Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.3 (phospholipase C)
18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Studies of proliferative signaling via type 1 cytokine receptors have revealed a three-step activation mechanism. Cytokine-induced receptor dimerization mediates the trans-phosphorylation of Jak kinases, Jaks phosphorylate receptors at tyrosine sites, and SH2 domain-encoding effectors then are recruited to these sites. Signaling factors that associate with activated erythropoietin (Epo) receptor complexes include phospholipase C-gamma, phosphatidylinositol 3-kinase, SHIP, Shc, Grb2, Cbl, Crk-l, HCP, Syp, and STAT5. While at least certain of these factors modulate proliferative signaling, mutated Epo receptor forms lacking Tyr(P) sites retain substantial mitogenic activity. Presently we show that a highly truncated Epo receptor form that retains box-1, yet lacks the conserved box-2 domain (and all Tyr(P) sites) nonetheless effectively promotes mitogenesis, survival, and Myc and Pim-1 expression. In addition, mitogenesis and Myc expression are shown to be supported by a direct Epo receptor-Jak2 kinase domain chimera. Thus, Epo-dependent mitogenesis and inhibition of apoptosis each depend critically upon only the Epo receptor box-1 domain, with no essential role exerted in these response pathways by the box-2 domain.
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PMID:Mitogenic signaling and inhibition of apoptosis via the erythropoietin receptor Box-1 domain. 911 Oct 17

Stimulation of the T cell antigen receptor (TCR) activates a set of non-receptor protein tyrosine kinases that assist in delivering signals to the cell interior. Among the presumed substrates for these kinases, adaptor proteins, which juxtapose effector enzyme systems with the antigen receptor complex, figure prominently. Previous studies suggested that Lnk, a 38-kDa protein consisting of a single SH2 domain and a region containing potential tyrosine phosphorylation sites, might serve to join Grb2, phospholipase C-gamma1, and phosphatidylinositol 3-kinase to the TCR. To elucidate the physiological roles of Lnk in T cell signal transduction, we isolated the mouse Lnk cDNA, characterized the structure of the mouse Lnk gene, and generated transgenic mice that overproduce Lnk in thymocytes. Here we report that although Lnk becomes phosphorylated during T cell activation, it plays no limiting role in the TCR signaling process. Moreover, we have distinguished p38(Lnk) from the more prominent 36-kDa tyrosine phosphoproteins that appear in activated T cells. Together these studies suggest that Lnk participates in signaling from receptors other than antigen receptors in lymphocytes.
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PMID:Characterization of Lnk. An adaptor protein expressed in lymphocytes. 916 14

Apoptosis of normal and leukemic immature B-cells in vitro is suppressed by contact with bone marrow-derived stromal layers. In stroma-supported cultures of immature B-cells, we found that ligation of CD38, a type II transmembrane protein, inhibited the cell growth and induced apoptosis. CD38 ligation also induced tyrosine phosphorylation and activation of intracellular substrates, including syk, phospholipase C-gamma, c-cbl, and phosphatidylinositol 3-kinase (PI 3-K). Wortmannin and LY294002, two potent inhibitors of PI 3K, rescued immature B cells from CD38-mediated growth suppression. In vitro culture of leukemic lymphoblasts may have potentially important clinical application. First, stroma-supported cultures of acute lymphoblastic leukemia (ALL) cells can determine the growth potential of leukemic cells. In a series of 70 children enrolled in a single program of chemotherapy, cell growth on stroma was a powerful and independent prognostic indicator. Second, a culture system capable of maintaining the majority of ALL blast cells at high levels of viability is also ideally suited for testing antileukemic drugs. Promising results were obtained with 2-chloro-deoxyadenosine and interleukin-4, leading to clinical trials of these two compounds in children with refractory ALL. In addition, we compared the direct antileukemic activities of dexamethasone and prednisolone and found that dexamethasone is five to six times more cytotoxic (on a molar basis) than prednisolone, in agreement with the anti-inflammatory activities of these drugs. This finding may serve to guide the selection of dexamethasone dosage in the treatment of ALL.
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PMID:Human B-cell progenitors and bone marrow microenvironment. 918 64

Neurturin (NTN) is a neurotrophic factor that shares homology with glial cell line-derived neurotrophic factor (GDNF). Recently, a receptor complex has been identified for GDNF that includes the Ret tyrosine kinase receptor and a glycosylphosphatidylinositol-linked protein termed "GDNFRalpha." However, differences in the phenotype of Ret and GDNF knockout animals suggest that Ret has at least one additional ligand. In this report, we demonstrate that NTN induces Ret phosphorylation in primary cultures of rat superior cervical ganglion (SCG) neurons. NTN also caused Ret phosphorylation in fibroblasts that were transfected stably with Ret and GDNFRalpha but not in cells expressing Ret alone. A glycosylphosphatidylinositol-linked protein also was important for NTN and GDNF signaling in SCG neurons; phosphatidylinositol-specific phospholipase C treatment of SCG cultures reduced the ability of NTN to phosphorylate Ret and the ability of NTN or GDNF to activate the mitogen-activated protein kinase pathway. NTN and GDNF also caused sustained activation of Ret and the mitogen-activated protein kinase pathway in SCG neurons. Finally, both NTN and GDNF activated the phosphatidylinositol 3-kinase pathway in SCG neurons, which may be important for the ability of NTN and GDNF to promote neuronal survival. These data indicate that NTN is a physiologically relevant ligand for the Ret receptor and suggest that NTN may have a critical role in the development of many neuronal populations.
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PMID:Neurturin shares receptors and signal transduction pathways with glial cell line-derived neurotrophic factor in sympathetic neurons. 919 84

CD38 is a 45-kDa transmembrane glycoprotein highly expressed in lymphoid progenitors. Ligation of CD38 with specific Abs inhibits growth and induces apoptosis in human immature B cells. CD38 ligation also triggers tyrosine phosphorylation of syk, c-cbl, and phospholipase C-gamma and activates phosphatidylinositol 3-kinase (PI3-K). In the present study, we investigated whether the cell surface membrane molecules used in B cell receptor-mediated signaling, such as Ig alpha, Ig beta, and CD19, could be involved in the CD38-mediated signaling cascade. In the B cell receptor-negative immature B cell lines RS4;11, 380, and REH, Ig alpha and Ig beta were expressed exclusively in the cytoplasm and were not tyrosine phosphorylated after CD38 ligation. By contrast, CD19 was markedly tyrosine phosphorylated and was associated with lyn and PI3-K. PI3-K activation appears to be directly linked to the growth-arresting effects of CD38 ligation, which are reduced by PI3-K inhibitors. Ligation of either CD38 or CD19 resulted in a similar pattern of protein tyrosine phosphorylation; both signaling pathways caused tyrosine phosphorylation of c-cbl. Levels of CD38 surface expression were not affected by prolonged incubation with anti-CD19 Ab, while CD19 expression markedly decreased. These results indicate that CD19 is a major component of the CD38 signaling cascade in B cell precursors, serving as a cell surface membrane docking site for cytoplasmic kinases. CD38 and CD19 are not physically linked, but activate an overlapping set of kinases in human immature B cells.
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PMID:CD38 ligation in human B cell progenitors triggers tyrosine phosphorylation of CD19 and association of CD19 with lyn and phosphatidylinositol 3-kinase. 920 Apr 54

Middle T (mT), the oncogene of murine polyomavirus, causes transformation of rat fibroblasts by activating a number of signal transducing pathways usually used by polypeptide growth factors and their receptors. Here, we report data regarding the activation of signal transducing pathways involving phospholipase D (PL-D). The hydrolysis of phospholipids by PL-D produces phosphatidic acid (PA), a compound with multiple biological effects. The PA content of cells expressing wild-type mT, introduced via a number of different methods, is approximately 50% higher than their untransformed counterparts. This increase in cellular PA content is associated with an approximately 65% increase in PL-D activity in cells expressing wild-type mT. We have also examined the effects of a number of site-directed mutants of mT, on both cellular PA levels and on PL-D activity. Mutants that do not produce mT (Py808A) or that produce a truncated, nonmembrane bound mT (Py1387T) have PA levels similar to that of control cells. Cells expressing the 322YF mutant of mT (which abolishes interaction of mT with phospholipase C gamma1) show increases in both PA levels and PL-D activity that are similar to those seen with wild-type mT. Expression of mutants that abolish the interaction of mT with either shc or with phosphatidylinositol 3-kinase (250YS and 315YF, respectively) cause an increase in PL-D activity comparable to that seen with wild-type mT. However, the PA content of cells expressing these mutants is not elevated. These results suggest that mT causes activation of cellular PL-D, but this activation alone is not sufficient to cause an increase in cellular PA content. Therefore, wild-type mT must affect another, as yet unknown, step in PA metabolism.
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PMID:The elevation of cellular phosphatidic acid levels caused by polyomavirus transformation can be disassociated from the activation of phospholipase D. 921 62

In response to insulin-like growth factor-I (IGF-I), neonatal rat cardiac myocytes exhibit a hypertrophic response. The elucidation of the IGF-I signal transduction system in these cells remains unknown. We show here that cardiac myocytes present a single class of high affinity receptors (12,446 +/- 3,669 binding sites/cell) with a dissociation constant of 0.36 +/- 0.10 nM. Two different beta-subunits of IGF-I receptor were detected, and their autophosphorylation was followed by increases in the phosphotyrosine content of extracellular signal-regulated kinases (ERKs), insulin receptor substrate 1, phospholipase C-gamma1, and phosphatidylinositol 3-kinase. IGF-I transiently activates c-Raf in cultured neonatal cardiac myocytes, whereas A-raf is activated much less than c-Raf. Two peaks of ERK activity (ERK1 and ERK2) were resolved in cardiac myocytes treated with IGF-I by fast protein liquid chromatography, both being stimulated by IGF-I (with EC50 values for the stimulation of ERK1 and ERK2 by IGF-I of 0.10 and 0. 12 nM, respectively). Maximal activation of ERK2 (12-fold) and ERK1 (8.3-fold) activities was attained after a 5-min exposure to IGF-I. Maximal activation of p90 S6 kinase by IGF-I was achieved after 10 min, and then the activity decreased slowly. Interestingly, IGF-I stimulates incorporation of [3H]phenylalanine (1.6-fold) without any effect on [3H]thymidine incorporation. These data suggest that IGF-I activates multiple signal transduction pathways in cardiac myocytes some of which may be relevant to the hypertrophic response of the heart.
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PMID:Insulin-like growth factor-I rapidly activates multiple signal transduction pathways in cultured rat cardiac myocytes. 923

Inorganic phosphate (Pi) is a major regulator of cell metabolism. The Pi transport activity in the plasma membrane is a main determinant of the intracellular level of this ion. In bone-forming cells, Pi transport is important for the calcification of the bone matrix. In this study, the effect of platelet-derived growth factor (PDGF) on Pi transport activity and the signaling mechanism involved in this cellular response were analyzed. The results indicate that PDGF is a potent and selective stimulator of sodium-dependent Pi transport in the mouse calvaria-derived MC3T3-E1 osteoblast-like cells. The change in Pi transport induced by PDGF-BB was dependent on translational processes and affected the Vmax of the Pi transport system. These observations suggested that enhanced Pi transport activity in response to PDGF resulted from insertion of newly synthesized Pi transporters in the plasma membrane. The role of activation of mitogen activated protein (MAP) kinase, phospholipase C (PLC)gamma or phosphatidylinositol 3-kinase (PI-3-kinase), in mediating this effect of PDGF, was investigated. A selective inhibitor of the PDGF receptor tyrosine kinase activity (CGP 53716) completely blocked PDGF-induced protein tyrosine phosphorylation of several proteins including the PDGF receptor, PLCgamma, MAP kinase, and association of the p85 subunit of PI-3'-kinase. Associated with this effect, the increase in Pi transport induced by PDGF was completely blunted by 5 microM CGP 53716. Inhibition of MAP kinase activity by cAMP agonists did not influence Pi transport stimulation induced by PDGF. However, inhibitors of protein kinase C completely blocked this response. A selective inhibitor of PI-3-kinase, LY294002, also significantly reduced this effect of PDGF. In summary, these results indicate that PDGF is a potent and selective stimulator of Pi transport in osteoblastic cells. The mechanism responsible for this effect is not mediated by MAP kinase but involves tyrosine phosphorylation-dependent activation of PLCgamma and PI-3-kinase.
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PMID:Platelet-derived growth factor stimulates sodium-dependent Pi transport in osteoblastic cells via phospholipase Cgamma and phosphatidylinositol 3' -kinase. 924 Jul 23

Activation of the nociceptin receptor stably expressed in Chinese hamster ovary cells induced a transient mitogen-activated protein kinase (MAPK) activation, via pertussis toxin-sensitive G-proteins. The nociceptin receptor-mediated MAPK activation was partially blocked by down-regulation or inhibition of protein kinase C, and suppressed by pretreatment with a phosphatidylcholine-specific phospholipase C inhibitor, D609. Furthermore, a tyrosine protein kinase inhibitor, genistein, and phosphatidylinositol 3-kinase inhibitors, wortmannin and LY294002, affected the nociceptin-induced MAPK activity. The nociceptin-induced MAPK activation may lead to activation of phospholipase A2 and induce changes in gene expression.
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PMID:Activation of mitogen-activated protein kinase by the nociceptin receptor expressed in Chinese hamster ovary cells. 925 37

Polyomavirus middle T antigen is phosphorylated on several tyrosine residues which act as binding sites for cellular proteins, including phosphatidylinositol 3-kinase, Shc, and phospholipase C-gamma. In this report we describe the transforming properties and tumor-inducing ability of a polyomavirus that contains a single-site mutation in middle T antigen which changes a tyrosine residue at amino acid position 250 to serine. This mutation disrupts the association of middle T with the transforming protein Shc. The mutant virus is weakly transforming, inducing foci which are smaller and of different morphology than those of the wild type. Although the virus induced tumors in close to 100% of inoculated mice, the spectrum of tumors and their morphology were altered compared to those of wild-type virus. The mutant virus induced a reduced frequency of kidney and thymic tumors. Both the mammary gland and the thymic tumors that were induced were histologically distinct from those induced by wild-type polyomavirus. These results demonstrate that the signal transduction pathway that is deregulated by the middle T-Shc association is important for full transformation of cells in culture and for tumor induction in some target tissues in the mouse-polyomavirus system.
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PMID:Transformation and tumorigenic properties of a mutant polyomavirus containing a middle T antigen defective in Shc binding. 926 44


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