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Biomedical subjects

S Yanagi

Publications and source records attributed to S Yanagi.

At least 37 records · Page 2Linked to original sources
PubMed2000

Syk is required for the activation of Akt survival pathway in B cells exposed to oxidative stress.

Syk has been demonstrated to play a crucial role in oxidative stress signaling in B cells. Here we report that Syk is required for the activation of the phosphatidylinositol (PI) 3-kinase-Akt survival pathway in B cells exposed to oxidative stress. Phosphorylation and activation of the serine-threonine kinase Akt were markedly increased in B cells treated with H(2)O(2). In Syk-deficient DT40 cells treated with low doses of H(2)O(2) (10-100 microm), Akt activation was considerably reduced. Pretreatment with wortmannin, a PI 3-kinase-specific inhibitor, completely blocked the Syk-dependent Akt activation. Following stimulation by low doses of H(2)O(2), a significant increase in PI 3-kinase activity was found in wild-type but not in Syk-deficient cells. These findings suggest that PI 3-kinase mediates Syk-dependent Akt activation pathway. Furthermore, viability of Syk-deficient cells, after exposure to H(2)O(2), was dramatically decreased and caspase-9 activity was greatly increased compared with that of the wild-type cells. These results suggest that Syk is essential for the Akt survival pathway in B cells and enhances cellular resistance to oxidative stress-induced apoptosis.

Androstadienes↗
PubMed2000

Identification of CRAM, a novel unc-33 gene family protein that associates with CRMP3 and protein-tyrosine kinase(s) in the developing rat brain.

Four members of collapsin response mediator proteins (CRMPs) are thought to be involved in the semaphorin-induced growth cone collapse during neural development. Here we report the identification of a novel CRMP3-associated protein, designated CRAM for CRMP3-associated molecule, that belongs to the unc-33 gene family. The deduced amino acid sequence reveals that the CRAM gene encodes a protein of 563 amino acids, shows 57% identity with dihydropyrimidinase, and shows 50-51% identity with CRMPs. CRAM appears to form a large complex composed of CRMP3 and other unidentified proteins in vivo. Indeed, CRAM physically associates with CRMP3 when co-expressed in COS-7 cells. The expression of CRAM is brain-specific, is high in fetal and neonatal rat brain, and decreases to very low levels in adult brain. Moreover, CRAM expression is up-regulated during neuronal differentiation of embryonal carcinoma P19 and PC12 cells. Finally, immunoprecipitation analysis of rat brain extracts shows that CRAM is co-immunoprecipitated with proteins that contain protein-tyrosine kinase activity. Taken together, our results suggest that CRAM, which interacts with CRMP3 and protein-tyrosine kinase(s), is a new member of an emerging family of molecules that potentially mediate signals involved in the guidance and outgrowth of axons.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Prognostic value of Doppler transmittal flow patterns and cardiac natriuretic peptides in patients with chronic congestive heart failure admitted for episodes of acute decompensation.

This study was designed to determine whether the restrictive filling transmitral flow velocity pattern is associated with increased plasma levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). It was also designed to evaluate the prognostic value of these parameters from patients with chronic congestive heart failure (CHF) admitted for episodes of acute decompensation. We performed Doppler echocardiography, measured plasma levels of ANP and BNP in 33 patients at the time of admission, and assessed the subsequent cardiac mortality for 3 months. Eleven patients (33%) had a restrictive filling pattern of deceleration time (DcT) < 120ms. Plasma ANP and BNP levels were markedly increased in all patients to 189 +/- 145 pg/ml and 865 +/- 559 pg/ml, respectively. Seventeen patients (52%) showed more than 700 pg/ml of plasma levels of BNP. There was a significant correlation of DcT with the plasma ANP level (r = -0.41, P = 0.017), and a better correlation of DcT with the plasma BNP level (r =-0.50, P = 0.003). The combined index of both shorter DcT (< 120 ms) and higher plasma BNP levels (>700 pg/ml) was the best predictor of cardiac mortality by Cox univariate analysis (chi2 = 5.87, P = 0.015). Furthermore, the sensitivity and specificity of this index for the detection of cardiac mortality were 80% and 86%, respectively. In conclusion, the combined analysis of the Doppler transmitral flow velocity pattern and measurement of the plasma BNP level is noteworthy since it is noninvasive and convenient. Moreover, it is extremely useful in predicting the prognosis for patients with chronic CHF admitted for episodes of acute decompensation.

Acute Disease↗
PubMed2000

Purification of a 72-kDa protein-tyrosine kinase from rat liver and its identification as Syk: involvement of Syk in signaling events of hepatocytes.

Syk protein-tyrosine kinase (PTK) has been implicated in a variety of hematopoietic cell responses including immunoreceptor signaling. However, so far, there has been no evidence of the expression of Syk or Syk-related PTK in non-hematopoietic tissues. In this study, we have purified from blood cell-depleted rat liver a 72-kDa cytoplasmic PTK which shows cross-reactivity with anti-Syk antibody. Partial amino acid sequence analysis revealed that this 72-kDa PTK is identical to Syk. Immunohistochemical and RT-PCR analyses demonstrated that Syk is expressed in human hepatocytes and two rat liver-derived cell lines, JTC-27 and RLC-16. Furthermore, Syk is significantly tyrosine-phosphorylated in response to angiotensin II in JTC-27 cells, and angiotensin II-induced MAP kinase activation is blocked by the treatment of cells with a Syk-selective inhibitor, piceatannol. These results suggest that Syk plays an important role in signaling events of hepatocytes, such as signaling steps leading to MAP kinase activation by G-protein-coupled receptors. This is the first report of the expression of Syk in non-hematopoietic tissue.

Amino Acid Sequence↗
PubMed2000

Distinctive functions of Syk N-terminal and C-terminal SH2 domains in the signaling cascade elicited by oxidative stress in B cells.

Syk plays a crucial role in the transduction of oxidative stress signaling. In this paper, we investigated the roles of Src homology 2 (SH2) domains of Syk in oxidative stress signaling, using Syk-negative DT40 cells expressing the N- or C-terminal SH2 domain mutant [mSH2(N) or mSH2(C)] of Syk. Tyrosine phosphorylation of Syk in cells expressing mSH2(N) Syk after H(2)O(2) treatment was higher than that in cells expressing wild-type Syk or mSH2(C) Syk. The tyrosine phosphorylation of wild-type Syk and mSH2(C) Syk, but not that of mSH2(N), was sensitive to PP2, a specific inhibitor of Src-family protein-tyrosine kinase. In oxidative stress, the C-terminal SH2 domain of Syk was demonstrated to be required for induction of tyrosine phosphorylation of cellular proteins, phospholipase C (PLC)-gamma2 phosphorylation, inositol 1,4, 5-triphosphate (IP(3)) generation, Ca(2)(+) release from intracellular stores, and c-Jun N-terminal kinase activation. In contrast, in mSH2(N) Syk-expressing cells, tyrosine phosphorylation of intracellular proteins including PLC-gamma2 was markedly induced in oxidative stress. The enhanced phosphorylation of mSH2(N) Syk and PLC-gamma2, however, did not link to Ca(2)(+) mobilization from intracellular pools and IP(3) generation. Thus, the N- and C-terminal SH2 domains of Syk possess distinctive functions in oxidative stress signaling.

Animals↗
PubMed2000

Bilateral coronary artery dilatation in a child with Noonan syndrome.

A rare case of a child with Noonan syndrome who had huge bilateral coronary artery dilatation is presented. Noonan syndrome is one of the most common nonchromosomal syndromes seen in children with cardiovascular abnormalities. Coronary artery abnormality should be considered in Noonan syndrome, because this syndrome may be associated with a higher incidence of coronary anomalies than previously thought.

Child↗
PubMed2000

Correlation between erythropoietin and lactate in humans during altitude exposure.

The plasma concentrations of both immunoreactive erythropoietin (EPO) and lactate were determined in four healthy untrained subjects at sea level and on the 2nd or 3rd day at altitudes (1,300 and 3,500 m). The mean plasma EPO (18.8 +/- 1.6 mU/ml at sea level) increased significantly on the 3rd day at 1,300 m (25.5 +/- 2.0 mU/ml, p < 0. 05) and showed an almost three-fold increase on the 2nd day at 3,500 m (53.5 +/- 3.7 mU/ml, p < 0.001). Likewise, the mean plasma lactate at 3,500 m (3.98 +/- 0.27 mmol/l) was 3.6 times as high as that at sea level (1.11 +/- 0.05 mmol/l) (p < 0.001). The plasma EPO concentrations were found to correlate well with the lactate concentrations at sea level and altitudes (r = 0.86, p < 0.01). These results are consistent with the well-known EPO/lactate response to altitudes and suggest that the circulating EPO concentration as well as blood lactate concentration can be used as an index of anaerobic condition.

Adult↗
PubMed2000

[CA19-9-producing testicular tumor: a case report].

A rare case of CA19-9-producing testicular tumor is reported. A 37-year-old male who had complained of high fever and right scrotal swelling was referred to our department. Ultrasonography and computed tomography demonstrated a right testicular tumor with right lung metastasis and aortocaval lymph node metastasis. Right high orchiectomy was performed. The histopathological diagnosis was mixed type of teratoma, yolk sac tumor, embryonal carcinoma and seminoma. Immuno-histochemical analysis showed CA19-9 to be expressed in the cancer cells. After 5 courses of combination chemotherapy, the operation for right lung metastasis was performed. The CA19-9 level was lowered to the normal range within four weeks after the first operation. He has been free of recurrence for about 18 months after the lung operation.

Adult↗
PubMed2000

[A case of paragonimiasis westermani with a high level of interleukin 5 in bronchoalveolar lavage fluid].

A 49-year-old man was admitted to our hospital with a productive cough and bloody sputum. Peripheral blood eosinophil counts and serum IgE values were elevated. Chest radiography and chest computed tomography revealed a solitary nodule with cavitation and satellite lesions in the right middle lobe, in contact with the pleura. The diagnosis of paragonimiasis westermani was confirmed by detection of ova in the sputum and bronchoalveolar lavage fluid (BALF) samples, and by immunoserological examination. The patient was treated with praziquantel for 3 days at a daily dosage of 75 mg/kg. After treatment, his clinical symptoms and radiological abnormalities disappeared. The IL-5 level was high in BALF, but it was undetectable in the plasma, suggesting that IL-5 in inflammatory lesions may be particularly important in mediating eosinophilia in the blood and BALF in paragonimiasis westermani.

Anthelmintics↗
PubMed1999

Cross-linking of the B cell receptor induces activation of phospholipase D through Syk, Btk and phospholipase C-gamma2.

Phospholipase D (PLD) has been proposed to play a key role in the signal transduction of cellular responses to various extracellular signals. Herein we provide biochemical and genetic evidence that cross-linking of the B cell receptor (BCR) induces rapid activation of PLD through a Syk-, Btk- and phospholipase C (PLC)-gamma2-dependent pathway in DT40 cells. Activation of PLD upon BCR engagement is completely blocked in Syk- or Btk-deficient cells, but unaffected in Lyn-deficient cells. Furthermore, in PLC-gamma2-deficient cells, BCR engagement failed to activate PLD. These results demonstrate that Syk, Btk and PLC-gamma2 are essential for BCR-induced PLD activation.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed1998

Antibodies directed against ZAP-70 cross-react with a 66 kDa tyrosine kinase in the rat brain.

ZAP-70 is another member of Syk family tyrosine kinases which plays an essential role in growth, differentiation, and function of T lymphocytes. In this study, we report the specific expression of a 66 kDa tyrosine kinase that is specifically cross-reacted with anti-ZAP-70 antibodies in the developing neurons. By immunoblot and immunoprecipitation assay using various anti-ZAP-70 antibodies, a 66 kDa tyrosine kinase was detected in lysates from rat brain. During the development of rat brain, expression levels of this 66 kDa tyrosine kinase were highest around 3 weeks after birth and decreased thereafter in the adult. In addition, immunoblot analysis demonstrated that this 66 kDa tyrosine kinase was expressed almost solely in the nervous system. These results suggest that this ZAP-70-related tyrosine kinase may play an important role in growth and differentiation in the developing neurons. Our observations will provide the clue to approach the regulatory system common to neurogenesis and immune response.

Age Factors↗
PubMed1997

Deletion of SHIP or SHP-1 reveals two distinct pathways for inhibitory signaling.

Two signaling molecules have been implicated in the modulation of immune receptor activation by inhibitory coreceptors: an inositol polyphosphate 5'-phosphatase, SHIP, and a tyrosine phosphatase, SHP-1. To address the necessity, interaction, or redundancy of these signaling molecules, we have generated SHP-1- or SHIP-deficient B cell lines and determined their ability to mediate inhibitory signaling. Two distinct classes of inhibitory responses are defined, mediated by the selective recruitment of SHP-1 or SHIP. The Fc gammaRIIB class of inhibitory signaling is dependent on SHIP and not SHP-1; conversely, the KIR class requires SHP-1 and not SHIP. The consequence of this selective recruitment by inhibitory receptor engagement is seen in BCR-triggered apoptosis. SHP-1-mediated inhibitory signaling blocks apoptosis, while SHIP recruitment attenuates a proapoptotic signal initiated by Fc gammaRIIB.

Animals↗
PubMed1997

Tyrosine phosphorylation and Syk activation are involved in thrombin-induced aggregation of epinephrine-potentiated platelets.

Thrombin and epinephrine in combination exert synergistic effects on platelet activation. On the other hand, tyrosine phosphorylation and activation of tyrosine kinases including Syk have been shown to play a critical role in the induction of platelet responses to thrombin stimulation. This study investigated the role of tyrosine phosphorylation and Syk activation in the synergistic mechanisms between thrombin and epinephrine. Although epinephrine alone (4 microM) slightly induced protein-tyrosine phosphorylation and Syk activation, the presence of epinephrine caused a shift to the left in the dose-dependence of thrombin (0.01-0.5 U/ml)-induced tyrosine phosphorylation and Syk activation, as well as platelet aggregation. Phenoxybenzamine, an alpha-adrenoceptor antagonist, canceled this potentiation by epinephrine. Since platelets dominantly express alpha 2-adrenoceptor, this result indicates that epinephrine acts through the occupancy of alpha 2-adrenoceptor. Furthermore, pretreatment with a tyrosine kinase inhibitor, genistein, or a cAMP-elevating agent, prostacyclin (PGI2), significantly reduced these synergistic effects of epinephrine. Taken together, our results suggested that the potentiation by epinephrine may be mediated via enhancement of tyrosine phosphorylation and Syk activation, in part through a decrease of intracellular cAMP levels.

Adrenergic alpha-Agonists↗
PubMed1997

Occurrence and spontaneous remission of Graves' hyperthyroidism preceded by painless thyroiditis.

A 45-year-old woman was referred to our hospital because of discomfort in the cervical region. Laboratory findings revealed thyrotoxicosis with positive TSH receptor antibodies, but acute inflammatory data were absent. After three weeks the thyroid hormone levels spontaneously decreased to hypothyroid levels, and thyroidal radioactive iodine uptake (RAIU) was below normal. A needle-biopsy specimen of the thyroid gland obtained two months later showed diffuse lymphocytic thyroiditis, and she was therefore diagnosed as having had painless thyroiditis. Two months after returning to euthyroidism, a second thyrotoxicosis developed. TSH receptor antibodies remained positive, but RAIU was slightly above normal, indicating Graves' hyperthyroidism. Treatment with antithyroidal drugs was commenced but was soon discontinued due to an allergic reaction. Although only beta-adrenergic antagonist was administered for treating the thyrotoxicosis, thyroid function was gradually normalized in parallel with the reduction in TSH receptor antibody. In this case, painless thyroiditis would be followed by Graves' disease and subsequent spontaneous remission.

Autoantibodies↗
PubMed1996

CD45 modulates phosphorylation of both autophosphorylation and negative regulatory tyrosines of Lyn in B cells.

CD45 is a tyrosine phosphatase that is required for normal B cell receptor (BCR)-mediated signaling. It has been shown that Src-family tyrosine kinases such as Lyn could be a potential substrate for CD45. In vitro studies indicate that activities of Src family tyrosine kinases are regulated by tyrosine phosphorylation; C-terminal phosphorylation is inhibitory, and autophosphorylation is stimulatory. We report here that both autophosphorylation and C-terminal negative regulatory tyrosines of Lyn were hyperphosphorylated in CD45-deficient DT40 B cells. In this mutant cell, BCR-induced protein-tyrosine phosphorylation and calcium mobilization were severely compromised, as seen in Lyn-deficient cells. Consistent with this observation, Lyn activation upon receptor ligation was profoundly decreased in CD45-deficient cells. Taken together, our results suggest that dephosphorylation of tyrosine residues at both autophosphorylation and negative regulatory sites is mediated by CD45 in vivo, and that dephosphorylation of C-terminal tyrosine is a prerequisite for participation of Lyn in BCR signaling.

Animals↗
PubMed1995

Cyclic AMP-insensitive activation of c-Src and Syk protein-tyrosine kinases through platelet membrane glycoprotein VI.

Platelet glycoprotein (GP) VI is a so-far uncharacterized 62-kDa membrane protein, whose deficiency results in selective impairment in collagen-induced platelet aggregation. Our group previously reported a human polyclonal antibody (anti-p62 IgG) that induces activation of normal, but not of GPVI-deficient, platelets in an Fc-independent manner. The F(ab')2 fragments of this antibody (F(ab')2-anti-p62) stimulated tyrosine phosphorylation of numerous proteins, which was not prevented even in the presence of cAMP-increasing agents such as prostacyclin. Pretreatment of platelets with the protein-tyrosine kinase (PTK) inhibitor tyrphostin A47 completely abolished F(ab')2-anti-p62-induced platelet aggregation in parallel with dose-dependent inhibition of protein-tyrosine phosphorylation, indicating an essential requirement of PTK activity for generating GPVI-mediated signaling. We found that two cytosolic PTKs, c-Src and Syk, became rapidly activated in response to F(ab')2-anti-p62 in a way insensitive to elevation of cAMP. In contrast, in the presence of prostacyclin, F(ab')2-anti-p62 did not stimulate tyrosine phosphorylation of the focal adhesion kinase. cAMP-insensitive activation of c-Src and Syk was also observed in collagen but not thrombin-stimulated platelets. Moreover, either F(ab')2-anti-p62 or collagen stimulated cAMP-insensitive tyrosine phosphorylation of phospholipase C-gamma 2. These results indicate that the receptor-mediated activation of several PTKs in platelets is regulated through a cAMP-sensitive or -insensitive mechanism depending on the nature of each stimulus, and also suggest that GPVI engagement is coupled to cAMP-insensitive activation of c-Src and Syk accompanied by tyrosine phosphorylation of numerous substrates including phospholipase C-gamma 2 in a manner similar to collagen stimulation.

Adult↗
PubMed1995

Anti-CD9 monoclonal antibody activates p72syk in human platelets.

NNKY 1-19, anti-CD9 monoclonal antibody (MoAb), induced protein tyrosine phosphorylation of 125-, 97-, 75-, 64-, and 40-kDa proteins in human platelets, whereas F(ab')2 fragments of NNKY 1-19 did not, suggesting that the stimulation of Fc gamma II receptors is required for the induction of protein tyrosine phosphorylation. Tyrosine-phosphorylated proteins of 97 and 125 kDa were associated with aggregation, while NNKY 1-19-induced protein tyrosine phosphorylation was completely inhibited by prostaglandin I2 (PGI2). The activity of p72syk was assessed in immunoprecipitation kinase assays to determine at which step the signal transduction pathway leading to protein tyrosine phosphorylation was suspended. NNKY 1-19 induced a rapid and transient increase in the p72syk-associated tyrosine kinase activity that peaked at 10 s and subsided to the original level 2 min after stimulation. Coinciding with this time course, p60c-src transiently associated with p72syk. In platelets preexposed to GRGDS peptides or PGI2, NNKY 1-19 also increased the p72syk-associated tyrosine kinase activity and led to the association of p60c-src with p72syk. However, in contrast to the control without any inhibitor, the elevated tyrosine kinase activity and the associated state of the two tyrosine kinases persisted as long as 5 min after stimulation. F(ab')2 fragments of NNKY 1-19 induced changes similar to those observed with the effects of GRGDS peptides or PGI2 treatment on intact IgG NNKY 1-19 stimulation. F(ab')2 fragments of another CD9 MoAb, PMA2, had effects on p72syk essentially similar to those of NNKY 1-19. These findings suggest that the binding of anti-CD9 MoAb to CD9 on the platelet membrane per se induces an increase in the p72syk-associated tyrosine kinase activity but that Fc gamma II receptor-mediated signal(s) is required for the full activation of platelets and the appearance of tyrosine-phosphorylated proteins. The elevated intracellular cAMP level induced by PGI2 acts at a step distal to the activation of p72syk and inhibited the signal transduction pathway leading to protein tyrosine phosphorylation and aggregation. p72syk activation occurs in the absence of aggregation, but aggregation appears to reduce the elevated p72syk activity induced by anti-CD9 MoAb.

Antibodies, Monoclonal↗