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)

The review is focused on recent data on the primary sequences of erythroid and non-erythroid spectrins. As in other fields, the techniques of molecular genetics have allowed great advances in our knowledge of the structure and the genetic story of these molecules. Comparison of alpha-chains sequences of the non-erythroid (fodrin) and erythroid spectrin demonstrated that the fodrin alpha-genes are strictly conserved across species, while the mammalian spectrin genes have diverged rapidly. Spectrin and fodrin alpha-chains are largely composed of homologous 106-amino-acid repeat units. Spectrin alpha-chain is lacking a 37 amino-acid sequence which bears the calmodulin-binding site of the fodrin alpha-chain. The highest degree of homology between the spectrin alpha-chain and the fodrin alpha-chain lies in a central atypical segment unrelated to the canonical repeat sequence. This region is closely related to the N-terminal segment of several src-tyrosine kinases and to a domain of phospholipase C. Like the spectrin alpha-chain, the major central part of the spectrin beta-chain is made up of repeat units of 106 amino-acids. The N-terminal domain of the beta-chain, and especially the actin binding site, is the region of greatest homology among members of the spectrin super-family, including Drosophila spectrin beta-chain, dystrophin and alpha-actinin. The C-terminal extremity of the erythroid beta-chain is also of great interest, since tissue-specific differential processing of 3'beta-spectrin gene pre-mRNA generates a beta spectrin-isoform with a unique C-terminus in human skeletal muscle.
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PMID:The spectrin super-family. 193 22

The complete nucleotide sequence coding for the chicken brain alpha-spectrin was determined. It comprises the entire coding frame, 5'- and 3'-untranslated sequences terminating in a poly(A)-tail. The deduced amino acid sequence shows that the alpha-chain contains 22 segments, 20 of which correspond to the typical 106 residue repeat of the human erythrocyte spectrin. Some segments non-homologous to the repeat structure reside in the middle and COOH-terminal regions. Sequence comparisons with other proteins show that these segments evidently harbour some structural and functional features such as: homology to alpha-actinin and dystrophin, two typical EF-hand structures (calcium-binding) and a putative calmodulin-binding site in the COOH-terminus and a sequence homologous to various src-tyrosine kinases and to phospholipase C in the middle of the molecule. Comparison of our sequence with other partial alpha-spectrin sequences shows that alpha-spectrin is well conserved in different species and that the human erythrocyte alpha-spectrin is divergent.
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PMID:From the spectrin gene to the assembly of the membrane skeleton. 248 1

We have determined the nucleotide sequence coding for the chicken brain alpha-spectrin. It is derived both from the cDNA and genomic sequences, comprises the entire coding frame, 5' and 3' untranslated sequences, and terminates in the poly(A)-tail. The deduced amino acid sequence was used to map the domain structure of the protein. The alpha-chain of brain spectrin contains 22 segments of which 20 correspond to the repeat of the human erythrocyte spectrin (Speicher, D. W., and V. T. Marchesi. 1984. Nature (Lond.). 311:177-180.), typically made of 106 residues. These homologous segments probably account for the flexible, rod-like structure of spectrin. Secondary structure prediction suggests predominantly alpha-helical structure for the entire chain. Parts of the primary structure are excluded from the repetitive pattern and they reside in the middle part of the sequence and in its COOH terminus. Search for homology in other proteins showed the presence of the following distinct structures in these nonrepetitive regions: (a) the COOH-terminal part of the molecule that shows homology with alpha-actinin, (b) two typical EF-hand (i.e., Ca2+-binding) structures in this region, (c) a sequence close to the EF-hand that fulfills the criteria for a calmodulin-binding site, and (d) a domain in the middle of the sequence that is homologous to a NH2-terminal segment of several src-tyrosine kinases and to a domain of phospholipase C. These regions are good candidates to carry some established as well as some yet unestablished functions of spectrin. Comparative analysis showed that alpha-spectrin is well conserved across the species boundaries from Xenopus to man, and that the human erythrocyte alpha-spectrin is divergent from the other spectrins.
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PMID:Primary structure of the brain alpha-spectrin. 291 Aug 79

We report that engagement of a particular epitope near the C-terminal region of complement receptor type 3 (CR3, CD11b/CD18) alpha-chain with CD11b mAb VIM12 induces granulocyte activation with a rise in cytosolic-free Ca2+, actin polymerization, an up-regulation of CR3 cell surface expression and enhanced adhesiveness. Induction of enhanced adhesiveness and homotypic aggregation of human granulocytes represents an active process. It is temperature and energy dependent, requires divalent cations, and an intact cytoskeleton. The mAb VIM12-induced enhanced adhesiveness seems to be mediated, at least in part, by activated CR3 molecules. It can be significantly inhibited, although not completely abolished, with blocking mAbs against adhesiotopes of CR3. VIM12-induced adhesion could be blocked with the serine/threonine inhibitors okadaic acid and calyculin A and with dibuturyl-cAMP but not with the protein kinase inhibitors herbimycin A and staurosporine. We further present evidence that the particular molecular region of CR3 recognized by mAb VIM12 might be involved in the reported intramembrane sugar-lectin type interaction and complex formation between transmembrane CR3 and glycosylphosphatidylinositol (GPI)-anchored Fc gamma RIIIB (CD16) molecules on human granulocytes. Binding of mAb VIM12 to CR3 on granulocytes enhances the release of GPI-anchored Fc gamma RIIIB molecules from granulocytes upon phosphoinositol-phospholipase C treatment. The sugar preparation N-acetyl-D-glucosamine, previously shown to dissociate CR3-Fc gamma RIIIB complex formation, inhibits mAb VIM12 binding. Engagement of CR3 with mAb VIM12 may thus mimic a biologically relevant intramembrane cooperation between two distinct receptor molecules on human granulocytes.
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PMID:Granulocyte activation via a binding site near the C-terminal region of complement receptor type 3 alpha-chain (CD11b) potentially involved in intramembrane complex formation with glycosylphosphatidylinositol-anchored Fc gamma RIIIB (CD16) molecules. 773 Jun 47

Hepatocyte growth factor/scatter factor (HGF/SF) is a heparin-binding polypeptide which shares structural domains with enzymes of the blood clotting cascade. HGF/SF is secreted by cells of mesodermal origin and has powerful mitogenic, motogenic and morphogenic activity on epithelial and endothelial cells. HGF/SF is produced as a biologically inactive single-chain precursor (pro-HGF/SF) most of which is sequestered on the cell surface or bound to the extracellular matrix. Maturation into the active alpha beta heterodimer results from proteolytic cleavage by a urokinase-type protease, which acts as a pro-HGF/SF convertase. The primary determinant for receptor binding appears to be located within the alpha-chain. The interaction of the alpha-chain with the receptor is sufficient for the activation of the signal cascade involved in the motility response. However, the complete HGF/SF protein seems to be required to elicit a mitogenic response. HGF/SF binds with high affinity to a transmembrane receptor, p190MET, encoded by the MET proto-oncogene. p190MET is the prototype of a distinct subfamily of heterodimeric tyrosine kinases, including the putative receptors Ron and Sea. The mature form of p190MET is a heterodimer of two disulfide-linked subunits (alpha and beta). The alpha-subunit is extracellular and heavily glycosylated. The beta-subunit consists of an extracellular portion involved in ligand binding, a membrane spanning segment, and a cytoplasmic tyrosine kinase domain. Both subunits derive from glycosylation and proteolytic cleavage of a common precursor of 170 kDa. In polarized epithelial cells the HGF/SF receptor is selectively exposed in the basolateral plasmalemma, where it is associated with detergent-insoluble components. Two Met isoforms, carrying an intact ligand binding domain but lacking the kinase domain due to truncation of the beta-subunit, arise from alternative post-transcriptional processing of the mature form. One truncated form is soluble and released from the cells. HGF/SF binding triggers tyrosine autophosphorylation of the receptor beta-subunit. Autophosphorylation on the major phosphorylation site Y1235 upregulates the kinase activity of the receptor, increasing the Vmax of the phosphotransfer reaction. Negative regulation of the kinase activity occurs through phosphorylation of a unique serine residue (S985) located in the juxtamembrane domain of the receptor. This phosphorylation is triggered by two distinct pathways involving either protein kinase C activation or increase in intracellular Ca2+ concentration. Upon ligand binding, the HGF/SF receptor recruits and activates several cytoplasmic effectors, including phosphatidylinositol 3-kinase (PI 3-K), phospholipase C-gamma (PLC-gamma), pp60c-Src, a tyrosine phosphatase, and a Ras-guanine nucleotide exchanger.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Identification of functional domains in the hepatocyte growth factor and its receptor by molecular engineering. 776 52

Post-translational modifications are important in regulating the functions of signal proteins. This is well established for intracellular proteins, but little is known in the case of extracellular domains of cell surface molecules. We recently described a cell surface protein, mono-ADP-ribosyltransferase (ADPRT), on cytotoxic T cells and showed that it mediates attachment of ADP-ribose to cell surface proteins. Concomitantly, cytolytic activity and cell proliferation are inhibited. Here we report that one of the principal proteins modified by this enzyme is lymphocyte function-associated molecule-1 (LFA-1). While both chains are ADP-ribosylated on the extracellular domain of the molecule, persistence of the modification differs between the chains. Label is released from the beta-chain by 1 h, yet remains for at least 6 h on the alpha-chain. Loss of label is suppressed by phosphodiesterase inhibitors such as ADP-ribose and p-nitrophenylthymidine 5'-monophosphate, pointing to the involvement of this class of enzyme. Modification of LFA-1 requires expression of the cell surface ADPRT and causes the loss of epitopes recognized by alpha- and beta-chain-specific Abs. Concomitantly, the generation of inositol phosphates induced by Ab cross-linking of LFA-1 is significantly inhibited. Consistent with this effect, anti-LFA-1-induced homotypic cell adhesion is also inhibited. These effects are not seen in cells from which the ADPRT was removed by phospholipase C. Moreover, cells lacking the cell surface ADPRT are not inhibited by NAD in the cell adhesion assay, but gain this property upon transfection with the ADPRT gene. It is concluded that the cell surface protein mono-ADPRT regulates LFA-1 functions.
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PMID:Cell surface ADP-ribosyltransferase regulates lymphocyte function-associated molecule-1 (LFA-1) function in T cells. 887 30

Activating mutations of the TSH receptor and alpha-subunit of Gs (G alpha s) that increase adenylyl cyclase activity have been identified in a subset of hyperfunctioning benign thyroid follicular adenomas and, less commonly, in hypofunctioning adenomas and carcinomas. In addition some thyroid tumors exhibit inappropriate activation of phospholipase C (PLC), a signaling pathway that has been implicated in the growth and dedifferentiation of thyroid cells. We therefore hypothesized that some thyroid tumors might be caused by somatic mutations in the genes encoding the alpha-chain of Gq or G11 that result in constitutive activation of the PLC pathway. We amplified regions of the alpha q and alpha 11 genes that encode amino acids, Q209 and R183, and we screened the DNA for mutations by sequence analysis and denaturing gradient gel electrophoresis. No mutations were identified after analysis of DNA from 38 thyroid tumors and 2 poorly differentiated thyroid carcinoma cell lines, including: 13 follicular adenomas, 10 follicular carcinomas, 5 papillary carcinomas, and 10 hyperplastic nodules from multinodular goiters. We conclude that activating mutations of alpha q and alpha 11 are absent or rare in hypofunctioning thyroid neoplasms and that other mechanisms must explain the elevated PLC activity reported in thyroid carcinoma.
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PMID:Absence of activating mutations of the genes encoding the alpha-subunits of G11 and Gq in thyroid neoplasia. 946 74

Progesterone-induced blocking factor (PIBF) induces Th2-dominant cytokine production. Western blotting and EMSA revealed phosphorylation as well as nuclear translocation of STAT6 and inhibition of STAT4 phosphorylation in PIBF-treated cells. The silencing of STAT6 by small interfering RNA reduced the cytokine effects. Because the activation of the STAT6 pathway depends on the ligation of IL-4R, we tested the involvement of IL-4R in PIBF-induced STAT6 activation. Although PIBF does not bind to IL-4R, the blocking of the latter with an Ab abolished PIBF-induced STAT6 activation, whereas the blocking of the IL-13R had no effect. PIBF activated suppressor of cytokine signaling-3 and inhibited IL-12-induced suppressor of cytokine signaling-1 activation. The blocking of IL-4R counteracted all the described effects, suggesting that the PIBF receptor interacts with IL-4R alpha-chain, allowing PIBF to activate the STAT6 pathway. PIBF did not phosphorylate Jak3, suggesting that the gamma-chain is not needed for PIBF signaling. Confocal microscopic analysis revealed a colocalization and at 37 degrees C a cocapping of the FITC PIBF-activated PIBF receptor and PE anti-IL-4R-labeled IL-4R. After the digestion of the cells with phosphatidylinositol-specific phospholipase C, the STAT6-activating effect of PIBF was lost, whereas that of IL-4 remained unaltered. These data suggest the existence of a novel type of IL-4R composed of the IL-4R alpha-chain and the GPI-anchored PIBF receptor.
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PMID:Progesterone-induced blocking factor activates STAT6 via binding to a novel IL-4 receptor. 1639 65