Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The 47-kDa protein coimmunoprecipitated with phospholipase C (PLC)-gamma 1 by anti-PLC-gamma 1 monoclonal antibodies is proved to be Nck, a protein composed almost exclusively of one SH2 and three SH3 domains. Nck and PLC-gamma 1 are recognized by certain anti-PLC-gamma 1 monoclonal antibodies because Nck and PLC-gamma 1 share an epitope that likely is located in their SH3 domains. Nck is widely distributed in rat tissues, with an especially high level of expression in testes. The expression levels of Nck remains unchanged during the development of rat brain, whereas PLC-gamma 1 decreases during the same developmental period. Stimulation of A431 cells with epidermal growth factor elicits the tight association of Nck with the epidermal growth factor receptor and phosphorylation of Nck on both serine and tyrosine residues. The phosphorylation of Nck is also enhanced in response to stimulation of the nerve growth factor receptor in PC12 cells, the T-cell receptor complex in Jurkat cells, the membrane immunoglobulin M in Daudi cells, and the low-affinity immunoglobulin G receptor (Fc gamma RII) in U937 cells. The phosphorylation of Nck was also enhanced following treatment of A431 cells with phorbol 12-myristate 13-acetate or forskolin. These results suggest that Nck is a target for a variety of protein kinases that might modulate the postulated role of Nck as an adaptor for the physical and functional coordination of signalling proteins.
Mol Cell Biol 1992 Dec
PMID:Phosphorylation of Nck in response to a variety of receptors, phorbol myristate acetate, and cyclic AMP. 133 46

Signalling proteins such as phospholipase C-gamma (PLC-gamma) or GTPase-activating protein (GAP) of ras contain conserved regions of approximately 100 amino acids termed src homology 2 (SH2) domains. SH2 domains were shown to be responsible for mediating association between signalling proteins and tyrosine-phosphorylated proteins, including growth factor receptors. Nck is an ubiquitously expressed protein consisting exclusively of one SH2 and three SH3 domains. Here we show that epidermal growth factor or platelet-derived growth factor stimulation of intact human or murine cells leads to phosphorylation of Nck protein on tyrosine, serine, and threonine residues. Similar stimulation of Nck phosphorylation was detected upon activation of rat basophilic leukemia RBL-2H3 cells by cross-linking of the high-affinity immunoglobulin E receptors (Fc epsilon RI). Ligand-activated, tyrosine-autophosphorylated platelet-derived growth factor or epidermal growth factor receptors were coimmunoprecipitated with anti-Nck antibodies, and the association with either receptor molecule was mediated by the SH2 domain of Nck. Addition of phorbol ester was also able to stimulate Nck phosphorylation on serine residues. However, growth factor-induced serine/threonine phosphorylation of Nck was not mediated by protein kinase C. Interestingly, approximately fivefold overexpression of Nck in NIH 3T3 cells resulted in formation of oncogenic foci. These results show that Nck is an oncogenic protein and a common target for the action of different surface receptors. Nck probably functions as an adaptor protein which links surface receptors with tyrosine kinase activity to downstream signalling pathways involved in the control of cell proliferation.
Mol Cell Biol 1992 Dec
PMID:The SH2 and SH3 domain-containing Nck protein is oncogenic and a common target for phosphorylation by different surface receptors. 133 47

The two mechanisms for generating hypervariability at the reactive center of serine proteases and their inhibitors are gene conversion followed by natural selection and natural selection for point mutation. One way to clarify the effects of these two mechanisms is to calculate separately the number of nonsynonymous substitutions and that of synonymous substitutions at the variable regions and at the conserved regions. Our data analysis shows that not only the number of nonsynonymous substitutions but also the number of synonymous substitutions at the variable regions exceed the corresponding numbers at the conserved regions. Thus gene conversion has provided needed variability at the variable regions of serine proteases and their inhibitors. Natural selection has helped perpetuate such variability.
Mol Phylogenet Evol 1992 Jun
PMID:Gene conversion generates hypervariability at the variable regions of kallikreins and their inhibitors. 134 30

Type 1 protein phosphatases (PP-1) comprise a group of widely distributed enzymes that specifically dephosphorylate serine and threonine residues of certain phosphoproteins. They all contain an isoform of the same catalytic subunit, which has an extremely conserved primary structure. One of the properties of PP-1 that allows one to distinguish them from other serine/threonine protein phosphatases is their sensitivity to inhibition by two proteins, termed inhibitor 1 and inhibitor 2, or modulator. The latter protein can also form a 1:1 complex with the catalytic subunit that slowly inactivates upon incubation. This complex is reactivated in vitro by incubation with MgATP and protein kinase FA/GSK-3. In the cell the type 1 catalytic subunit is associated with noncatalytic subunits that determine the activity, the substrate specificity, and the subcellular location of the phosphatase. PP-1 plays an essential role in glycogen metabolism, calcium transport, muscle contraction, intracellular transport, protein synthesis, and cell division. The activity of PP-1 is regulated by hormones like insulin, glucagon, alpha- and beta-adrenergic agonists, glucocorticoids, and thyroid hormones.
Crit Rev Biochem Mol Biol 1992
PMID:The structure, role, and regulation of type 1 protein phosphatases. 135 Feb 40

Antral gastrin secretion and gene expression is inhibited by the paracrine release of somatostatin from antral D cells. Transforming growth factor-alpha and epidermal growth factor (EGF) stimulate gastrin reporter gene constructs when transfected into pituitary GH4 cells. Somatostatin inhibits EGF stimulation of gastrin gene expression, which is in part mediated at the level of transcriptional regulation as somatostatin inhibits EGF stimulation of gastrin reporter gene constructs. Somatostatin inhibition was abolished by pertussis toxin, indicating somatostatin inhibits transcription through the inhibitory G protein Gi. Somatostatin inhibition was unaffected by vanadate and okadaic acid, implying this inhibitory pathway is mediated neither through phosphotyrosine phosphatases nor serine/threonine phosphatases, respectively. Gastrin reporter genes containing 82 base pairs of the 5'-flanking DNA were sufficient to confer both EGF responsiveness and inhibition by somatostatin in GH4 cells. However, transcription of a gastrin reporter gene construct containing only the EGF response element (GGGGCGGGGTGGGGGG), located at -68 to -53, was stimulated by EGF but was not inhibited by somatostatin. Thus, somatostatin inhibits EGF-stimulated gastrin gene transcription by a mechanism other than by interfering with cell signals elicited by the EGF receptor. Since the 82 GASCAT is inhibited by somatostatin, this result also implies that sequences adjacent to the EGF response element contain a cis-regulatory element mediating transcriptional inhibition by somatostatin. This cis-element was located using gastrin reporter genes comprising sequential segments of the human gastrin promoter sequence from the transcriptional start site to -82 in the 5'-flanking DNA. Gastrin oligonucleotide constructs lacking the D oligonucleotide (gatcCATATGGCAGGGTA), located at -82 to -69 in the 5'-flanking DNA, were not inhibited by somatostatin, indicating that a somatostatin inhibitory cis-element is located between -82 and -69 in the 5'-flanking DNA of the human gastrin promoter.
Mol Endocrinol 1992 Aug
PMID:Identification of a cis-regulatory element mediating somatostatin inhibition of epidermal growth factor-stimulated gastrin gene transcription. 135 47

Based on amino acid sequence and computer modeling, two conflicting three-dimensional models of the dopamine D2 receptor have been proposed. One model (Dahl et al., 1991, Proc. Natl. Acad. Sci. USA 88, 8111) suggests that dopamine interacts with aspartate 80 of transmembrane (TM) 2 and asparagine 390 of TM6 with the transmembranes arranged in a clockwise manner, while a second model (Hibert et al., 1991, Mol. Pharmacol. 40, 8) suggests that dopamine interacts with aspartate 114 of TM3 and the serines of TM5 (194 and 197) with the transmembranes arranged in a counterclockwise manner when viewed from the extracellular space. The present study tests the latter model by selectively mutating aspartate 114 and serines 194 and 197 of the human dopamine D2 receptor by site-directed mutagenesis. In addition, two methionines (116 and 117) were mutated to evaluate whether residues near aspartate (114) of the dopamine D2 receptor are critical in differentiating dopamine receptor agonists from adrenoceptor agonists. Removal of the negative charge with the mutation of aspartate (114) to either asparagine or glycine led to a total loss of both agonist and antagonist binding. Individual or dual methionine mutations in positions 116 and 117, to make the dopamine D2 binding pocket more closely resemble the beta 2-adrenoceptor, did not result in a change in selectivity toward noradrenergic agonists or antagonists. The serine mutations revealed interesting differences between the dopamine D2 receptor and the adrenoceptors. In particular, serine 197 appeared more important than serine 194 for agonist binding. In addition, the binding of one agonist (N-0437) was unaffected by individual serine mutations, while the binding of some antagonists, such as raclopride and spiperone, was significantly altered. These findings are discussed in relation to ligand structure and their interactions with the putative binding pocket.
 ...
PMID:Site-directed mutagenesis of the human dopamine D2 receptor. 135 63

The selC gene product, tRNA(Sec), inserts selenocysteine at UGA (opal) codons in a specialized mRNA context. We have investigated the action of the tRNA at ordinary UGA codons, normally not translated, by changing the unusual structural features of tRNA(Sec). Sequences in the D arm, CCA arm and variable arm of the tRNA all contribute to the prohibition against translation of ordinary UGA codons. One multiple mutant is a moderately efficient serine-inserting UGA suppressor tRNA.
J Mol Biol 1992 Jan 05
PMID:Bar to normal UGA translation by the selenocysteine tRNA. 137 May 45

In this study we report identification of six members of a protein kinase gene family from soybean (Glycine max L.). Two fully degenerate oligonucleotide primers corresponding to two conserved motifs (DLK-PENV and GTHEYLAPE) in the catalytic domains of eukaryotic protein serine/threonine kinases were used in a polymerase chain reaction (PCR) to amplify soybean cDNA. Sequence analysis showed that 28 of the PCR sequences represented six different putative protein serine/threonine kinases. These results not only demonstrate that catalytic domains of protein kinases are highly conserved between plants and other eukaryotes but also suggest that there are multiple genes encoding protein kinases in plants.
Plant Mol Biol 1992 Feb
PMID:Molecular identification of a soybean protein kinase gene family by using PCR. 137 8

Mitogen-activated protein kinases (MAPKs) or extracellular signal-regulated kinases (ERKs) are serine/threonine kinases of apparent Mr 42-44 kDa that are rapidly activated by a variety of extracellular signals in many cell types. This activation coincides with their phosphorylation on tyrosine and threonine residues, and these covalent modifications are required for full activity of the enzymes. They are thought to play a pivotal role in integrating and transmitting transmembrane signals for growth and differentiation. Here, we report the cloning, sequence, and functional expression in fibroblasts of the hamster p44 MAP kinase (p44mapk). The protein deduced from the nucleotide sequence of an almost full-length cDNA is 98.6% homologous to the rat p44mapk (ERK1). To distinguish the expression of the cloned cDNA from the endogenous p44mapk, we fused to the 5' end of the cDNA an initiating codon followed by an influenza hemagglutinin 9-residue peptide epitope (HAP). The chimeric kinase HAP/p44mapk, under transcriptional control of the cytomegalovirus promoter, was stably expressed in Chinese hamster lung fibroblasts in a functional form. We show that its basal activity, measured by phosphorylation of the substrate myelin basic protein, is activated severalfold (up to 25) by the mitogens alpha-thrombin, platelet-derived growth factor, and fetal calf serum. In addition, we report that in response to alpha-thrombin, this activation is rapid (6-fold in 1 min), biphasic (first peak at 5 min, second broader peak at 1-2 h), persistent (for greater than or equal to 4 h), and parallel to an increased phosphorylation on tyrosine.We conclude that the constructed and stably expressed chimera, HAP/p44mapk, has retained apparently all the hormonal regulation features of the endogenous form. This system now offers the possibility to study structure-function relationships and to determine the role of this kinase in growth control.
Mol Biol Cell 1992 Jan
PMID:Functional expression and growth factor activation of an epitope-tagged p44 mitogen-activated protein kinase, p44mapk. 137 23

In nitrinergic signal transduction, nitrogen oxide (NO) synthases (NOS) (EC 1.14.23) catalyze the conversion of L-arginine to L-citrulline and NO, which in turn activates soluble guanylyl cyclase. Macrophages were reported to contain a single isoform of NOS (type II, soluble, Ca(2+)-independent, 130-kDa) and only upon activation of the cells by interferon-gamma (INF) and lipopolysaccharides (LPS). By a mechanism involving L-type Ca2+ channels, calmodulin, and serine proteases, INF/LPS also induce a cytotoxic activation of macrophages. In RAW264.7 macrophages, NO release was detected upon activation of the cells by INF/LPS but also, although at a 20-fold lower level, in control cells. The latter constitutive NOS activity and NO release were Ca2+ dependent and were decreased in INF/LPS-activated RAW264.7 cells or with increasing passage number. RAW264.7 cells did not express soluble guanylyl cyclase, suggesting other target molecules for NO. In INF/LPS-activated cells, NOS activities and NO release were Ca2+ independent (type II) and coinduced with NADPH-diaphorase activities both in the soluble and in the particulate fractions. The NOS-II activities corresponded to a 130-kDa protein, by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, which was not recognized in a protein immunoblot with anti-NOS-I antibody. The serine protease inhibitor tosyl-lysyl chloromethyl ketone abolished the induction of NOS-II by INF/LPS, by depleting intracellular thiol pools and interfering with protein synthesis. Induction of NOS-II by INF/LPS was transcriptionally based and, for maximal enzyme activity, required increased intracellular tetrahydrobiopterin levels, intracellular Ca2+ mobilization, and activation of non-L-type Ca2+ channels but, unlike the induction of macrophage-mediated cytotoxicity, neither L-type-Ca2+ channels nor calmodulin.
Mol Pharmacol 1992 Apr
PMID:Regulation and subcellular location of nitrogen oxide synthases in RAW264.7 macrophages. 137 97


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