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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The significance of the glycosylphosphatidylinositol (GPI) anchor is unknown. Since GPI-anchored proteins mediate signaling, it has been suggested that the GPI structure serves as a signal-transducing element. However, the division of signaling functions between transmembrane and GPI-anchored proteins is unclear. Studies of distinct membrane-anchored forms of the same protein may resolve this issue. The adhesion molecule CD58 is expressed on the cell surface in both a transmembrane and a GPI-anchored form and hence provides a useful model. We studied CD58 in the human B lymphoblastoid cell line JY. In addition to mediating adhesion, CD58 is involved in signal transduction. Incubation of JY cells with immobilized anti-CD58 Abs results in extensive tyrosine phosphorylation and in secretion of TNF-alpha. We demonstrate that CD58 is associated with protein kinase(s) and with several kinase substrates. We further demonstrate that both CD58 isoforms are involved. CD58 in JY variant cells, which express only the transmembrane form, as well as CD58 in JY variant cells, which express only the GPI-anchored form, are associated with kinase activity. This association results in a phosphorylation pattern that is common to the variant and to wild-type JY cells. Thus, these findings suggest that the capacity of GPI-anchored proteins to interact with kinases is not always dependent on the GPI anchor itself.
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PMID:The glycosylphosphatidylinositol-anchored form and the transmembrane form of CD58 associate with protein kinases. 957 40

Cytokines are important regulators of hematopoiesis. They exert their actions by binding to specific receptors on the cell surface. Interleukin-5 (IL-5) is a critical cytokine that regulates the growth, activation, and survival of eosinophils. Because eosinophils play a seminal role in the pathogenesis of asthma and allergic diseases, an understanding of the signal transduction mechanism of IL-5 is of paramount importance. The IL-5 receptor is a heterodimer of alpha- and beta-subunits. The alpha-subunit is specific, whereas the beta-subunit is common to IL-3, IL-5, and granulocyte/macrophage colony-stimulating factor (GM-CSF) receptors and is crucial for signal transduction. It has been shown that there are two major signaling pathways of IL-5 in eosinophils. IL-5 activates Lyn, Syk, and JAK2 and propagates signals through the Ras-MAPK and JAK-STAT pathways. Studies suggest that Lyn, Syk, and JAK2 tyrosine kinases and SHP-2 tyrosine phosphatase are important for eosinophil survival. In contrast to their survival-promoting activity, Lyn and JAK2 appear to have no role in eosinophil degranulation or expression of surface adhesion molecules. Raf-1 kinase, on the other hand, is critical for eosinophil degranulation and adhesion molecule expression. Btk is involved in IL-5 stimulation of B cell function. However, it does not appear to be important for eosinophil function. Thus a clear segregation of signaling molecules based on their functional importance is emerging. This review describes the signal transduction mechanism of the IL-3/GM-CSF/IL-5 receptor system and compares and contrasts IL-5 signaling between eosinophils and B cells.
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PMID:The mechanism of IL-5 signal transduction. 973 Sep 44

Sphingolipids and their metabolic products are now known to have second-messenger functions in a variety of cellular signaling pathways. Lactosylceramide (LacCer), a glycosphingolipid (GSL) present in vascular cells such as endothelial cells, smooth muscle cells, macrophages, neutrophils, platelets, and monocytes, contributes to atherosclerosis. Large amounts of LacCer accumulate in fatty streaks, intimal plaque, and calcified intimal plaque, along with oxidized low density lipoproteins (Ox-LDLs), growth factors, and proinflammatory cytokines. A possible role for LacCer in vascular cell biology was suggested when this GSL was found to stimulate the proliferation in vitro of aortic smooth muscle cells (ASMCs). A further link of LacCer in atherosclerosis was uncovered by the finding that Ox-LDLs stimulated specifically the biosynthesis of LacCer. Ox-LDL-stimulated endogenous synthesis of LacCer by activation of UDP-Gal:GlcCer,beta1-4galtransferase (GalT-2) is an early step in this signaling pathway. In turn, LacCer serves as a lipid second messenger that orchestrates a signal transduction pathway, ultimately leading to cell proliferation. This signaling pathway includes LacCer-mediated activation of NADPH oxidase that produces superoxide. Such superoxide molecules stimulate the GTP loading of p21(ras). Subsequently, the kinase cascade (Raf-1, Mek2, and p44MAPK [mitogen-activated protein kinase]) is activated. The phosphorylated form of p44MAPK translocates from the cytoplasm to the nucleus and engages in c-fos expression, proliferating cell nuclear antigen (PCNA) such as cyclin activation, and cell proliferation takes place. Interestingly, D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP), an inhibitor of GalT-2, can abrogate the Ox-LDL-mediated activation of GalT-2, the signal kinase cascade noted above, as well as cell proliferation. Additional studies have revealed that LacCer mediates the tumor necrosis factor-alpha (TNF-alpha)-induced nuclear factor-kappaB expression and intercellular adhesion molecule (ICAM-1) expression in vascular endothelial cells via the redox-dependent transcriptional pathway. LacCer also stimulates the expression of CD11/CD8, or Mac-1, on the surface of human neutrophils. Collectively, this phenomenon may contribute to the adhesion of neutrophils or monocytes to the endothelial cell surface and thus initiate the process of atherosclerosis. In addition, the LacCer-mediated proliferation of ASMCs may contribute to the progression of atherosclerosis. On the other hand, programmed cell death (apoptosis) by proinflammatory cytokines such as TNF-alpha, interleukin-1, and high concentrations of Ox-LDL occur via activation of a cell membrane-associated neutral sphingomyelinase (N-SMase). N-SMase hydrolyzes sphingomyelin into ceramide and phosphocholine. In turn, ceramide or a homologue serves as an important stress-signaling molecule. Interestingly, an antibody against N-SMase can abrogate Ox-LDL- and TNF-alpha-induced apoptosis and therefore may be useful for in vivo studies of apoptosis in experimental animals. Because plaque stability is an integral aspect of atherosclerosis management, activation of N-SMase and subsequent apoptosis may be vital events in the onset of plaque rupture, stroke, or heart failure. Interestingly, in human liver cells, N-SMase action mediates the TNF-alpha-induced maturation of the sterol regulatory-element binding protein. Moreover, a cell-permeable ceramide can reconstitute the phenomenon above in a sterol-independent fashion. Such findings may provide new avenues for therapy for patients with atherosclerosis. The findings described here indicate an important role for sphingolipids in vascular biology and provide an exciting opportunity for further research in vascular disease and atherosclerosis.
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PMID:Sphingolipids in atherosclerosis and vascular biology. 976 22

Heavy metal ions can be released by corroding metallic implants into the surrounding tissue. When they enter blood vessels some of them are carried by proteins like albumin and can be taken up by endothelial cells lining the vessels. To study their involvement in the inflammatory response we investigated heavy metal ion induced effects in cultured human vascular endothelial cells (HUVECs). NiCl2 and CoCl2 upregulate, especially in concentrations of 1 mM, the expression of adhesion molecules (e.g., E-selectin and intercellular adhesion molecule-1), as well as the cytokines IL-6 and IL-8, as shown by enzyme immunoassay and Northern blot analysis. In addition, possible signal transduction mechanisms were elucidated. The HUVECs were treated with various selective inhibitory drugs followed by the incubation of metal ions before measuring the expression of the above-mentioned endothelial factors. Two protein kinase inhibitors (H-7 and H-8) strongly repressed Ni2+ and Co2+ enhanced expression, as did the phospholipase A2 inhibitor quinacrine. Other selective inhibitors of protein kinases C or A, or cGMP-dependent protein kinases, as well as calcium antagonists like 1,2-bis(2-aminophenoxy)ethan-N,N,N',N'-tetraacetic acid and 3,4,5-trimethoxybenzosaure 8-(diethylamino)-octylester and inhibitors of receptor mediated endocytosis (primary amines), had no influence. We showed that NiCl2 and CoCl2 activate the translocation of the transcription factor nuclear factor (NF)-kappaB into the cell nucleus and enhance its binding to a NF-kappaB consensus sequence as shown by mobility shift analysis. Furthermore, we demonstrated the activation of AP-1. Despite the repression of heavy metal induced adhesion molecule synthesis, we did not detect any inhibition of NF-kappaB translocation by H-7 or H-8. Therefore, it must be concluded that heavy metal ions like Ni2+ and Co2+ activate two or more signal transduction pathways in endothelial cells. We clearly showed that there is one pathway in which H-7 and H-8 sensitive protein kinases are involved and a second pathway leading to NF-kappaB activation, which is insensitive to H-7 and H-8. Our results demonstrate that heavy metal ions induce mechanisms of gene activation in endothelial cells as do proinflammatory mediators, indicating that corroding metal ion containing biomaterials can provoke inflammatory reactions by known, as well as by yet unknown, intracellular signaling pathways.
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PMID:Mechanisms of cell activation by heavy metal ions. 1088 Jan

CD22 is a B-cell-specific adhesion molecule that modulates BCR-mediated signal transduction. Ligation of human CD22 with monoclonal antibodies (MoAbs) that block the ligand binding site triggers rapid tyrosine phosphorylation of CD22 and primary B-cell proliferation. Because extracellular signal-regulated kinases (ERKs) couple upstream signaling pathways to gene activation and are activated by B-cell antigen receptor (BCR) signaling, we examined whether CD22 ligation also activated ERKs and/or modified BCR-induced ERK activation. Ligation of CD22 on either primary B cells or B-cell lines failed to significantly activate the mitogen activated protein kinase (MAPK) ERK-2, but did activate the stress-activated protein kinases (SAPKs; c-jun NH2-terminal kinases or JNKs). In contrast, BCR ligation resulted in ERK-2 activation without significant SAPK activation. Concurrent ligation of CD22 and BCR enhanced BCR-mediated ERK-2 activation without appreciably modulating CD22-induced SAPK activation. Consistent with its induction of SAPK activity, there was a marked increase in nuclear extracts of activator protein-1 (AP-1) and c-jun levels within 2 hours of exposure of primary B cells to the CD22 MoAb. Despite their differences in ERK activation, both CD22 and BCR ligation triggered several Burkitt lymphoma cell lines to undergo apoptosis, and the 2 stimuli together induced greater cell death than either signal alone. The pro-apoptotic effects were CD22-blocking MoAb-specific and dose-dependent. Examination of expression levels of Bcl-2 protoncogene family members (Bcl-2, Bcl-x(L), Mcl-1, and Bax) showed a downregulation of Bcl-x(L) and Mcl-1 after CD22 ligation. This study provides a plausible mechanism to explain how CD22 and BCR signaling can costimulate B-cell proliferation and induce apoptosis in Burkitt lymphoma cell lines.
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PMID:CD22 cross-linking generates B-cell antigen receptor-independent signals that activate the JNK/SAPK signaling cascade. 1043 26

Although the absence of Substance P (SP), a neurotransmitter in the trigeminal nerve, has been speculated as a cause for developing neurotrophic keratitis, its exact pathogenesis is still not clarified. In a previous report, we showed with electron microscopic examination that epithelial cell attachment was weakened in denervated corneas. In this study, SV40-transformed human corneal epithelial cells (HCE-Ts) were used to explore the molecular mechanisms responsible for mediating regulation of E-cadherin expression in response to Substance P receptor stimulation. Expression of the mRNAs for specific SP receptors, neurokinin (NK)-1R, NK-2R, and NK-3R, was demonstrated with RT-PCR. The cells were treated with various concentrations of SP in vitro, and the expression of an adhesion molecule E-cadherin was analyzed by immunofluorescence, immunoblotting, and enzyme-linked immunosorbent assay (ELISA) using an anti-E-cadherin antibody. E-cadherin expression was increased by SP in a dose-dependent manner both in the cytosolic fraction and in the cell membrane fraction. This increase in E-cadherin expression was completely inhibited by Calphostin C (PKC inhibitor) and KN-62 (CaMK inhibitor), but not by H-89 (PKA inhibitor), indicating that SP-induced E-cadherin expression involves the activation of protein kinase C (PKC) and calmodulin kinase (CaMK). SP did not affect cell proliferation at all. All these findings indicate that SP induced E-cadherin expression through PKC and CaMK activation and suggest that a lack of SP may account in part for the pathogenesis of neurotrophic keratitis.
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PMID:Substance P-induced cadherin expression and its signal transduction in a cloned human corneal epithelial cell line. 1062 82

The carbohydrate antigen sialyl-Lewis(a) is important to pancreatic tumour biology because the circulating antigen is used in serological tests for malignancy and because cell surface antigen is involved in tumour cell binding to the endothelial adhesion molecule, E-selectin, in extravasation. In this study, we examined the effects of the adenylyl cyclase activator, forskolin, and the diacylglycerol analogue, phorbol 12-myristate 13-acetate (PMA), on the expression and release of sialyl-Lewis(a) in human pancreatic cancer cells. Increases in the release of sialyl-Lewis(a) from SW1990 cells produced by forskolin and PMA were associated with increases in the activities of protein kinases A and C, respectively, and could be blocked by inhibitors specific for these enzymes. Immunoprecipitation experiments showed that sialyl-Lewis(a) was associated with MUC1 mucin. Forskolin also increased the cellular content of antigen and MUC1 mRNA. Actinomycin D and a protein kinase A inhibitor, H8, blocked these effects. In contrast, PMA reduced cellular antigen and MUC1 mRNA levels, although it produced a temporary increase in release of the antigen. The effects of PMA were blocked by the protein kinase C inhibitor, H7. PMA also reduced cell binding to the adhesion molecule E-selectin. In summary, PKA and PKC alter cell MUC1-associated sialyl-Lewis(a) in opposite directions. These changes may have clinical utility in the diagnosis of pancreatic cancer and the prevention of metastases.
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PMID:Forskolin and phorbol ester have opposite effects on the expression of mucin-associated sialyl-Lewis(a) in pancreatic cancer cells. 1074 4

The mitochondrial toxin 3-nitropropionic acid (3-NPA) causes neurodegeneration in the basal ganglia and neurological symptoms resembling Huntington's disease (HD) when applied to primates or rodents, and therefore might be used as an animal model for this disorder. For that reason, the molecular mechanisms involved in 3-NPA-induced neurodegeneration are of considerable interest. In our model, murine neuroblastoma cells (Neuro-2a) were treated with different doses of 3-NPA, and changes in gene expression were analyzed by means of mRNA differential display (DDRT-PCR). Using 18 primer combinations, we have identified a set of 33 candidate cDNAs deriving from 29 excised DDRT bands whose expression appeared to be changed in response to the 3-NPA insult (mostly elevated). DNA sequencing revealed that novel, as well as previously described genes, are included in this panel. Amongst the known cDNAs, the differential mRNA expression of the ribosomal proteins S6 and L40, of the protein kinase A (PKA) catalytic beta subunit and of the intercellular adhesion molecule ICAM-1 could be verified using Northern hybridization and RT-PCR, respectively. Furthermore, ICAM-1 expression could also be shown to increase at the protein level, which points to a possible function for this molecule in neuronal cells in the course of neurodegeneration. The results may prove useful in elucidating the multiple processes causing neurodegeneration subsequent to lesions by mitochondrial toxins and excitotoxins as well.
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PMID:Differentially displayed genes in neuroblastoma cells treated with a mitochondrial toxin: evidence for possible involvement of ICAM-1 in 3-nitropropionic acid-mediated neurodegeneration. 1081 91

Using genome screen, DNA sequence and mapping data, we scanned the human chromosomal region 17q21-q24 for polymorphic markers in single copy genes. Three such genes were identified: the gene for myeloperoxidase (MPO) at 17q21.3-q23.2, containing a CA-microsatellite in the eighth intron and a functional single base substitution (G to A) in the promoter region, the platelet endothelial cell adhesion molecule-1 gene (PECAM1) at 17q23, which has a CA-repeat sequence in the sixth intron, and the gene for the regulatory subunit RIalpha of cAMP-dependent protein kinase (PRKAR1A) at 17q23-q24, in which a GA-microsatellite was detected in the 5'-flanking region. Association of these polymorphisms with multiple sclerosis (MS) was studied in a Swedish case-control population of 199 MS patients and 145 control subjects, and in 203 simplex families from Sardinia. None of these polymorphic genes was found to be a genetic marker for disease susceptibility. These results are in contrast with previous studies on the involvement of MPO in MS and suggest that the elevated expression of PECAM-1 in MS, as earlier documented, is related to transactivation by other gene products.
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PMID:PECAM1, MPO and PRKAR1A at chromosome 17q21-q24 and susceptibility for multiple sclerosis in Sweden and Sardinia. 1090 Mar 49

E-selectin, a cytokine-inducible adhesion molecule, supports rolling and stable arrest of leukocytes on activated vascular endothelium. Previous studies have suggested that this transmembrane protein can also transduce signals into the endothelial cell. We now demonstrate activation of the mitogen-activated protein kinase (MAPK) signaling cascade in cultured HUVEC in response to E-selectin-dependent leukocyte adhesion and Ab-mediated cross-linking of cell surface E-selectin. Adhesion of increasing numbers of HL60 cells to IL-1beta-activated HUVEC stimulated robust increases in MAPK activity that were abrogated by an E-selectin blocking Ab. Cross-linking of cell surface E-selectin with Abs, as a mimic of multivalent ligand engagement, strongly stimulated MAPK/extracellular signal-related kinase (ERK) kinase (MEK)-dependent MAPK activation and concomitant up-regulation of mRNA for c-fos, an immediate early response gene, whereas Ab cross-linking of HLA class I molecules (present at comparable density) failed to do so. Coimmunoprecipitation documented Ras, Raf-1 and, phospho-MEK complex formation. Unactivated HUVEC transduced with a full-length adenoviral E-selectin construct also exhibited cross-link-induced MAPK activation, macromolecular complex formation, and c-fos up-regulation, whereas HUVEC transduced with a cytoplasmic domain deletion mutant failed to respond. These observations indicate that E-selectin can transduce an activating stimulus via the MAPK cascade into the endothelial cell during leukocyte adhesion.
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PMID:E-selectin-dependent signaling via the mitogen-activated protein kinase pathway in vascular endothelial cells. 1092


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