Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The number of gene assignments to human chromosome 20 has increased slowly until recently. Only seven genes and one fragile site were confirmed assignments to chromosome 20 at the Ninth Human Gene Mapping Workshop in September 1987 (HGM9). One fragile site, 13 additional genes, and 10 DNA sequences that identify restriction fragment length polymorphisms (RFLPs), however, were provisionally added to the map at HGM9. Five mutated genes on chromosome 20 have a relation to disease: a mutation in the adenosine deaminase gene results in a deficiency of the enzyme and severe combined immune deficiency; mutations in the gene for the growth hormone releasing factor result in some forms of dwarfism; mutations in the closely linked genes for the hormones arginine vasopressin and oxytocin and their neurophysins are probably responsible for some diabetes insipidus; and mutations in the gene that regulates both alpha-neuraminidase and beta-galactosidase activities determine galactosialidosis. The gene for the prion protein is on chromosome 20; it is related to the infectious agent of kuru, Creutzfeld-Jacob disease, and Gertsmann-Straussler syndrome, although the nature of the relationship is not completely understood. Two genes that code for tyrosine kinases are on the chromosome, SRC1 the proto-oncogene and a gene (HCK) coding for haemopoietic kinase (an src-like kinase), but no direct relation to cancer has been shown for either of these kinases. The significance of non-random loss of chromosome 20 in the malignant diseases non-lymphocytic leukaemia and polycythaemia vera is not understood. Twenty-four additional loci are assigned to the chromosome: five genes that code for binding proteins, one for a light chain of ferritin, genes for three enzymes (inosine triphosphatase, s-adenosylhomocysteine hydrolase, and sterol delta 24-reductase), one for each of a secretory protein and an opiate neuropeptide, a cell surface antigen, two fragile sites, and 10 DNA sequences (one satellite and nine unique) that detect RFLPs.
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PMID:The map of chromosome 20. 307 44

To evaluate the role of N-linked oligosaccharides in the molecular action of rat placental lactogen (PL), recombinant PL-Im (recPL-Im) and three recPL-Im mutants were produced in COS-7 cells. The mutants, carrying Gln substitutions of Asn at putative N-glycosylation sites, were generated via site-directed mutagenesis, i.e. two single mutants (N79Q, N128Q) and one double mutant (N79Q/N128Q). Western blot analysis revealed that wild type recPL-Im had a molecular mass of 34 kDa , which was reduced to 29 kDa by tunicamycin present during expression. N79Q and N128Q had a lower molecular mass than the wild type, and a further decrease was observed for N79Q/N128Q. PL-Im was therefore N-glycosylated at both Asn79 and Asn128. Treatment of the wild type with neuraminidase caused a reduction in molecular mass, indicating that the N-linked oligosaccharides contained N-acetylneuraminic acids. In the Nb2 cell bioassay for lactogenic hormones, recPL-Im and its mutants all had growth-promoting activity but there was a decline in the growth-stimulating potency following decreases in N-glycosylation, i.e. the order of relative potencies was the wild type>N128Q> N79Q>N79Q/N128Q, suggesting that the N-linked oligosaccharides are important in the mitogenic action of the PL-Im. Wild type and all mutants had rat PRL receptor (PRL-R)-binding activity in radioreceptor assays and stimulated JAK2 phosphorylation in Nb2 cells. Interestingly however, the binding activity to PRL-R and phosphorylation of JAK2 was similar in the wild type and mutants, and these results are not in accord with the biological activity. In conclusion, the study suggested that PL-Im has two N-linked oligosaccharides which are involved in its biological activity. The ability of PL-Im to bind PRL-R and activate JAK2 appears to be independent of the N-glycosylation.
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PMID:Evaluation of the role of N-linked oligosaccharides in rat placental lactogen action by site-directed mutagenesis. 1039 47

Evidence linking bacterial vaginosis (BV) to chorioamnionitis and spontaneous preterm birth is mounting. Successful treatment of BV could reduce the rate of late miscarriage and preterm birth. Mucinase and sialidase activity have been implicated in the pathogenesis of BV. This study extends the work of previous studies to investigate sialidase, other known mucin degrading enzymes and overall mucin degrading activity in samples of vaginal fluid from women with and without BV. Samples from 31 women were diagnosed for BV, and tested for enzyme activity using established assays. Activity was recorded in all samples. Significant increases in activity were detected in BV samples for sialidase using a mucin (BSM P<0.005) and serum type glycoprotein (AGP P<0.005) substrates, beta-galactosidase (P<0.001), and beta-N-acetylhexosaminidase (P<0.01). No significant increases in BV patients were detected in O-glycanase, proteinase, arylesterase, sulphatase or whole mucinase activities. These results support the hypothesis that certain BV-associated enzymes may detrimentally affect the mucosal barrier, permitting bacteria access to the uterus.
Int J STD AIDS 1999 Jul
PMID:Mucinase and sialidase activity of the vaginal microflora: implications for the pathogenesis of preterm labour. 1045 78

Polyclonal lymphocyte activation and hypergammaglobulinemia characterize the acute phase of Chagas' disease, a debilitating condition caused by Trypanosoma cruzi. Such pathogenic hyper-reactivities not only compromise specific host defense against the pathogen, but may also contribute to infection-induced chronic autoimmune responses. Recent studies showed that T. cruzi trans-sialidase (TS) directly stimulates the polyclonal proliferation and Ig secretion of normal murine B cells in a T-independent, Bruton's tyrosine kinase (Btk)-dependent manner. Related to this observation, we now show that parasite-derived and recombinant TS potentiate the proliferation and cytokine secretion of normal T cells triggered by antigen-specific and non-specific stimuli. TS potentiates T cell activation through stimulating B cells and macrophages, independent of CD40/CD40L and CD43 pathways. In contrast, optimal TS potentiation requires interleukin-6 (IL-6) and Btk, as it is significantly reduced in splenocytes from IL-6-/- and Btk-defective Xid mice. The results suggest that TS, directly and indirectly, activates both antigen-presenting cell and T cell compartments, and that TS-induced IL-6 may further amplify such activation. These observations open up the possibility that TS drives the polyclonal lymphocyte activation in acute T. cruzi infection, a phenomenon contributing to the pathogenesis of Chagas' disease.
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PMID:Trypanosoma cruzi trans-sialidase potentiates T cell activation through antigen-presenting cells: role of IL-6 and Bruton's tyrosine kinase. 1146 7

Polyclonal lymphocyte activation and hypergammaglobulinemia characterize the acute phase of many parasitic diseases, including Chagas' disease, a debilitating condition caused by Trypanosoma cruzi. Polyclonal lymphocyte activation correlates with disease susceptibility inT. cruzi infection. Thus, identifying factors that drive such reactivities should provide insight into mechanisms of parasite evasion from host immunity and of disease pathogenesis. Sensitization of mice with small doses of T. cruzi trans-sialidase (TS) turns the mice into highly susceptible hosts to T. cruzi. In addition, TS heterologously expressed in Leishmania major greatly enhances virulence of the parasite to mice. In attempt to study the mechanism of TS-induced virulence, we found that TS and its C-terminal long tandem repeat (LTR) are T-independent polyclonal activators for mouse B cells. While B cells deficient/defective in L-6, CD40 or Toll-like receptor-4 are similarly activated by TS as compared to wild-type cells, B cells from Bruton's tyrosine kinase-defective X-linked immunodeficient mice are remarkably insensitive to TS activation. TS-induced B cell activation in vitro is accompanied by Ig secretion independent of T cells. Furthermore, administration of TS into normal mice leads to non-specific Ig secretion that peaks 4-6 days after injection. Thus TS, through its LTR, induces abnormal polyclonal B cell activation and Ig secretion, which could explain in part its virulence-enhancing activity.
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PMID:The Trypanosoma cruzi trans-sialidase is a T cell-independent B cell mitogen and an inducer of non-specific Ig secretion. 1186 66

In this report we demonstrate that soluble peptides, elastin degradation products stimulate proliferation of arterial smooth muscle cells. We show that these effects are due to generation of intracellular signals transduced through the cell surface elastin receptor, which consists of peripheral 67-kDa elastin-binding protein (EBP) (spliced variant of beta-galactosidase), immobilized to the transmembrane sialidase and the protective protein. We found that elastin receptor-transduced signaling triggers activation of G proteins, opening of l-type calcium channels, and a sequential activation of tyrosine kinases: FAK, c-Src, platelet-derived growth factor-receptor kinase and then Ras-Raf-MEK1/2-ERK1/2 phosphorylation cascade. This, in turn, causes an increase in expression of cyclins and cyclin-dependent kinases, and a consequent increase in cellular proliferation. The EBP-transduced signals also induce tyrosine kinase-dependent phosphorylation of beta-tubulin, LC3, microtubule-associated protein 1, and alpha-actin and troponin-T, which could be linked to reorganization of cytoskeleton. We have also disclosed that induction of these signals can be abolished by anti-EBP antibody or by galactosugars, which cause shedding of EBP from the cell surface. Moreover, elastin-derived peptides did not induce proliferation of EBP-deficient cells derived from patients bearing a nonsense mutation of the beta-galactosidase gene or sialidase-deficient cells from patients with congenital sialidosis.
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PMID:Signaling pathways transduced through the elastin receptor facilitate proliferation of arterial smooth muscle cells. 1224 48

Enzymes produced in bacterial vaginosis (BV) have been proposed as possible mediators of pre-term birth. Most studies have concentrated on mid-trimester measurements of enzyme activity, and utilize synthetic substrates to measure enzyme activity, which may not accurately represent mucinase activity in vivo. We have developed a novel ELISA mucinase assay using biotinylated human cervical mucin as a substrate. The assay is rapid, sensitive and can be used to screen large numbers of samples. The new assay has been used to assess vaginal mucinase activities in 92 women <14 weeks gestational age with and without BV. No differences in mucinase activity were detected between normal and BV groups while significant elevation of sialidase and other glycosidases was confirmed as reported before. This study shows that significant mucinase activity is a normal event in the mucus barrier, but does not reflect changes identified for individual enzyme activities associated with BV.
Int J STD AIDS 2002 Nov
PMID:Application of a novel human cervical mucin-based assay demonstrates the absence of increased mucinase activity in bacterial vaginosis. 1243 95

We have found previously that human plasma-membrane-associated sialidase (NEU3), a key glycosidase for ganglioside degradation, was markedly up-regulated in human colon cancers, with an involvement in suppression of apoptosis. To elucidate the molecular mechanisms underlying increased NEU3 expression, in the present study we investigated its role in cell adhesion of human colon cancer cells. DLD-1 cells transfected with NEU3 exhibited increased adhesion to laminins and consequent cell proliferation, but decreased cell adhesion to fibronectin and collagens I and IV, compared with control cells. When triggered by laminins, NEU3 clearly stimulated phosphorylation of FAK (focal adhesion kinase) and ERK (extracellular-signal-regulated kinase), whereas there was no activation on fibronectin. NEU3 markedly enhanced tyrosine phosphorylation of integrin beta4 with recruitment of Shc and Grb-2 only on laminin-5, and NEU3 was co-immunoprecipitated by an anti-(integrin beta4) antibody, suggesting that association of NEU3 with integrin beta4 might facilitate promotion of the integrin-derived signalling on laminin-5. In addition, the promotion of phosphorylation of integrin beta1 and ILK (integrin-linked kinase) was also observed on laminins. G(M3) depletion as the result of NEU3 overexpression, assessed by TLC, appeared to be one of the causes of the increased adhesion on laminins and, in contrast, of the decreased adhesion on fibronectin - NEU3 probably having bimodal effects. These results indicate that NEU3 differentially regulates cell proliferation through integrin-mediated signalling depending on the extracellular matrix and, on laminins, NEU3 did indeed activate molecules often up-regulated in carcinogenesis, which may cause an acceleration of the malignant phenotype in cancer cells.
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PMID:Plasma-membrane-associated sialidase (NEU3) differentially regulates integrin-mediated cell proliferation through laminin- and fibronectin-derived signalling. 1624 5

Using STD NMR experiments, we have studied the binding epitopes of p-nitrophenyl glycosides of sialic acid and analogs thereof when bound to Trypanosoma cruzi trans-sialidase (TSia). Time-dependent NMR spectra yielded data on the rate of substrate hydrolysis in comparison to sialic acid transfer. Our experiments clearly demonstrate that shortening of the glycerol side chain significantly favors the transfer reaction over hydrolysis. Our results extend the basis on which specific trans-sialidase inhibitors may be designed.
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PMID:Donor substrate binding to trans-sialidase of Trypanosoma cruzi as studied by STD NMR. 1759 93

Previous studies demonstrated that cross-linking of GM1 ganglioside with multivalent ligands, such as B subunit of cholera toxin (CtxB), induced Ca2+ influx through an unidentified, voltage-independent channel in several cell types. Application of CtxB to undifferentiated NG108-15 cells resulted in outgrowth of axon-like neurites in a Ca2+ influx-dependent manner. In this study, we demonstrate that CtxB-induced Ca2+ influx is mediated by TRPC5 channels, naturally expressed in these cells and primary neurons. Both Ca2+ influx and neurite induction were blocked by TRPC5 small interfering RNA (siRNA). Pretreatment of NG108-15 cells with neuraminidase increased cell-surface GM1 and greatly enhanced the signal. GM1 was not directly associated with TRPC5 but rather with alpha5beta1 integrin, which opened the channel through a signaling sequence after cross-linking of the GM1/integrin complex. This cascade included autophosphorylation of focal adhesion kinase and subsequent activation of phospholipase Cgamma (PLCgamma) and phosphoinositide-3 kinase [PI(3)K]. Pharmacological blockers that inhibited tyrosine kinase, PLC, and PI(3)K suppressed both CtxB-induced Ca2+ influx and neurite outgrowth. These were also suppressed by SK&F96365, a nonspecific transient receptor potential channel blocker. Confocal immunocytochemistry revealed that GM1 cross-linking induced colocalization of GM1 with these signaling elements in sprouting regions of plasma membrane. In primary cerebellar granular neurons (CGNs), TRPC5 was detected at 2 d in vitro (2 DIV), a stage corresponding to CtxB-stimulated Ca2+ influx. Neurite outgrowth in CGNs, determined at 3 DIV, was accelerated by CtxB and suppressed by TRPC5 siRNA and the above blockers. The crucial role of GM1 was indicated with CGNs from ganglio-series null mice, in which growth of axons was significantly retarded.
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PMID:Induction of calcium influx through TRPC5 channels by cross-linking of GM1 ganglioside associated with alpha5beta1 integrin initiates neurite outgrowth. 1762 5


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