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)

In the mammalian nervous system, serotonin (5-hydroxytryptamine) binds to distinct cell surface receptor subtypes that are defined by their ligand binding and effector-coupling properties. The 5HT1c receptor is a G-protein coupled receptor that stimulates phospholipase C-catalyzed hydrolysis of phosphatidylinositol bisphosphate, leading to the mobilization of intracellular calcium and to the activation of protein kinase C. By using somatic cell hybrid analysis and FISH, we have mapped the HTR1C locus to the human X chromosome, band q24 and to the mouse X chromosome region D-F4. Comparison of these map positions offers new insights into the evolution of human and murine X chromosomes. Since HTR1C is expressed in certain parts of the central nervous system and abnormal function of the serotoninergic system has been implicated in affective disorders, obsessive-compulsive disorder and epilepsy, establishing the precise map position of HTR1C is an important first step toward evaluating this locus as a candidate for mutations in these syndromes and in X-linked mental disorders.
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PMID:Serotonin receptor 1c gene assigned to X chromosome in human (band q24) and mouse (bands D-F4). 130 5

We have compared assays for products of the neutrophil respiratory burst in normal EBV-transformed B cell lines stimulated with agonists of protein kinase C. Those measuring O2- directly or its immediate product, H2O2, were successful. Of these, the most sensitive were the lucigenin- and luminol-based chemiluminescence assays for O2- and H2O2 respectively. Cell lines from CGD patients, with X-linked or autosomal recessive genetic defects in the neutrophil NADPH oxidase, did not respond in these assays, indicative of their inability to produce O2-. The defects in the lines studied encompass both proteins forming the cytochrome b-245 membrane component, and the 47 kDa cytosolic component of the NADPH oxidase. The possession of the disease associated phenotype by these cell lines provides evidence that in the normal situation both neutrophils and B cells produce O2- via the same system.
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PMID:Superoxide production by normal and chronic granulomatous disease (CGD) patient-derived EBV-transformed B cell lines measured by chemiluminescence-based assays. 133 Dec 41

XLH (X-linked hypophosphataemia, gene symbol HYP, McKusick 307800, 307810) and its murine counterparts (Hyp and Gy) map to a conserved segment on the X-chromosome (Xp 22.31-p.21.3, human; distal X, mouse). Gene dosage has received relatively little attention in the long history of research on this disease, which began over 50 years ago. Bone and teeth are sites of the principal disease manifestations in XLH (rickets, osteomalacia, interglobular dentin). Newer measures of quantitative XLH phenotypes reveal gene dose effects in bone and teeth with heterozygous values distributed between those in mutant hemizygotes and normal homozygotes. On the other hand, serum phosphate concentrations (which are low in the mutant phenotype and thereby contribute to bone and tooth phenotypes) do not show gene dosage. In Hyp mice serum values in mutant hemizygotes, mutant homozygotes and heterozygotes are similar. Phosphate homeostasis reflects its renal conservation. Renal absorption of phosphate on a high-affinity, Na+ ion-gradient coupled system in renal brush border membrane is impaired and gene dosage is absent at this level; the mutant phenotype is fully dominant. Synthesis and degradation of 1,25(OH)2D are also abnormal in XLH (and Hyp), but gene dosage in these parameters has not yet been measured. An (unidentified) inhibitory trans-acting product of the X-linked locus, affecting phosphate transport and vitamin D metabolism, acting perhaps through cytosolic protein kinase C, could explain the renal phenotype. But why would it have a normal gene dose effect in bone and teeth? Since the locus may have duplicated (to form Hyp and Gy), and shows evidence of variable expression in different organs (inner ear, bone/teeth, kidney), it may have been recruited during evolution to multiple functions.
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PMID:X-linked hypophosphataemia: a homologous phenotype in humans and mice with unusual organ-specific gene dosage. 152 20

To test whether protein kinase C plays a role in the regulation of renal brush border membrane phosphate transport and mitochondrial vitamin D metabolism, we examined the activity, distribution and endogenous substrates of protein kinase C in renal subcellular fractions derived from two mouse models exhibiting perturbations in both renal functions. The X-linked Hyp mouse is characterized by reduced phosphate transport and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) synthesis relative to normal, whereas the phosphate-deprived mouse exhibits elevated phosphate transport and vitamin D hormone synthesis. Protein kinase C activity was higher in renal cytosol of Hyp mice, when compared to normal littermates (358 +/- 11 vs. 244 +/- 31 pmol 32P/mg prot/min, P less than 0.02), whereas genotype differences in brush border membrane and mitochondrial kinase were not apparent. Phosphate deprivation of normal mice elicited a 50% reduction in brush border membrane protein kinase C (from 819 +/- 56 to 460 +/- 48 pmol 32P/mg prot/min, P less than 0.03), an increase in mitochondrial kinase (from 57 +/- 7 to 87 +/- 10 pmol 32P/mg prot/min, P less than 0.03), and no change in cytosolic kinase activity. Phosphate deprivation of Hyp mice led to an increase in mitochondrial protein kinase C (from 72 +/- 7 to 98 +/- 9 pmol 32P/mg prot/min, P less than 0.03) and no change in either brush border membrane or cytosolic kinase activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Protein kinase C in mouse kidney: effect of the Hyp mutation and phosphate deprivation. 230 58

Aggregating agents including phorbol esters which activate protein kinase C induce the rapid phosphorylation of a Mr = 47,000 cytosolic protein in blood platelets (P47 or pleckstrin). This protein is well resolved by analytical 16-BAC----SDS two-dimensional PAGE and was purified from platelets by preparative 16-BAC----SDS PAGE. Polyclonal antibodies were raised to the protein in mice and rabbits. These antisera detected a single protein with the migration of P47 on Western blots of platelet extracts, and the rabbit antisera immunoprecipitated 32P-labelled P47 from platelet cytosol. The presence of P47 in other haematopoietic cells was determined by prelabelling them with 32P and observing increased 32P incorporation into the location of P47 on autoradiographs of 16-BAC----SDS analytical PAGE of cells exposed to phorbol ester. The identity of the phosphoprotein found in this location was further established by probing Western blots of SDS PAGE gels of cultured cell lines with the P47 antisera. P47 was detected in peripheral blood lymphocytes, monocytes and granulocytes (including the granulocytes of two unrelated patients with X-linked chronic granulomatous disease). P47 was also found in HL-60 promyelocytes (especially after differentiation with retinoic acid), U937 histiocytes, HEL leukaemia cells, and Raji 'B' lymphoblasts. It was not detected in normal erythrocytes, K562 leukaemic cells, MOLT-3 'T' lymphoblasts, or in wide range of non-haematopoietic cell lines. We conclude that P47 is a major target for the action of phorbol ester induced phosphorylation in platelets, normal leucocytes and some haematopoietic cell lines. These cells have as their common feature the ability when stimulated to develop adhesive functions on their plasma membranes.
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PMID:P47 phosphoprotein of blood platelets (pleckstrin) is a major target for phorbol ester-induced protein phosphorylation in intact platelets, granulocytes, lymphocytes, monocytes and cultured leukaemic cells: absence of P47 in non-haematopoietic cells. 231 54

The superoxide-generating enzyme of human neutrophils, NADPH oxidase, is converted from an inactive to an active form upon stimulation of the neutrophil. This activation process was examined using a recently developed cell-free system in which dormant oxidase is activated by arachidonic acid in the presence of a soluble factor from the neutrophil (Curnutte, J. T. (1985) J. Clin. Invest. 75, 1740-1743). NADPH oxidase from unstimulated human neutrophils was detected only in the membrane fraction. The soluble activation factor was localized entirely to the cytosolic fraction and exhibited two peaks of activity when partially purified under nondenaturing conditions: a major peak with a molecular mass of approximately 250 kDa and a variable minor peak with a mass of approximately 40 kDa. Both forms activated NADPH oxidase in a similar manner and did not exhibit synergy when combined. The cytosolic factor is not protein kinase C (or another kinase) as both peaks of factor activity could be resolved from the protein kinase C peak and neither required calcium or ATP to activate the oxidase. Activation of NADPH oxidase did require the simultaneous presence of the membrane fraction, the cytosolic factor, arachidonic acid, and magnesium. Following activation, however, only the membrane fraction was then required for O2- production. Cytosolic factor levels were normal in five patients with either X-linked or autosomal recessive cytochrome b-negative chronic granulomatous disease. In contrast, the membrane fractions from each failed to generate O2-, indicating that the defects in these two genetic forms of chronic granulomatous disease reside either in the oxidase itself or in a membrane component required for activation.
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PMID:Activation of neutrophil NADPH oxidase in a cell-free system. Partial purification of components and characterization of the activation process. 357 Dec 24

Tyrosine phosphorylation of several cellular proteins is one of the earliest signaling events induced by cross-linking of the high-affinity receptor for immunoglobulin E (Fc epsilon RI) on mast cells or basophils. Tyrosine kinases activated during this process include the Src family kinases, Lyn, c-Yes, and c-Src, and members of another subfamily, Syk and PTK72 (identical or highly related to Syk). Recently, some of us described two novel tyrosine kinases, Emb and Emt, whose expression was limited to subsets of hematopoietic cells, including mast cells. Emb turned out to be identical to Btk, a gene product defective in human X-linked agammaglobulinemia and in X-linked immunodeficient (xid) mice. Here we report that Fc epsilon RI cross-linking induced rapid phosphorylation on tyrosine, serine, and threonine residues and activation of Btk in mouse bone marrow-derived mast cells. A small fraction of Btk translocated from the cytosol to the membrane compartment following receptor cross-linking. Tyrosine phosphorylation of Btk was not induced by either a Ca2+ ionophore (A23187), phorbol 12-myristate 13-acetate, or a combination of the two reagents. Co-immunoprecipitation between Btk and receptor subunit beta or gamma was not detected. The data collectively suggest that Btk is not associated with Fc epsilon but that its activation takes place prior to protein kinase C activation and plays a novel role in the Fc epsilon RI signaling pathway.
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PMID:Tyrosine phosphorylation and activation of Bruton tyrosine kinase upon Fc epsilon RI cross-linking. 751 58

Bruton tyrosine kinase (EC 2.7.1.112) [Btk, encoded by Btk in mice and BTK in humans (formerly known as atk, BPK, or emb)], which is variously mutated in chromosome X-linked agammaglobulinemia patients and X-linked immunodeficient (xid) mice, has the pleckstrin homology (PH) domain at its amino terminus. The PH domain of Btk expressed as a bacterial fusion protein directly interacts with protein kinase C in mast cell lysates. Evidence was obtained that Btk is physically associated with protein kinase C in intact murine mast cells as well. Both Ca(2+)-dependent (alpha, beta I, and beta II) and Ca(2+)-independent protein kinase C isoforms (epsilon and zeta) in mast cells interact with the PH domain of Btk in vitro, and protein kinase C beta I is associated with Btk in vivo. Btk served as a substrate of protein kinase C, and its enzymatic activity was down-regulated by protein kinase C-mediated phosphorylation. Furthermore, depletion or inhibition of protein kinase C with pharmacological agents resulted in an enhancement of the tyrosine phosphorylation of Btk induced by mast cell activation.
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PMID:The pleckstrin homology domain of Bruton tyrosine kinase interacts with protein kinase C. 752 30

A mouse genomic clone named HGMP01B has been isolated by homology screening with a probe representing part of the human melanocortin 3 receptor gene. HGMP01B was found to encode a 325 amino acid protein with all the landmarks of G-protein-coupled receptors and belonging to the growing melanocortin receptor family. This receptor displays four potential sites for N-linked glycosylation and five potential sites of phosphorylation by protein kinase C. The HGMP01B gene was found to be expressed in many tissues, including skin, adrenal gland, skeletal muscle, bone marrow, spleen, thymus, gonads, uterus, and brain. A stable Chinese hamster ovary (CHO) cell line expressing approximately 10,000 receptors per cell was established. This cell line displayed a saturable binding capacity for the radioiodinated alpha-melanocyte-stimulating hormone (alpha-MSH) analog [Nle4,D-Phe7]-alpha-MSH (NDP-MSH) with an apparent Kd of 1.47 +/- 0.15 nM. Binding of the labeled ligand was competed for by all melanocortin peptides, except beta-endorphin or corticotropin-like intermediate lobe peptide (CLIP). NDP-MSH was the most powerful competitor, followed by alpha-MSH, adrenocorticotropic hormone (ACTH), beta-MSH, the gamma-MSHs, and ACTH 4-10. Functional assays confirmed that HGMP01B, like other melanocortin receptors, stimulated adenylyl cyclase. The potency order obtained in these cyclic adenosine monophosphate (cAMP) accumulation assays was consistent with that of the binding studies. HGMP01B therefore appears as a fifth melanocortin receptor (MC5), responding mainly to alpha-MSH (EC50 = 1.07 +/- 0.13 nM) and endowed with a pharmacological profile similar to that of the melanocyte MSH (MC1) receptor, but characterized by a broad tissue distribution.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Molecular cloning of a mouse melanocortin 5 receptor gene widely expressed in peripheral tissues. 816 9

We describe the cloning of the mouse HGMP01A gene that encodes a melanocortin receptor functionally distinct from the adrenal cortex corticotropin (adrenocorticotrophic hormone; ACTH) receptor and the melanocyte-stimulating hormone (MSH) receptor expressed in melanoma. The gene encodes a protein of 323 amino acids with a calculated molecular mass of 35,800 Da, displaying potential sites for N-linked glycosylation and phosphorylation by protein kinase C. An RNAase protection assay detected weak expression in the brain, but not in adrenal gland, skin, or any of the other tissues tested. Stable CHO cell lines expressing over 100,000 receptors per cell were generated. The recombinant receptor binds iodinated [Nle4,D-Phe7]alpha-MSH (NDP-MSH) with an apparent Kd of 700 pM. Displacement of the ligand by a variety of pro-opiomelanocortin-derived peptides revealed a pharmacological profile distinct from that of the classical ACTH and MSH receptors. NDP-MSH was the most powerful competitor (IC50 1.4 nM), followed by gamma-MSH (IC50 7 nM). alpha-MSH, beta-MSH and ACTH-(1-39) were significantly less potent, with IC50 values of 30, 19 and 21 nM respectively. ACTH-(4-10) was poorly active (IC50 2.4 microM), while corticotropin-like intermediate lobe peptide (CLIP) and beta-endorphin were totally ineffective. The recombinant receptor was found to stimulate adenylate cyclase. The potency order of the agonists in this assay was consistent with that of the binding displacement assays. This receptor represents the orthologue of the human melanocortin 3 receptor reported recently. The growing family of melanocortin receptors constitute the molecular basis for the variety of actions of melanocortins that have been described over the years. The availability of functionally expressed receptors from the melanocortin family will allow the development of a specific pharmacology, and a better understanding of the function of the pro-opiomelanocortin-derived peptides.
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PMID:Molecular cloning, functional expression and pharmacological characterization of a mouse melanocortin receptor gene. 817 96


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