелаАнотація:
ABSTRACT Sphingosine kinase has been recognized as an essential signaling molecule that mediates the intracellular conversion of sphingosine to sphingosine-1-phosphate. In mast cells, induction of sphingosine kinase and generation of sphingosine-1-phosphate have been linked to the initial rise in Ca2+, released from internal stores, and to degranulation. These events either precede or are concomitant with the activation of phospholipase C-γ and the generation of inositol trisphosphate. Here we show that sphingosine kinase type 1 (SPHK1) interacts directly with the tyrosine kinase Lyn and that this interaction leads to the recruitment of this lipid kinase to the high-affinity receptor for immunoglobulin E (FcεRI). The interaction of SPHK1 with Lyn caused enhanced lipid and tyrosine kinase activity. After FcεRI triggering, enhanced sphingosine kinase activity was associated with FcεRI in sphingolipid-enriched rafts of mast cells. Bone marrow-derived mast cells from Lyn−/ − mice, compared to syngeneic wild-type cells, were defective in the initial induction of SPHK1 activity, and the defect was overcome by retroviral Lyn expression. These findings position the activation of SPHK1 as an FcεRI proximal event.
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Dygas, A., M. Sidorko, M. Bobeszko, and J. Barańska. "Exogenous sphingosine 1-phosphate and sphingosylphosphorylcholine do not stimulate phospholipase D in C6 glioma cells." Acta Biochimica Polonica 46, no. 1 (March 31, 1999): 99–106. http://dx.doi.org/10.18388/abp.1999_4187.
Повний текст джерелаАнотація:
In the present study we investigate the effect of exogenous sphingosine, sphingosine 1-phosphate and sphingosylphosphorylcholine on phospholipase D (PLD) activity in glioma C6 cells. The cells were prelabeled with [1-14C]palmitic acid and PLD-mediated synthesis of [14C]phosphatidylethanol was measured. Sphingosine 1-phosphate and sphingosylphosphorylcholine did not stimulate [14C]phosphatidylethanol formation either at low (0.1-10 microM) or high (25-100 microM) concentrations. On the other hand, sphingosine at concentrations of 100-250 microM strongly stimulated PLD activity as compared to the effect of phorbol ester, 12-O-tetradecanoylphorbol 13-acetate (TPA), known as a PLD activator. The effect of TPA on PLD is linked to the activation of protein kinase C. The present study also shows that sphingosine additively enhances TPA-mediated PLD activity. This is in contrast to the postulated role of sphingosine as a protein kinase C inhibitor. These results demonstrate that in glioma C6 cells sphingosine not only affects PLD independently of its effect on protein kinase C, but also is unable to block TPA-mediated PLD activity.
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El-Shewy, Hesham M., Souzan A. Abdel-Samie, Abdelmohsen M. Al Qalam, Mi-Hye Lee, Kazuyuki Kitatani, Viviana Anelli, Ayad A. Jaffa, Lina M. Obeid та Louis M. Luttrell. "Phospholipase C and Protein Kinase C-β 2 Mediate Insulin-Like Growth Factor II-Dependent Sphingosine Kinase 1 Activation". Molecular Endocrinology 25, № 12 (1 грудня 2011): 2144–56. http://dx.doi.org/10.1210/me.2011-0101.
Повний текст джерелаАнотація:
Abstract We recently reported that IGF-II binding to the IGF-II/mannose-6-phosphate (M6P) receptor activates the ERK1/2 cascade by triggering sphingosine kinase 1 (SK1)-dependent transactivation of G protein-coupled sphingosine 1-phosphate (S1P) receptors. Here, we investigated the mechanism of IGF-II/M6P receptor-dependent sphingosine kinase 1 (SK1) activation in human embryonic kidney 293 cells. Pretreating cells with protein kinase C (PKC) inhibitor, bisindolylmaleimide-I, abolished IGF-II-stimulated translocation of green fluorescent protein (GFP)-tagged SK1 to the plasma membrane and activation of endogenous SK1, implicating PKC as an upstream regulator of SK1. Using confocal microscopy to examine membrane translocation of GFP-tagged PKCα, β1, β2, δ, and ζ, we found that IGF-II induced rapid, transient, and isoform-specific translocation of GFP-PKCβ2 to the plasma membrane. Immunoblotting of endogenous PKC phosphorylation confirmed PKCβ2 activation in response to IGF-II. Similarly, IGF-II stimulation caused persistent membrane translocation of the kinase-deficient GFP-PKCβ2 (K371R) mutant, which does not dissociate from the membrane after translocation. IGF-II stimulation increased diacylglycerol (DAG) levels, the established activator of classical PKC. Interestingly, the polyunsaturated fraction of DAG was increased, indicating involvement of phosphatidyl inositol/phospholipase C (PLC). Pretreating cells with the PLC inhibitor, U73122, attenuated IGF-II-dependent DAG production and PKCβ2 phosphorylation, blocked membrane translocation of the kinase-deficient GFP-PKCβ2 (K371R) mutant, and reduced sphingosine 1-phosphate production, suggesting that PLC/PKCβ2 are upstream regulators of SK1 in the pathway. Taken together, these data provide evidence that activation of PLC and PKCβ2 by the IGF-II/M6P receptor are required for the activation of SK1.
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PYNE, Susan, and Nigel J. PYNE. "Sphingosine 1-phosphate signalling in mammalian cells." Biochemical Journal 349, no. 2 (July 10, 2000): 385–402. http://dx.doi.org/10.1042/bj3490385.
Повний текст джерелаАнотація:
Sphingosine 1-phosphate is formed in cells in response to diverse stimuli, including growth factors, cytokines, G-protein-coupled receptor agonists, antigen, etc. Its production is catalysed by sphingosine kinase, while degradation is either via cleavage to produce palmitaldehyde and phosphoethanolamine or by dephosphorylation. In this review we discuss the most recent advances in our understanding of the role of the enzymes involved in metabolism of this lysolipid. Sphingosine 1-phoshate can also bind to members of the endothelial differentiation gene (EDG) G-protein-coupled receptor family [namely EDG1, EDG3, EDG5 (also known as H218 or AGR16), EDG6 and EDG8] to elicit biological responses. These receptors are coupled differentially via Gi, Gq, G12/13 and Rho to multiple effector systems, including adenylate cyclase, phospholipases C and D, extracellular-signal-regulated kinase, c-Jun N-terminal kinase, p38 mitogen-activated protein kinase and non-receptor tyrosine kinases. These signalling pathways are linked to transcription factor activation, cytoskeletal proteins, adhesion molecule expression, caspase activities, etc. Therefore sphingosine 1-phosphate can affect diverse biological responses, including mitogenesis, differentiation, migration and apoptosis, via receptor-dependent mechanisms. Additionally, sphingosine 1-phosphate has been proposed to play an intracellular role, for example in Ca2+ mobilization, activation of non-receptor tyrosine kinases, inhibition of caspases, etc. We review the evidence for both intracellular and extracellular actions, and extensively discuss future approaches that will ultimately resolve the question of dual action. Certainly, sphingosine 1-phosphate will prove to be unique if it elicits both extra- and intra-cellular actions. Finally, we review the evidence that implicates sphingosine 1-phosphate in pathophysiological disease states, such as cancer, angiogenesis and inflammation. Thus there is a need for the development of new therapeutic compounds, such as receptor antagonists. However, identification of the most suitable targets for drug intervention requires a full understanding of the signalling and action profile of this lysosphingolipid. This article describes where the research field is in relation to achieving this aim.
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Desai, N. N., R. O. Carlson, M. E. Mattie, A. Olivera, N. E. Buckley, T. Seki, G. Brooker, and S. Spiegel. "Signaling pathways for sphingosylphosphorylcholine-mediated mitogenesis in Swiss 3T3 fibroblasts." Journal of Cell Biology 121, no. 6 (June 15, 1993): 1385–95. http://dx.doi.org/10.1083/jcb.121.6.1385.
Повний текст джерелаАнотація:
Sphingosylphosphorylcholine (SPC), or lysophingomyelin, a wide-spectrum growth promoting agent for a variety of cell types (Desai, N. N., and S. Spiegel. 1991. Biochem. Biophys. Res. Comm. 181: 361-366), stimulates cellular proliferation of quiescent Swiss 3T3 fibroblasts to a greater extent than other known growth factors or than the structurally related molecules, sphingosine and sphingosine-1-phosphate. SPC potentiated the mitogenic effect of an activator of protein kinase C, 12-O-tetradecanoylphorbol 13-acetate, and did not compete with phorbol esters for binding to protein kinase C in intact Swiss 3T3 fibroblasts. However, downregulation of protein kinase C, by prolonged treatment with phorbol ester, reduced, but did not eliminate, the ability of SPC to stimulate DNA synthesis, indicating that SPC may act via both protein kinase C-dependent and -independent signaling pathways. SPC induced a rapid rise in intracellular free calcium ([Ca2+]i) in viable 3T3 fibroblasts determined with a digital imaging system. Although the increases in [Ca2+]i were observed even in the absence of calcium in the external medium, no increase in the levels of inositol phosphates could be detected in response to mitogenic concentrations of SPC. Furthermore, in contrast to sphingosine or sphingosine-1-phosphate, the mitogenic effect of SPC was not accompanied by increases in phosphatidic acid levels or changes in cAMP levels. SPC, but not sphingosine or sphingosine-1-phosphate, stimulates the release of arachidonic acid. Therefore, the ability of SPC to act an extremely potent mitogen may be due to activation of signaling pathway(s) distinct from those used by sphingosine or sphingosine-1-phosphate.
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King, Charles C., Frank T. Zenke, Philip E. Dawson, Erica M. Dutil, Alexandra C. Newton, Brian A. Hemmings, and Gary M. Bokoch. "Sphingosine Is a Novel Activator of 3-Phosphoinositide-dependent Kinase 1." Journal of Biological Chemistry 275, no. 24 (March 29, 2000): 18108–13. http://dx.doi.org/10.1074/jbc.m909663199.
Повний текст джерела
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Spertini, F., A. V. Wang, T. Chatila, and R. S. Geha. "Engagement of the common leukocyte antigen CD45 induces homotypic adhesion of activated human T cells." Journal of Immunology 153, no. 4 (August 15, 1994): 1593–602. http://dx.doi.org/10.4049/jimmunol.153.4.1593.
Повний текст джерелаАнотація:
Abstract The transmembrane tyrosine phosphatase CD45 plays an important role in TCR/CD3-mediated signaling. We demonstrate in this study that ligand binding to the CD45 molecule induces homotypic cell adhesion of activated, but not resting, T lymphocytes. mAbs to CD45 (4B2 and 10G10) and to CD45RO (UCHL1), but not to CD45RA (IOL2), caused sustained adhesion of alloreactive T cell lines. In contrast, none of the anti-CD45 mAbs induced aggregation of resting peripheral T cells. CD45-mediated adhesion of activated T cells involved both CD11a/18-dependent as well as CD11a/18-independent mechanisms. mAb 4B2 induced a strictly CD11a/18-dependent adhesion that was completely inhibited by both the protein kinase C (PKC) inhibitor sphingosine and the protein tyrosine kinase (PTK) inhibitors genestein and herbimycin A. In contrast, mAb 10G10, which recognized an epitope on CD45 distinct from the one recognized by mAb 4B2, induced CD11a/18-independent adhesion that was inhibited by sphingosine, but not by genestein or herbimycin A. Biochemical studies revealed direct evidence for activation of protein kinase C and protein tyrosine kinase after engagement of CD45 on activated T cells by mAb 4B2. These results indicate that in addition to its role in TCR/CD3-mediated activation, engagement of CD45 transduces signals that result in enhanced adhesiveness of activated T cells.
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Mourad, W., R. S. Geha, and T. Chatila. "Engagement of major histocompatibility complex class II molecules induces sustained, lymphocyte function-associated molecule 1-dependent cell adhesion." Journal of Experimental Medicine 172, no. 5 (November 1, 1990): 1513–16. http://dx.doi.org/10.1084/jem.172.5.1513.
Повний текст джерелаАнотація:
Antigenic stimulation is associated with enhanced adhesion between T cells and antigen-presenting cells (APC). Binding of ligands to the T cell antigen receptor activates the adhesion function of lymphocyte function-associated molecule 1 (LFA-1; CD11a/CD18). We demonstrate here that ligand binding to major histocompatibility complex class II (Ia) molecules also activates LFA-1 function, providing a reciprocal mechanism for the induction of adhesion between T cells and Ia+ APC. Adhesion was affected by a qualitative change in LFA-1 molecules and was reversed by the protein kinase C inhibitor sphingosine. These results define a novel role for Ia molecules as signal transducing receptors that regulate LFA-1-dependent adhesion via a putative, Ia-coupled protein kinase(s).
Дисертації з теми "Sphingosine kinase activator molecule"
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Sankala, Heidi M. "The Role of Sphingosine Kinase 2 in Cell Growth and Apoptosis." VCU Scholars Compass, 2007. http://scholarscompass.vcu.edu/etd/1242.
Повний текст джерелаАнотація:
Two isoforms of sphingosine kinase (SphK) catalyze the formation of sphingosine-1-phosphate (SIP). Whereas, SphKl stimulates cell growth and survival, it was found that when overexpressed in mouse NIH 3T3 fibroblasts SphK2 enhances caspase-dependent apoptosis in response to serum deprivation, independently of S1P receptors. Sequence analysis revealed that SphK2 contains a 9 amino acid motif similar to that present in BH3-only proteins. Studies showed that the BH3-only domain, catalytic activity, endoplasmic reticulum (ER) stress, and uptake of calcium by the mitochondria may all contribute to the apoptotic effects of overexpressed SphK2 in NIH 3T3 cells. Further studies in human carcinoma cells showed that overexpression of SphK2 increased the expression of the cyclin dependent kinase (cdk) inhibitor p21, but interestingly had no effect on p53 or its phosphorylation. Correspondingly, downregulation of endogenous SphK2 with small interfering RNA (siRNA) targeted to unique mRNA sequences decreased basal and doxorubicin-induced expression of p21 without affecting p53. In addition, downregulation of SphK2 decreased G2/M arrest in response to doxorubicin. Surprisingly however, siSphK2 markedly enhanced apoptosis induced by doxorubicin in MCF7 and HCT-116 cells. This result raises the question of how overexpression of SphK2 decreases cell growth and enhances apoptosis while its downregulation sensitizes cells to apoptosis. A partial answer may come from the possibility that when SphK2 is overexpressed it does not always have the same subcellular distribution as the endogenous protein. It may also be possible that proteolysis of overexpressed SphK2 might induce apoptosis due to liberation of its BH3 peptide domain, which does not occur at the levels at which endogenous SphK2 is expressed. Collectively, these results demonstrate that endogenous SphK2 is important for p53-independent induction of p21 expression by doxorubicin and suggest that SphK2 expression may influence the balance between cytostasis and apoptosis.
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Omar, Hany Ahmed Mostafa Mohamed. "Molecular Pharmacology and Preclinical Studies of Novel Small-molecule Targeted Agents for The Treatment of Hepatocellular Carcinoma." The Ohio State University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=osu1290565602.
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Leclercq, Tamara Marie. "Regulation of sphingosine kinase by interacting proteins." Thesis, 2010. http://hdl.handle.net/2440/64752.
Повний текст джерелаАнотація:
Sphingosine kinase 1 (SK1) is responsible for phosphorylating the lipid sphingosine, generating the bio-active phospholipid, sphingosine 1-phosphate (S1P). Cells possess basal SK1 activity
which has been proposed to serve in a ‘housekeeping’ function to limit the levels of proapoptotic sphingosine and ceramide in the cell. In some circumstances, however, such as cell exposure to growth factors and cytokines this basal level of SK1 activity is increased, resulting in an increased production of S1P. As S1P is a pro-proliferative, pro-survival molecule, its increased production is associated with enhanced cell proliferation, survival and an oncogenic phenotype. The Pitson laboratory has shown previously that one mechanism by which SK1 is activated is through phosphorylation at Ser-225 by ERK1/2. Here, my studies focused on alternative mechanisms of SK1 activation that arise through its interaction with two proteins, eukaryotic elongation factor 1A (eEF1A) and a relatively uncharacterised protein, SK activator molecule 1 (SKAM). eEF1A is able to directly increase the catalytic activity of SK1 in vitro and is also able to increase endogenous SK activity when over-expressed in quiescent cells that have reduced levels of endogenous eEF1A protein. Due to the abundance of eEF1A protein within a cell, I hypothesized that the effect of eEF1A on SK activity may be dynamically regulated. eEF1A contains a ‘G protein-like’ domain that enables it to bind GDP and GTP. When bound by GTP, eEF1A undergoes a large conformational change that enables it to bind aminoacyltRNA for transport to the ribosome. Similarly, just as the nucleotide-bound state of eEF1A regulates its role in protein synthesis, I found that the nucleotide-bound state of eEF1A also regulates its ability to activate SK1. Strikingly, it is only the translationally inactive eEF1A.GDP that can activate SK1. A truncated form of eEF1A named PTI-1 has been described that lacks the ‘G protein-like’ domain and thus can not bind guanine nucleotides, rendering it structurally analogous to eEF1A.GDP. In keeping with my finding that only eEF1A.GDP activates SK1, I found that PTI-1 also activates SK1 both in vitro and in cells. Importantly, PTI-1 has been previously characterized as an oncoprotein and for the first time my studies have shown a likely mechanism by which PTI-1 induces a tumourigenic phenotype. Expression of PTI-1 in NIH 3T3 cells induces neoplastic transformation, as measured by focus formation. Notably, this PTI-1-induced transformation is blocked when cells are treated with SK inhibitors or when cells are co-transfected with PTI-1 and a dominant negative SK1, indicating that oncogenesis by PTI-1 is mediated through SK1. The current study also investigated the regulation of SK1 activity by its interaction with SKAM1. Previous studies have shown that SKAM1, like eEF1A, can directly increase the catalytic activity of SK1 in vitro and in cells. My studies have determined the minimal region of interaction of SKAM1 that is still able to interact with and activate SK1. Remarkably, a 35 amino acid SKAM1 peptide retained the ability to activate SK1. The physiological relevance of the SK1-SKAM1 interaction was also examined and I have shown that knock-down of SKAM1, and the related protein SKAM2, in HEK 293T cells resulted in decreased cell proliferation coupled with increased susceptibility to apoptosis. Results presented here, also suggest that phosphorylation of SKAM1 at Tyr-46 acts as a negative regulator for SKAM1-induced SK1 activation. In summary, the current study presents two novel SK1 interacting proteins that directly increase the catalytic activity of this enzyme, and investigates mechanisms by which their effects on SK1 activity are regulated. While the guanine nucleotide bound state of eEF1A1 determines its effects on SK1 activity, the phosphorylation status of SKAM1 appears to determine its ability to activate SK1.Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 2010
Тези доповідей конференцій з теми "Sphingosine kinase activator molecule"
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Siffert, W., P. Scheid, and JW N. Akkerman. "PROTEIN KINASE C CONTROLS CA2+ MOBILIZATION IN HUMAN PLATELETS." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644509.
Повний текст джерелаАнотація:
Platelet stimulation has been shown to result in a rise of cytosolic pH (pHi) as a result of an activation of a Na+/H+ antiport. We have investigated the role of pH in Ca2+ mobilization in human platelets. pHi and free Ca2+, {Ca2+)i, were measured in platelets loaded with the fluorescent indicators BCECF and quin2, respectively. Stimulation of platelets by either thrombin or OAG, an activator of protein kinase C (Pk-C), increased pHi. Pretreatment of platelets with inhibitors of Pk-C, trifluoperazine (TFP) or sphingosine (SPH), blocked the stimulus-induced rise in pHi, suggesting a role of Pk-C in the activation of Na+/H+ exchange. Blocking Na+/H+ exchange by an amiloride analogue or by TFP similarly suppressed the thrombin-induced increase in {Ca2*}i. This effect could be prevented by increasing pHi with the Na+/H+ ionophore monensin or with NH4Cl. The thrombin-induced (0.05 U/ml) rise in {Ca2+}i was more than 3-fold enhanced when the pH was raised from 6.8 to 7.4.Our results demonstrate that pHi controls Ca2+ mobilization in human platelets and suggest that Pk-C contributes to this control by activating the Na+/H+ exchanger.Supported by the Deutsche Forschungsgemeinschaft. No Sche 46/5-2.
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Timmons, Sheila, and Jack Hawiger. "REGULATION OF PLATELET RECEPTORS FOR FIBRINOGEN AND VON WILLEBRAND FACTOR BY PROTEIN KINASE." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644674.
Повний текст джерелаАнотація:
Positive and negative regulation of platelet receptors for adhesive proteins, fibrinogen (F) and von Willebrand Factor (vWF) determines whether binding of these ligands will or will not take place. We have shown previously that ADP stimulates and cyclic AMP inhibits binding of F and vWF to human platelets. Now we show that positive regulation of F and vWF binding to platelets via the glycoprotein 11b/1111a complex is dependent on platelet Protein Kinase C, a calcium- and phospholipid-dependent enzyme. A potent activator of Protein Kinase C, phorbol-12-myristoyl-13-acetate (PMA) induced saturable and specific binding of F and vWF which was inhibited by synthetic peptides, gamma chain .dodecapeptide (gamma 400-411) and RGDS. The phosphorylation of 47kDa protein (P47), a marker of Protein Kinase C activation in platelets, preceded binding of F and vWF induced with PMA as well as with ADP and thrombin. Sphingosine, an inhibitor of Protein Kinase C, blocked binding of F and vWF to platelets stimulated with PMA, ADP, and thrombin. Inhibition of binding was concentration-dependent and it was accompanied by inhibition of platelet aggregation. Thus, stimulation of Protein Kinase C is required for exposure of platelet receptors for adhesive proteins whereas inhibition of Protein Kinase C prevents receptorexposure. Protein Kinase C fulfills the role of an intraplatelet signal transducer, regulating receptors for adhesive proteins, and constitutes a target for pharmacologic modulation of the adhesive interactions of platelets.
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Nassar, Nicolas N., Shailaja Hegde, Kark Wunderlich, Yuan Lin, Reza Ahmadian, William Seibel, Yi Zheng, Benjamin E. Mizukawa, Lisa Privette Vinnedge, and Jose A. Cancelas. "Abstract LB198: Inhibition of the RAC Activator VAV3 by the small molecule IODVA1 impedes RAC signaling & overcomes resistance to tyrosine kinase inhibition in lymphoblastic leukemia." In Proceedings: AACR Annual Meeting 2021; April 10-15, 2021 and May 17-21, 2021; Philadelphia, PA. American Association for Cancer Research, 2021. http://dx.doi.org/10.1158/1538-7445.am2021-lb198.
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