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Biomedical subjects

J Kitaura

Publications and source records attributed to J Kitaura.

13 recordsLinked to original sources
PubMed2001

PKCbeta modulates antigen receptor signaling via regulation of Btk membrane localization.

Mutations in Bruton's tyrosine kinase (Btk) result in X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (xid) in mice. While targeted disruption of the protein kinase C-beta (PKCbeta) gene in mice results in an immunodeficiency similar to xid, the overall tyrosine phosphorylation of Btk is significantly enhanced in PKCbeta-deficient B cells. We provide direct evidence that PKCbeta acts as a feedback loop inhibitor of Btk activation. Inhibition of PKCbeta results in a dramatic increase in B-cell receptor (BCR)-mediated Ca2+ signaling. We identified a highly conserved PKCbeta serine phosphorylation site in a short linker within the Tec homology domain of Btk. Mutation of this phosphorylation site led to enhanced tyrosine phosphorylation and membrane association of Btk, and augmented BCR and FcepsilonRI-mediated signaling in B and mast cells, respectively. These findings provide a novel mechanism whereby reversible translocation of Btk/Tec kinases regulates the threshold for immunoreceptor signaling and thereby modulates lymphocyte activation.

3T3 Cells↗
PubMed2001

Regulation of mast cell survival by IgE.

Mast cells play critical roles in hypersensitivity and in defense against certain parasites. We provide evidence that mouse mast cell survival and growth are promoted by monomeric IgE binding to its high-affinity receptor, Fc epsilon RI. Monomeric IgE does not promote DNA synthesis but suppresses the apoptosis induced by growth factor deprivation. This antiapoptotic effect occurs in parallel with IgE-induced increases in Fc epsilon RI surface expression but requires the continuous presence of IgE. This process does not involve the FasL/Fas death pathway or several Bcl-2 family proteins and induces a distinctly different signal than Fc epsilon RI cross-linking. The ability of IgE to enhance mast cell survival and Fc epsilon RI expression may contribute to amplified allergic reactions.

Animals↗
PubMed2001

Genetic relationship among Japanese sentinel crabs (Decapoda: Ocypodidae: genus Macrophthalmus).

Seven species (eight populations) of sentinel crabs (genus Macrophthalmus) from the Japan coast and Uca vocans and Ocypode ceratophthalma, were examined electrophoretically for genetic variations in 13 enzymatic and one non-enzymatic protein comprising 17 loci. Most species were highly differentiated from each other (Nei's genetic distance, 0.29-1.63). The least genetic distance was found between M. japonicus and M. banzai, the genetic distinctiveness of the two taxa being supported by three divergent loci with no common allele. The genetic relationships among Macrophthalmus species differed greatly from those inferred from morphological features, with a UPGMA tree suggesting that the sub-genus Macrophthalmus is polyphyletic.

Alleles↗
PubMed2000

Akt-dependent cytokine production in mast cells.

Cross-linking of FcepsilonRI induces the activation of three protein tyrosine kinases, Lyn, Syk, and Bruton's tyrosine kinase (Btk), leading to the secretion of a panel of proinflammatory mediators from mast cells. This study showed phosphorylation at Ser-473 and enzymatic activation of Akt/protein kinase B, the crucial survival kinase, upon FcepsilonRI stimulation in mouse mast cells. Phosphorylation of Akt is regulated positively by Btk and Syk and negatively by Lyn. Akt in turn can regulate positively the transcriptional activity of interleukin (IL)-2 and tumor necrosis factor (TNF)-alpha promoters. Transcription from the nuclear factor kappaB (NF-kappaB), nuclear factor of activated T cells (NF-AT), and activator protein 1 (AP-1) sites within these promoters is under the control of Akt activity. Accordingly, the signaling pathway involving IkappaB-alpha, a cytoplasmic protein that binds NF-kappaB and inhibits its nuclear translocation, appears to be regulated by Akt in mast cells. Catalytic activity of glycogen synthase kinase (GSK)-3beta, a serine/threonine kinase that phosphorylates NF-AT and promotes its nuclear export, seems to be inhibited by Akt. Importantly, Akt regulates the production and secretion of IL-2 and TNF-alpha in FcepsilonRI-stimulated mast cells. Altogether, these results revealed a novel function of Akt in transcriptional activation of cytokine genes via NF-kappaB, NF-AT, and AP-1 that contributes to the production of cytokines.

Animals↗
PubMed2000

Redundant and opposing functions of two tyrosine kinases, Btk and Lyn, in mast cell activation.

Protein-tyrosine kinases play crucial roles in mast cell activation through the high-affinity IgE receptor (FcepsilonRI). In this study, we have made the following observations on growth properties and FcepsilonRI-mediated signal transduction of primary cultured mast cells from Btk-, Lyn-, and Btk/Lyn-deficient mice. First, Lyn deficiency partially reversed the survival effect of Btk deficiency. Second, FcepsilonRI-induced degranulation and leukotriene release were almost abrogated in Btk/Lyn doubly deficient mast cells while singly deficient cells exhibited normal responses. Tyrosine phosphorylation of cellular proteins including phospholipases C-gamma1 and C-gamma2 was reduced in Btk/Lyn-deficient mast cells. Accordingly, FcepsilonRI-induced elevation of intracellular Ca2+ concentrations and activation of protein kinase Cs were blunted in the doubly deficient cells. Third, in contrast, Btk and Lyn demonstrated opposing roles in cytokine secretion and mitogen-activated protein kinase activation. Lyn-deficient cells exhibited enhanced secretion of TNF-alpha and IL-2 apparently through the prolonged activation of extracellular signal-related kinases and c-Jun N-terminal kinase. Potentially accounting for this phenomenon and robust degranulation in Lyn-deficient cells, the activities of protein kinase Calpha and protein kinase CbetaII, low at basal levels, were enhanced in these cells. Fourth, cytokine secretion was severely reduced and c-Jun N-terminal kinase activation was completely abrogated in Btk/Lyn-deficient mast cells. The data together demonstrate that Btk and Lyn are involved in mast cell signaling pathways in distinctly different ways, emphasizing that multiple signal outcomes must be evaluated to fully understand the functional interactions of individual signaling components.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed2000

Regulation of protein kinase CbetaI by two protein-tyrosine kinases, Btk and Syk.

Two protein-tyrosine kinases, Bruton's tyrosine kinase (Btk) and Syk, and members of the protein kinase C (PKC) subfamily of serine/threonine kinases play crucial roles in signal transduction through antigen receptors in B lymphocytes and high-affinity IgE receptors (FcepsilonRI) in mast cells. The present study provides genetic, biochemical, and pharmacological evidence that, on FcepsilonRI stimulation, Syk regulates Btk, and Btk selectively regulates the membrane translocation and enzymatic activity of PKCbetaI among the conventional PKC isoforms (alpha, betaI, and betaII) expressed in mast cells. Syk/Btk-mediated PKCbetaI regulation is involved in transcriptional activation of the IL-2 and tumor necrosis factor alpha genes through the JNK pathway induced by FcepsilonRI stimulation. Accordingly, FcepsilonRI-induced production of these cytokines is inhibited by specific inhibitors of Btk and Syk, as well as broad-specificity inhibitors of PKC and a selective inhibitor of PKCbeta. Specific regulation of PKCbetaI by Btk is consistent with the selective association of Btk with PKCbetaI. Components of this signaling pathway may represent an attractive set of potential targets of pharmaceutical interference for the treatment of allergic and other immunologic diseases.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed1999

Terreic acid, a quinone epoxide inhibitor of Bruton's tyrosine kinase.

Bruton's tyrosine kinase (Btk) plays pivotal roles in mast cell activation as well as in B cell development. Btk mutations lead to severe impairments in proinflammatory cytokine production induced by cross-linking of high-affinity IgE receptor on mast cells. By using an in vitro assay to measure the activity that blocks the interaction between protein kinase C and the pleckstrin homology domain of Btk, terreic acid (TA) was identified and characterized in this study. This quinone epoxide specifically inhibited the enzymatic activity of Btk in mast cells and cell-free assays. TA faithfully recapitulated the phenotypic defects of btk mutant mast cells in high-affinity IgE receptor-stimulated wild-type mast cells without affecting the enzymatic activities and expressions of many other signaling molecules, including those of protein kinase C. Therefore, this study confirmed the important roles of Btk in mast cell functions and showed the usefulness of TA in probing into the functions of Btk in mast cells and other immune cell systems. Another insight obtained from this study is that the screening method used to identify TA is a useful approach to finding more efficacious Btk inhibitors.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed1999

Functions of Bruton's tyrosine kinase in mast and B cells.

Bruton's tyrosine kinase (Btk) plays crucial roles in B cell differentiation as well as mast cell activation through the high-affinity IgE receptor (FcepsilonRI). Defects in the btk gene lead to agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (xid) in mice. Mast cells from xid and btk null mice exhibit mild defects in degranulation and severe impairments in the production of proinflammatory cytokines upon FcepsilonRI cross-linking. Recent studies demonstrated the role of Btk in a sustained increase in intracellular calcium concentrations in response to antigen receptor stimulation. Btk is also involved in the activation of stress-activated protein kinases, JNK/SAPK1/2, and thereby regulates c-Jun and other transcription factors that are important in cytokine gene activation. Regulation of the JNK/SAPK activation pathway by Btk may be related to the proapoptotic function of Btk in the programmed cell death in these hematopoietic cells.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed1999

Hyperinsulinaemic hypoglycaemia associated with persistent hyperammonaemia.

UNLABELLED: Two cases of hyperinsulinaemic hypoglycaemia associated with persistent hyperammonaemia in unrelated infants of 7 days and 4 months of age are reported. Blood ammonia levels were 100-300 micromol/l (normal values <40 micromol/l). The hyperammonaemia was asymptomatic and not associated with any of the abnormalities of amino acids or organic acids observed in urea cycle enzyme defects. Orotic aciduria was normal. The hyperammonaemia was not influenced by the levels of blood glucose nor by subtotal pancreatectomy. On admission blood glucose was ca. 1.2 mmol/l (21.6 mg/dl) corresponding to blood insulin levels of 35 and 22 mU/l respectively in both infants. Continuous intravenous glucose perfusion was necessary to prevent hypoglycaemia. Furthermore 2-oxoglutaric acid in urine was increased in the second infant to 3.15 mg/mg creatinine (normal 0.41+/-0.12). This may point to mutations in the glutamate dehydrogenase gene. CONCLUSION: 2-Oxoglutaric aciduria may be an important clue to the diagnose in this syndrome.

Ammonia↗
PubMed1999

[Effectiveness of hypoallergenic rice-by cast analysis].

Rice is the main food taken every day in Japan. We introduced hypoallergenic rice (95% of albumin and globulin were taken off by hyperpressure method) for 4 weeks to 7 atopic dermatitis patients (m 3, f 4), 11 mo-4 y 8 m (mean 3 y 2 m) who showed the RAST score of rice 1 or more. Stimulation Index by CAST (cellular antigen stimulation test) were compared before and after taking the rice (50-100 g). By albumin (0.1-100 micrograms/ml), maximum decreases of S.I. were 22.4-96.5% (mean 70.9) and by globulin maximum decreases of S.I. were (0.1-100 micrograms/ml) 33.3-97.0% (mean 72.9). In all the patients the skin conditions were improved.

Adult↗
PubMed1998

Bruton's tyrosine kinase-mediated interleukin-2 gene activation in mast cells. Dependence on the c-Jun N-terminal kinase activation pathway.

Cross-linking of the high affinity IgE receptor (FcepsilonRI) on mast cells induces secretion of cytokines, including interleukin (IL)-2, through transcriptional activation of cytokine genes. Previously, defects in the gene coding for Bruton's tyrosine kinase (Btk) were shown to result in defective cytokine production in mast cells, and thereby mice carrying btk mutations exhibited diminished anaphylactic reactions in response to IgE and antigen. In this study, we provide evidence that the transcription factors involved in the IL-2 gene expression in T cells are also required for maximal activation of the IL-2 gene in FcepsilonRI-stimulated mast cells. Among them, AP-1 (Jun/Fos) and NF-AT were identified as candidate transcription factors that are regulated by Btk. Consistent with our previous data indicating that Btk regulates stress-activated protein kinases, c-Jun N-terminal kinase (JNK), c-Jun and other JNK-regulatable transcription factors are activated by FcepsilonRI cross-linking in a Btk-dependent manner. Further, FcepsilonRI-induced IL-2 gene activation is dependent on c-Jun and a component, SEK1, of its upstream activation pathway. Collectively, these data demonstrate that Btk regulates the transcription of the IL-2 gene through the JNK-regulatable transcription factors in FcepsilonRI-stimulated mast cells.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed1998

Molecular phylogeny and evolution of unique mud-using territorial behavior in ocypodid crabs (Crustacea: Brachyura: Ocypodidae).

Among crabs of the family Ocypodidae, Ilyoplax has been known to exhibit unique mud-using territorial behavior against neighbors, including neighbor burrow plugging, barricade building, and fence building. To assess the evolution of current behavioral forms observed in Ilyoplax, 1,416-bp nucleotide sequences from the mitochondrial 12S rRNA to 16S rRNA genes of 20 species, representing four recognized subfamilies of Ocypodidae, were analyzed. The resultant phylogenetic tree revealed the subfamily Dotillinae, including Ilyoplax, to be monophyletic, with a sister group relationship with subfamily Camptandriinae. These two subfamilies were branched after Ocypodinae, with Macrophthalminae being most basal. Species of Ilyoplax fell into three different Dotillinae lineages, indicating the genus to be polyphyletic. Crabs in two of the three lineages showed differential geographic distribution and body size. Phylogenetic analyses of behavioral characters demonstrated that mud-using techniques had evolved multiple times and sequentially. From their behavioral similarity and evolutionary occurrence, fence building is hypothesized to have evolved from barricade building, and the latter, from burrow plugging. This scenario also appeared reasonable with respect to behavioral trends observed in the field. The evolution of such territorial behavior is considered to be associated with ecological conditions such as burrow fidelity and substrate condition.

Animals↗