UNIPROT:O95477 - FACTA Search

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Query: UNIPROT:O95477 (membrane-bound)
29,236 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To study the role of soluble interleukin-6 receptor (sIL-6R) during pregnancy, sIL-6R levels in the sera of pregnant women in the first, second, and third trimesters were determined and found to remain unchanged during pregnancy, but were significantly higher than those in nonpregnant women in the follicular, ovulatory, and luteal phases of the menstrual cycle (P < 0.001). IL-6 levels, however, in the sera of pregnant women at all trimesters showed no difference from those in nonpregnant women at any stage of the menstrual cycle. Recombinant sIL-6R (rsIL-6R) augmented hCG production by rIL-6-stimulated trophoblasts dose dependently, but failed to enhance hCG production by unstimulated trophoblasts. rIL-6- and rsIL-6R-induced hCG production was significantly blocked by anti-IL-6R antibody, PM1; antisignal transducing glycoprotein 130 (gp130) antibody, GPX7; or a tyrosine kinase inhibitor, genistein. Thus, sIL-6R in serum from pregnant women forms a complex with placental and decidual IL-6 in a manner similar to trophoblast membrane-bound IL-6R. These two discrete types of IL-6R and IL-6 complex might act cooperatively by binding to gp130 and subsequently evoking tyrosine kinase activity in the trophoblasts to produce hCG in vivo.
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PMID:Soluble interleukin-6 (IL-6) receptor in the sera of pregnant women forms a complex with IL-6 and augments human chorionic gonadotropin production by normal human trophoblasts through binding to the IL-6 signal transducer. 755 74

C-CAMs are epithelial cell-adhesion molecules of the immunoglobulin supergene family with sequences highly homologous to carcinoembryonic antigen (CEA). C-CAMs and their human homologues, biliary glycoproteins, are unique among the CEA-family proteins in that they have cytoplasmic domains. Furthermore, alternative splicing generates C-CAM isoforms with different cytoplasmic domains, suggesting that the cytoplasmic domains of C-CAM may play important roles in regulating the function or functions of C-CAM. By using both sense and antisense approaches, we have shown that C-CAM1 is a tumour suppressor in prostate carcinogenesis. This observation raises the possibility that the cytoplasmic domain of C-CAM1 may be involved in signal transduction or interaction with cytoskeletal elements to elicit the tumour suppressor function. The cytoplasmic domain of C-CAM1 contains several potential phosphorylation sites, including putative consensus sequences for cyclic AMP-dependent kinase and tyrosine kinase. One of the potential tyrosine phosphorylation sites is located within the antigen-receptor homology (ARH) domain. The ARH domain of the membrane-bound IgM molecule is necessary for signal transduction in B-cells. These structural features suggest that the cytoplasmic domain of C-CAM1 may be important for signal transduction. To test this possibility, we generated several site-directed C-CAM1 mutants and tested their ability to support adhesion and their abilities to be phosphorylated in vivo. Results from these studies revealed that Tyr-488 is phosphorylated in vivo. However, replacing this tyrosine with phenylalanine did not significantly compromise its adhesion function. Similarly, Ser and Thr residues are phosphorylated in vivo, but deletion of the potential cyclic AMP-dependent kinase site did not significantly reduce the adhesion function. These results suggest that the kinase phosphorylation sites in the cytoplasmic domain of C-CAM1 are not required for the adhesion function. However, these phosphorylation sites are probably involved in the regulation of C-CAM-mediated signal transduction. Thus, there are probably distinct structural requirements for the adhesion and the signal transduction functions of C-CAM. Incidentally, a C-CAM1 deletion mutant containing a 10-amino-acid cytoplasmic domain was able to support adhesion activity. This is in contrast to our previous finding that a C-CAM isoform, C-CAM3, with a 6-amino-acid cytoplasmic domain could not support cell adhesion. This result indicates that the extra four amino acids, which are absent in C-CAM3 and contain a potential Ser/Thr phosphorylation site, are important for the adhesion function.
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PMID:Structure and function of C-CAM1: effects of the cytoplasmic domain on cell aggregation. 757 60

Insulin stimulation of 3T3-L1 adipocytes results in rapid activation of the insulin receptor tyrosine kinase followed by autophosphorylation of the receptor and phosphorylation of insulin receptor substrate 1 (IRS-1), its major substrate. The insulin receptor resides mostly at the cell surface of 3T3-L1 adipocytes under basal conditions, while about two-thirds of IRS-1 fractionates with intracellular membranes and one-third fractionates with cytosol. To test whether insulin receptor internalization is required for optimal tyrosine phosphorylation of IRS-1, 3T3-L1 adipocytes and CHO-T cells were incubated at 4 degrees C which inhibits receptor endocytosis but not its tyrosine kinase activity. Under these conditions, tyrosine phosphorylation of IRS-1 in the low density microsome fraction in response to insulin was as intense as that observed at 37 degrees C, indicating that endocytosis of insulin receptors is not necessary for tyrosine phosphorylation of IRS-1 to occur. Surprisingly, at 37 degrees C, insulin action on 3T3-L1 adipocytes progressively decreased the amount of IRS-1 protein associated with the low density microsome fraction and increased that in the cytosol. This redistribution of IRS-1 from the low density microsome fraction to the cytosol in response to insulin was accompanied by decreased electrophoretic mobility of IRS-1 on SDS-polyacrylamide gel electrophoresis. Incubation of adipocytes at 4 degrees C blocked the appearance of tyrosine-phosphorylated IRS-1 in the cytosol. Taken together, these data indicate that insulin receptors phosphorylate IRS-1 at the cell surface, perhaps in coated pits which are included in the low density microsome fraction. The results also suggest a desensitization mechanism in which the tyrosine-phosphorylated membrane-bound IRS-1, associated with signaling molecules such as phosphatidylinositol 3-kinase, is released into the cytoplasm in concert with its serine/threonine phosphorylation.
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PMID:Insulin regulation of membrane-associated insulin receptor substrate 1. 759 59

Cytosolic components of the phagocyte NADPH oxidase (p47phox, p67phox, and Rac2) translocate to the plasma membrane on cell activation where they interact with a membrane-bound cytochrome b to generate superoxide anion. Phosphorylation reactions are known to be important for activity of NADPH oxidase. Translocation of Rac2, p47phox, and p67phox were all enhanced in formyl-Met-Leu-Phe-stimulated neutrophils treated with 50 nM of the protein phosphatase 1/2A inhibitor calyculin A. Rac translocation was blocked by the tyrosine kinase inhibitors genistein (50 microM) and herbimycin (17 microM), whereas movement of p47phox and p67phox were not inhibited. Cell-free analysis of Rac translocation also demonstrated that translocation of p47phox and p67phox were not linked to the movement or availability of Rac2. Thus, Rac2 does not appear to regulate NADPH oxidase by controlling movements of the cytosolic components to the membrane-associated enzyme but may exert its effect at the level of the assembled complex. Tyrosine kinase activity is required for translocation of Rac in the chemoattractant-stimulated human neutrophil.
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PMID:Dissociation of Rac translocation from p47phox/p67phox movements in human neutrophils by tyrosine kinase inhibitors. 761 2

Genistein, a potent tyrosine kinase inhibitor, inhibits contraction of several types of smooth muscle, suggesting that protein tyrosine phosphorylation may be an important regulatory mechanism for smooth muscle contraction. We suspected that one site between activation of smooth muscle and contraction which might be modulated by protein tyrosine phosphorylation involved mechanisms for control of Ca2+ sensitivity. Since smooth muscle permeabilized with staphylococcal alpha-toxin permits direct assessment of agonist-induced Ca2+ sensitivity, we studied the effects of genistein on potential coupling between tyrosine phosphorylation and Ca2+ sensitivity in permeabilized ileal smooth muscle. Results show that contraction of intact preparations with carbachol is markedly and reversibly inhibited by 40% at 4 micrograms genistein/ml and by 60% at 20 micrograms genistein/ml. Permeabilized preparations that are contracted with a submaximal [Ca2+] in the presence of GTP relax when genistein is added to the medium. Genistein also reversibly inhibits contractions induced in permeabilized muscle with either a submaximal or maximal [Ca2+] in the presence of GTP, as well as receptor-coupled activation of Ca2+ sensitization with 10 microM carbachol/10 microM GTP. Activation of permeabilized preparations at pCa 4.6 in the presence of 100 microM GTP promotes time-dependent tyrosine phosphorylation of several substrates. Both phosphorylation and force are inhibited by genistein. However, relatively high levels of myosin light chain phosphorylation persist during genistein-induced inhibition of Ca2+ sensitivity. In contrast, genistein has no effect on Ca(2+)-activated contraction in Triton-skinned preparations in either the presence or the absence of GTP. This shows that it does not directly inhibit actin-myosin interaction and suggests that its target(s) may be a cytosolic or membrane-bound regulatory protein(s) that is leached from the preparations during Triton-skinning. Taken together, these new data suggest that (a) tyrosine phosphorylation of one or more substrates may be coupled to mechanisms which regulate Ca2+ sensitivity and (b) the inhibitory effects of genistein are probably due to inhibition of agonist-induced Ca2+ sensitivity.
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PMID:Modulation of Ca2+ sensitivity in smooth muscle by genistein and protein tyrosine phosphorylation. 762 29

The E5 polypeptide of bovine papillomavirus type 1 is a small membrane-bound protein which induces the transformation of immortalized fibroblasts, apparently via the formation of a ternary complex with the platelet-derived growth factor receptor (PDGFR) and the 16-kDa V-ATPase protein. This interaction seems to be mediated, at least in part, by their respective transmembrane domains. E5 also cooperates with transfected beta PDGFR to induce interleukin-3 (IL-3)-independent growth of a mouse myeloid precursor cell line (32D) which normally lacks expression of most known tyrosine kinase growth factor receptors. Cell proliferation induced by beta PDGFR and E5 is also highly specific, since the highly conserved alpha PDGFR and other related receptors did not physically or functionally interact with E5 in these cells. In the current study, analysis of chimeric alpha and beta PDGFRs confirmed that a short region encompassing the beta PDGFR transmembrane domain was sufficient for complex formation with E5, receptor autophosphorylation, and sustained proliferation of 32D cells in the absence of IL-3. Furthermore, a deletion mutant lacking the entire extracellular domain efficiently bound E5 and induced IL-3-independent growth. These data provide direct evidence that the interaction between E5 and the beta PDGFR involves amino acids 531 to 556 of the receptor transmembrane region and that this specific interaction is critical for activation of the PDGFR signaling complex.
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PMID:Mutational analysis of the beta-type platelet-derived growth factor receptor defines the site of interaction with the bovine papillomavirus type 1 E5 transforming protein. 766 52

Eosinophils are implicated as major inflammatory cells in parasite infection and allergic reactions. Among various mediators, eosinophil granule cationic proteins play an important role in the pathophysiology of diseases. However, little is known about the actual physiologic stimuli for eosinophil degranulation and the signaling events for triggering eosinophil degranulation. A series of in vivo and in vitro studies suggest that the interaction between antibody coated parasites and Fc receptors on eosinophils is one of the most effective triggers for eosinophil degranulation. Similarly, eosinophil degranulation can be induced in vitro by Sepharose beads coated with human sIgA or IgG. Eosinophil degranulation induced by these stimuli is mediated by PTX-sensitive membrane-bound heterotrimeric G protein(s), and is accompanied by the rapid turnover of inositol phosphates. The production of inositol phosphates is inhibited by PTX. Eosinophil activation by sIgA and IgG also involves tyrosine phosphorylation of several proteins and is inhibited by tyrosine kinase inhibitors. Thus phospholipase C-coupled G protein(s) and tyrosine kinases are key molecules in early signal transduction of eosinophil activation induced by sIgA and IgG. Although further studies are needed to identify which tyrosine kinase(s) is specifically involved in the eosinophil degranulation mechanism, these molecules could be a target for therapies of human diseases where eosinophils are involved.
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PMID:Tyrosine phosphorylation and inositol phosphate production: are early events in human eosinophil activation stimulated by immobilized secretory IgA and IgG? 779 68

Although tyrosine kinases are clearly activated after ligand engagement of the human IL-3R in both hematopoietic and nonhematopoietic cytoplasmic environments, a role for phospholipid hydrolysis and protein kinase C in IL-3R signal transduction is emerging. We have used NIH 3T3 cells transiently transfected with human IL-3R alpha- and beta-subunits to study phosphatidylcholine hydrolysis in response to human IL-3. We have found that NIH 3T3 cells expressing the complete human IL-3R respond to human IL-3 with a rapid and sustained increase in sn-1'2'-diacylglycerol. Accompanying this was a rapid increase in intracellular levels of phosphorylcholine. The protein kinase C inhibitor H-7, however, was not effective in inhibiting phosphatidylcholine hydrolysis in response to human IL-3 in NIH 3T3 cells expressing the human receptor. Thus the human IL-3R induces a rapid protein-kinase-C-independent hydrolysis induced by the murine receptor. Simultaneous with the increase in phosphatidylcholine hydrolysis induced by the murine receptor. Simultaneous with the increase in diacylglycerol levels was an increase in membrane-bound protein kinase C enzyme activity. Immunoblotting with isoform-specific Abs against protein kinase C showed that, whereas the zeta-isoform is constitutively membrane bound, the alpha-isoform of protein kinase C is translocated to the membrane in response to IL-3. Activation of phosphatidylcholine hydrolysis and protein kinase C activation required both alpha- and beta-receptor subunits. To determine the relationship of tyrosine phosphorylation to the activation of phosphatidylcholine hydrolysis and protein kinase C translocation, we used the specific and structurally unrelated tyrosine kinase inhibitors genistein and herbimycin. Both inhibitors effectively blocked human IL-3-induced tyrosine phosphorylation. In addition, both inhibitors blocked phosphatidylcholine hydrolysis and protein kinase C translocation. These data, combined with our previous report showing that c-jun induction by IL-3 is dependent on protein kinase C, suggest that, in hematopoietic and nonhematopoietic cells expressing the human IL-3R, phosphatidylcholine hydrolysis and protein kinase C are downstream effectors of tyrosine phosphorylation in the IL-3 signal transduction cascade resulting in immediate early response gene induction.
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PMID:Human IL-3 receptor signaling: rapid induction of phosphatidylcholine hydrolysis is independent of protein kinase C but dependent on tyrosine phosphorylation in transfected NIH 3T3 cells. 783 50

The epidermal growth factor (EGF) and erbB-2 receptors are structurally related membrane-bound tyrosine kinases. While these proteins exhibit close sequence homology, 50% overall and 80% in the tyrosine kinase domains, they respond very differently to heat stress. In NIH-3T3 or NR6 cells transfected with wild-type EGF-R and incubated at 37 degrees C or heat shocked at 46 degrees C, EGF binds to its receptor and stimulates receptor autophosphorylation to equivalent extents. At 46 degrees C, however, the basal tyrosine kinase activity of the wild-type erbB-2 receptor is rapidly lost. When cells containing chimeric receptors composed of the EGF-R extracellular domain and intracellular domain of erbB-2 were heat stressed, 125I-EGF bound to the receptors, but did not stimulate receptor autophosphorylation. The decline in EGF-stimulated chimeric erbB-2 receptor autophosphorylation is dependent on the length of heat shock, with nearly 100% of the kinase activity lost after 60 min at 46 degrees C. The loss of chimeric receptor erbB-2 kinase activity is not due to degradation of receptor protein, nor is it attributable to a specific transmembrane domain from either the EGF or erbB-2 receptors. Sensitivity of erbB-2 to heat stress is also not a result of denaturation of this receptor's carboxy-terminal domain. Insertion of the erbB-2 tyrosine kinase domain into the EGF-R confers heat stress sensitivity to the resultant chimeric receptor. Thus, although the EGF-R and erbB-2 kinase domains show a high degree of homology, the secondary/tertiary structures of these domains would seem to be stabilized in distinct manners.
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PMID:Differential heat stress stability of epidermal growth factor receptor and erbB-2 receptor tyrosine kinase activities. 790 Dec 24

Tumor necrosis factor (TNF) is known to induce the activation of a nuclear transcription factor, nuclear factor kappa B (NF-kappa B), in a wide variety of cell types. The post-receptor binding events that culminate in TNF-dependent NF-kappa B activation are not understood. To dissect this pathway, we developed a reconstitution system consisting of membrane, cytosolic, and post-nuclear fractions. Our results indicate that when incubated with the post-nuclear fraction derived from TNF-untreated cells, the membrane fraction from TNF-treated cells causes the activation of NF-kappa B with kinetics similar to that observed in intact cells. Under these conditions, the cytosolic fraction has no effect. This activation is tyrosine kinase-dependent since erbstatin completely abolished the effect. Furthermore, as revealed by immunoblotting, no degradation of the inhibitory subunit of NF-kappa B was observed. In this reconstitution system, we can also demonstrate the activation of NF-kappa B by ceramide, but this activation is not tyrosine kinase-dependent. Overall, our results indicate that intermediates required for NF-kappa B activation by TNF or ceramide are membrane-bound, but the mechanism of activation by TNF is most likely different from that of ceramide.
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PMID:Reconstitution of nuclear factor kappa B activation induced by tumor necrosis factor requires membrane-associated components. Comparison with pathway activated by ceramide. 792 33

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