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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Polyclonal rabbit antisera against soluble human milk galactosyltransferase and bovine colostrum sialyltransferase were used to localize by indirect immunofluorescence the respective intracellular enzymes in primary cultures from bovine fetal kidneys and established cell lines of human and bovine fibroblasts. Staining for galactosyltransferase was juxtanuclear and crescent shaped in epitheloid cells; a similar staining, occasionally perinuclear and sparsely distributed in the cytoplasm, was found in fibroblasts. In contrast, staining for sialyltransferase in epitheloid kidney cells derived from the same primary culture was observed predominantly in cytoplasmic vesicles that were spread over the whole cytoplasm. Sialyltransferase-positive vesicles had a similar distribution in fibroblasts and often appeared concentrated around an unstained Golgi area. Thus, in both cell types galactosyl- and sialyltransferase were localized in different subcellular compartments. Since both galactosyl- and sialyltransferase participate in formation of the terminal glycan NeuAc(alpha 2----6)Gal(beta 1----4)GlcNAc(Neu, neuraminic acid) present in many N-glycosidic complex types of glycans, different subcellular compartments for these enzymes support a model of functional compartmentalization of the Golgi apparatus that is compatible with an assembly-line model for glycan chain elongation and termination.
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PMID:Localization of galactosyl- and sialyltransferase by immunofluorescence: evidence for different sites. 392 89

Human IgM kappa monoclonal antibody to human tumors of neuroectodermal origin was produced in the spent medium of an Epstein-Barr virus-transformed B-lymphoblastoid cell line, L72. Chemically, the antigen was identified as ganglioside GD2 [Gal NAc beta 1----4 (Neu Ac alpha 2----8 Neu Ac alpha 2---3) Gal beta 1----4 Glc----ceramide]. Twenty-seven mg of pure human IgM were obtained from 10 liters of L72 spent medium using salt and hypotonic precipitation, ultracentrifugation, and Sephacryl-S 300 superfine gel filtration. The monoclonal origin of the antibody was determined by agarose isoelectrofocusing. This human monoclonal antibody may be a particularly useful reagent for immunotherapy trials in cancer patients.
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PMID:Human monoclonal antibody to a neuroectodermal tumor antigen (OFA-I-2). 658 83

Five major sialyloligosaccharides and a sialylglycopeptide have been isolated from normal human urine by charcoal adsorption, gel filtration, ion-exchange chromatography, and paper chromatography. Structural studies including gas-liquid chromatography of monosaccharide and disaccharide derivatives, methylation analysis, glycosidase treatments, and CrO3 oxidation indicated the following structures for the compounds: 1, NeuAc(alpha 2-6)Gal(beta 1-4)Glc; 2, NeuAc(alpha 2-6)Gal(beta 1-4)GlcNAc; 3, NeuAc(alpha 2-3)Gal(beta 1-4)Glc; 4, NeuAc(alpha 2-3)Gal(beta 1-4) GlcNAc; 5, NeuAc(alpha 2-3)Gal(beta 1-3) [Neu-Ac(alpha 2-6)]GalNAc; and 6, NeuAc(alpha 2-3)Gal(beta 1-3) [NeuAc(alpha 2-6)]GalNAc (alpha 1-O)Ser. Compounds 4, 5, and 6 have not been described in a free form before. The presence of compound 5 in urine may suggest that it derives from glycoproteins through a catabolic pathway involving cleavage of the carbohydrate-peptide linkage by an endo-N-acetylgalactosaminidase. The predominating sialyloligosaccharides in urine were compounds 3 and 4. The predominance of the compounds with the sialyl(alpha 2-3) linkage is of interest in view of the recent discovery of uropathogenic Escherichia coli strains with binding specificity for sialyl(alpha 2-3)galactosides.
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PMID:Isolation and structural characterization of five major sialyloligosaccharides and a sialylglycopeptide from normal human urine. 662 86

The beta-(p-aminophenyl)ethylamine derivatives of sialyloligosaccharides can be coupled to proteins via their phenylisothiocyanate intermediates under conditions that preserve labile sugar linkages. Bovine serum albumin containing 10 to 40 mol of oligosaccharides/mol of protein and keyhole limpet hemocyanin containing 1,100 mol of oligosaccharide/mol of protein have been prepared with the following oligosaccharides: Neu-NAc alpha 2-3Gal beta 1-4Glc, NeuNAc alpha 2-6Gal beta 1-4Glc, Neu-NAc alpha 2-6Gal beta 1-4GlcNAc beta 1-4Glc, Gal beta 1-3[Neu-NAc alpha 2-6]GlcNAc beta 1-4Glc, and NeuNAc alpha 2-3Gal- beta 1-3[NeuNAc alpha 2-6]GlcNAc beta 1-4Glc. Rabbits immunized with these synthetic glycoproteins produce antibodies directed against the oligosaccharides. The specificities of these antibodies are determined by comparing inhibitory activities of structurally related oligosaccharides in radioimmunoassay and by double diffusion analysis in agarose gels using oligosaccharide-protein conjugates as precipitating antigens. The antibodies distinguish positional isomers of sialic acid.
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PMID:Antibodies against sialyloligosaccharides coupled to protein. 676 46

The carbohydrate structure and complete amino acid sequence of a human lambda-type immunoglobulin light chain, protein Sm lambda has been determined. The protein was isolated from the urine of a patient with a plasma cell dyscrasia resembling gamma-heavy-chain disease. 13 tryptic peptides covering the entire polypeptide chain of 135 residues were isolated from the aminoethylated protein, and 15 chymotryptic peptides, accounting for 131 residues, were recovered from the carboxymethylated protein. The sequence of 18 of these peptides was partially or completely determined by the Edman-dansyl technique or C-terminal analysis, permitting the establishment of the complete primary structure of the polypeptide chain. The sequences established that this light chain possessed an intramolecular deletion of 81 amino acid residues. The N-terminal 30 residues showed considerable homology with other lambda chains of subgroup II. The defect began at position 31, in the first hypervariable region, and encompassed the remainder of the variable region through position 109. The constant region was fully intact and normal synthesis recommenced with a glutaminyl residue at position 110, the first residue of the constant region. This light chain contained carbohydrate in the hypervariable region just preceding the deletion. The precise number and locations of the oligosaccharide chains were established by amino acid sequence analysis of glycopeptides isolated from proteolytic hydrolysates by chromatography on Bio-Gel P-6 columns. These studies showed that protein Sm lambda contains one N-glycosidically-linked chain attached to asparagine-25 and one O-glycosidically-linked oligosaccharide chain attached to serine-21. The structures of the oligosaccharide chains were determined by methylation analysis, gas chromatography and hydrolysis with specific glycosidases. The structure of the N-glycosidically-linked chain was NeuAc(alpha 2 leads to 6)Gal(beta 1 leads to 4)GlcNAc(beta 1 leads to 2)Man(alpha 1 leads to 6)[NeuAc(alpha 2 leads to 6)Gal(beta 1 leads to 4)GlcNAc(beta 1 leads to 2)Man(alpha 1 leads to 3)]Man(beta 1 leads to 4)GlcNAc(beta 1 leads to 4)[Fuc alpha 1 leads to 6]GlcNAc leads to Asn. The second O-glycosidically-linked chain was a disialylated tetrasaccharide with the structure, Neu(alpha 2 leads to 3)Gal(beta 1 leads to 3)[NeuAc(alpha 2 leads to 6)GalNAc leads to Ser. This mucin-type disialylated tetrasaccharide in close proximity to N-asparagine-linked chains has not been previously observed in the oligosaccharide chains of immunoglobulins.
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PMID:Localization of the carbohydrate units in a human immunoglobulin light chain, protein Sm lambda. 678 88

The importance of PLC activation in cell proliferation is evident from the fact that the hydrolysis of PtdIns(4,5)P2 is one of the early events that follow the interaction of many growth factors and mitogens with their respective receptors. However, the importance of PLC activation is not restricted to proliferation; it is one of the most common transmembrane signaling events elicited by receptors that regulate many other cellular processes, including differentiation, metabolism, secretion, contraction, and sensory perception. It is also clear that cell proliferation signaling does not always require PLC, as indicated by the fact that growth factors such as insulin and CSF-1 do not appear to elicit the hydrolysis of PtdIns(4,5)P2, even though the intracellular domains of their receptors carry a PTK domain and the receptors show topologies very similar to those of the PLC-activating growth factors PDGF, EGF, and FGF. The growth factor-dependent activation of PLC is initiated by the formation of a complex between the receptor PTK and PLC-gamma; the formation of this complex is mediated by a specific interaction between a tyrosine phosphate residue on the intracellular domain of PTK and the SH2 domain of PLC-gamma. The receptor PTK subsequently phosphorylates PLC-gamma, of which two distinct isozymes, PLC-gamma 1 and PLC-gamma 2, have been identified. Proliferation of T cells and B cells in response to the aggregation of their respective cell surface receptors is also accompanied by the activation of PLC-gamma isozymes at an early stage. Unlike growth factor receptors, the T cell and B cell receptors lack intrinsic PTK activity but associate with several non-receptor PTKs of the Src and Syk families. Although the specific kinases are not known, one or more of these enzymes phosphorylate and activate PLC-gamma 1 and PLC-gamma 2. Transduction of growth signals by G protein-coupled receptors such as those for thrombin or bombesin also requires PtdIns(4,5)P2 hydrolysis, which, in this instance, is mediated by PLC-beta isozymes. The PLC-beta subfamily consists of four distinct members: PLC-beta 1, PLC-beta 2, PLC-beta 3, and PLC-beta 4. Agonist interaction with specific G protein-coupled receptors causes the dissociation of Gq proteins into G alpha and G beta gamma subunits and the exchange of GDP bound to G alpha for GTP. The resulting GTP-bound G alpha subunit then activates PLC-beta isoforms by binding to the carboxyl-terminal region of the enzyme.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Phosphoinositide-specific phospholipase C and mitogenic signaling. 749 69

The three-dimensional structure of an unglycosylated T cell antigen receptor (TCR) beta chain has recently been determined to 1.7 A resolution. To investigate whether this soluble beta chain (murine V beta 8.2J beta 2.1C beta 1) retains superantigen (SAG)-binding activity, we measured its affinity for various bacterial SAGs in the absence of MHC class II molecules. Dissociation constants (KDs) were determined using two independent techniques: surface plasmon resonance detection and sedimentation equilibrium. Specific binding was demonstrated to staphylococcal enterotoxins (SEs) B, C1, C2, and C3 and to streptococcal pyrogenic exotoxin A (SPEA), consistent with the known proliferative effects of these SAGs on T cells expressing V beta 8.2. In contrast, SEA, which does not stimulate V beta 8.2-bearing cells, does not bind the recombinant beta chain. Binding of the beta chain to SAGs was characterized by extremely fast dissociation rates (> 0.1 s-1), similar to those reported for certain leukocyte adhesion molecules. Whereas the beta chain bound SEC1, 2, and 3 with KDs of 0.9-2.5 microM, the corresponding value for SEB was approximately 140 microM. The much weaker binding to SEB than to SEC1, 2, or 3 was surprising, especially since SEB was found to actually be 3- to 10-fold more effective, on a molar basis, than the other toxins in stimulating the parental T cell hybridoma. We interpret these results in terms of the ability of SEC to activate T cells independently of MHC, in contrast to SEB. We have also measured SE binding to the glycosylated form of the beta chain and found that carbohydrate apparently does not contribute to recognition, even though the N-linked glycosylation sites at V beta 8.2 residues Asn24 and Asn74 are at or near the putative SAG-binding site. This result, along with the structural basis for the V beta specificity of SEs, are discussed in relation to the crystal structure of the unglycosylated beta chain.
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PMID:Superantigen binding to a T cell receptor beta chain of known three-dimensional structure. 750 29

We used molecular cloning and functional analyses to extend the family of Neu differentiation factors (NDFs) and to explore the biochemical activity of different NDF isoforms. Exhaustive cloning revealed the existence of six distinct fibroblastic pro-NDFs, whose basic transmembrane structure includes an immunoglobulin-like motif and an epidermal growth factor (EGF)-like domain. Structural variation is confined to three domains: the C-terminal portion of the EGF-like domain (isoforms alpha and beta), the adjacent juxtamembrane stretch (isoforms 1 to 4), and the variable-length cytoplasmic domain (isoforms a, b, and c). Only certain combinations of the variable domains exist, and they display partial tissue specificity in their expression: pro-NDF-alpha 2 is the predominant form in mesenchymal cells, whereas pro-NDF-beta 1 is the major neuronal isoform. Only the transmembrane isoforms were glycosylated and secreted as biologically active 44-kDa glycoproteins, implying that the transmembrane domain functions as an internal signal peptide. Extensive glycosylation precedes proteolytic cleavage of pro-NDF but has no effect on receptor binding. By contrast, the EGF-like domain fully retains receptor binding activity when expressed separately, but its beta-type C terminus displays higher affinity than alpha-type NDFs. Likewise, structural heterogeneity of the cytoplasmic tails may determine isoform-specific rate of pro-NDF processing. Taken together, these results suggest that different NDF isoforms are generated by alternative splicing and perform distinct tissue-specific functions.
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PMID:Structural and functional aspects of the multiplicity of Neu differentiation factors. 750 48

Cultures consisting primarily of O-2A progenitor cells and immature oligodendrocytes with a few microglia and astrocytes were obtained by shaking primary cultures from neonatal rat brain after 12-14 days in vitro. Addition of 50 micrograms/ml exogenous Neu-NAc alpha 2-3Gal beta 1-4Glc beta 1-1'ceramide (GM3 ganglioside) to the cultures resulted in an increase in the number and thickness of cell processes that stained intensely for sulfatide and galactocerebroside (galC) in comparison to control cultures without added GM3. The treated cultures also contained fewer astrocytes than control cultures as revealed by immunostaining for glial fibrillary acidic protein (GFAP). Cells that immunostained for both GFAP and sulfatide/galC were very rare in control cultures but were frequently seen in the GM3-treated cultures, suggesting that these may represent cells changing their direction of differentiation away from type II astrocytes toward oligodendrocytes under the influence of GM3. These effects on the developing rat oligodendrocytes were specific for GM3 ganglioside and were not produced by adding GM1, GM2, GD3, or GD1a to the cultures. Lactosyl ceramide and neuraminyl lactose were also ineffective. When control cultures were initially plated on polylysine and incubated with [14C]galactose, GD3 was the principal labeled ganglioside. However, as the control cells differentiated over time in culture without the addition of exogenous GM3 and produced increasing amounts of myelin-related components, the incorporation of [14C]galactose into endogenous GM3 increased to become the predominant labeled ganglioside by 6 days after plating. Metabolic labeling of the GM3-treated oligodendrocytes with [14C]galactose revealed increased incorporation into galC and sulfatide in comparison to control cultures, but a decreased labeling of endogenous GM3. Similarly, incorporation of an amino acid precursor into the myelin-associated glycoprotein (MAG) was increased by GM3 treatment, but incorporation into myelin basic protein (MBP) was not affected. Although the overall effect of added GM3 was to decrease the phosphorylation of most proteins in the oligodendrocytes, including MBP, GM3 enhanced the phosphorylation of MAG. These findings indicate that GM3 ganglioside has an important role in the differentiation of cells of the O-2A lineage toward myelin production, since differentiation is associated with increased metabolic labeling of endogenous GM3 in control cultures and is enhanced by the addition of exogenous GM3.
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PMID:Differentiation of oligodendrocytes cultured from developing rat brain is enhanced by exogenous GM3 ganglioside. 752 87

Cytokines are known to be important regulators of normal hemopoiesis, acting in concert with components of the bone marrow microenvironment. Interactions with this microenvironment are known to regulate the proliferation, differentiation, and homing of hemopoietic progenitor (CD34+) cells. Adhesive interactions with the extracellular matrix retain CD34+ cells in close proximity to cytokines, but may also provide important costimulatory signals. Thus, the functional states of adhesion receptors are critical properties of CD34+ cells, but the physiological mechanisms responsible for regulating functional properties of cell adhesion receptors on primitive hemopoietic cells are still unknown. We confirm that the integrins very late antigen (VLA)-4 and VLA-5 are expressed on the CD34+ cell lines MO7e, TF1, and on normal bone marrow CD34+ progenitor cells, but in a low affinity state, conferring on them a weak adhesive phenotype on fibronectin (Fn). Herein, we show that the cytokines interleukin (IL)-3, granulocyte-macrophage CSF (GM-CSF), and KIT ligand (KL) are physiological activators of VLA-4 and VLA-5 expressed by MO7e, TF1, and normal bone marrow CD34+ progenitor cells. Cytokine-stimulated adhesion on Fn is dose dependent and transient, reaching a maximum between 15 and 30 min and returning to basal levels after 2 h. This cytokine-dependent activation is specific for VLA-4 and VLA-5, since activation of other beta 1 integrins was not observed. The addition of second messenger antagonists staurosporine and W7 abolished all cytokine-stimulated adhesion to Fn. In contrast, genistein inhibited KL-stimulated adhesion, but failed to inhibit GM-CSF- and IL-3-stimulated adhesion. Our data suggest that cytokines GM-CSF and IL-3 specifically stimulate beta 1 integrin function via an "inside-out" mechanism involving protein kinase activity, while KL stimulates integrin activity through a similar, but initially distinct, pathway via the KIT tyrosine-kinase. Thus, in addition to promoting the survival, proliferation, and development of hemopoietic progenitors, cytokines also regulate adhesive interactions between progenitor cells and the bone marrow microenvironment by modifying the functional states of specific integrins. These data are of importance in understanding the fundamental processes of beta 1 integrin activation and cellular response to mitogenic cytokines as well as on the clinical setting where cytokines induce therapeutic mobilization of hematopoietic progenitors.
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PMID:Cytokines increase human hemopoietic cell adhesiveness by activation of very late antigen (VLA)-4 and VLA-5 integrins. 753 95


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