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syk kinase activation by a src kinase-initiated activation loop phosphorylation chain reaction
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O. El-Hillal T. Kurosaki H. Yamamura J.-P. Kinet A. M. Scharenberg 《Proceedings of the National Academy of Sciences of the United States of America》1997,94(5):1919-1924
Activation of the syk tyrosine kinase occurs almost immediately following engagement of many types of antigen receptors, including Fc receptors, but the mechanism through which syk is activated is currently unclear. Here we demonstrate that Fc receptor-induced syk activation occurs as the result of phosphorylation of the syk activation loop by both src family kinases and other molecules of activated syk, suggesting that syk activation occurs as the result of a src kinase-initiated activation loop phosphorylation chain reaction. This type of activation mechanism predicts that syk activation would exhibit exponential kinetics, providing a potential explanation for its rapid and robust activation by even weak antigen receptor stimuli. We propose that a similar mechanism may be responsible for generating rapid activation of other cytoplasmic tyrosine kinases, such as those of the Bruton tyrosine kinase/tec family, as well. 相似文献
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Vav3 modulates B cell receptor responses by regulating phosphoinositide 3-kinase activation. 总被引:7,自引:0,他引:7
Kazunori Inabe Masamichi Ishiai Andrew M Scharenberg Norman Freshney Julian Downward Tomohiro Kurosaki 《The Journal of experimental medicine》2002,195(2):189-200
To elucidate the mechanism(s) by which Vav3, a new member of the Vav family proteins, participates in B cell antigen receptor (BCR) signaling, we have generated a B cell line deficient in Vav3. Here we report that Vav3 influences phosphoinositide 3-kinase (PI3K) function through Rac1 in that phosphatidylinositol-3,4,5-trisphosphate (PIP3) generation was attenuated by loss of Vav3 or by expression of a dominant negative form of Rac1. The functional interaction between PI3K and Rac1 was also demonstrated by increased PI3K activity in the presence of GTP-bound Rac1. In addition, we show that defects of calcium mobilization and c-Jun NH2-terminal kinase (JNK) activation in Vav3-deficient cells are relieved by deletion of a PIP3 hydrolyzing enzyme, SH2 domain-containing inositol polyphosphate 5'-phosphatase (SHIP). Hence, our results suggest a role for Vav3 in regulating the B cell responses by promoting the sustained production of PIP3 and thereby calcium flux. 相似文献
5.
Isao Kurosaki Kazuhiro Tsukada Hidenori Ueki Akira Ohya Katsuyoshi Hatakeyama 《Journal of Hepato-Biliary-Pancreatic Surgery》1997,4(1):131-134
We report a case of advanced gallbladder cancer in a 37-year-old man who presented in June 1993 with malignant obstructive jaundice. After percutaneous transhepatic biliary drainage and several diagnostic imaging examinations, the patient underwent laparotomy under a diagnosis of extremely advanced gallbladder cancer involving the confluence of the hepatic ducts. The tumor, however, was judged to be unresectable because of its massive spread into the liver along Glisson's sheath, and because of histologically proven peritoneal dissemination. After exploratory laparotomy, one course of anticancer chemotherapy (cisplatin, 100 mg/body IV, on day 1, and 5-fluorouracil, 1000 mg/body, on days 1–5, by continuous infusion) was administered and the completely obstructed hepatic duct was dramatically re-canalized. Four courses of chemotherapy were administered over a 16-month period until jaundice recurred. For these 16 months, the patient's quality of life was well maintained without biliary drainage. He died of increased peritoneal dissemination approximately 2 years after the first course of anticancer chemotherapy. 相似文献
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Regulation of B cell fates by BCR signaling components 总被引:5,自引:0,他引:5
Kurosaki T 《Current opinion in immunology》2002,14(3):341-347
Recent results obtained in mice harboring cytoplasmic mutations of Igalpha and/or Igbeta have reinforced the concept that the strength of BCR signaling is important for ensuring appropriate developmental outcomes as well as antigen-specific responses. To establish the optimal signaling intensity and duration, the BCR utilizes positive and negative regulatory molecules. Studies are beginning to reveal how these molecules maintain immunological homeostasis and tolerance. 相似文献
8.
Mice deficient in the B cell adaptor for phosphoinositide 3-kinase (BCAP) have reduced numbers of mature B lymphocytes, which show defects in cell survival and proliferation. We found here that the NF-kappa B (Rel) pathway was impaired in BCAP-deficient mature B cells and that NF-kappa B target genes, indispensable for cell survival and division, were not induced in response to B cell receptor (BCR) stimulation. Among the NF-kappa B (Rel) family, expression of c-Rel was specifically reduced in BCAP-deficient B cells. Retrovirus-mediated reintroduction of c-Rel restored the pool size of immunoglobulin (Ig)M(lo)IgD(hi) mature B cells in the spleen as well as proliferative responses to BCR stimulation. These results indicate BCAP is essential in the maintenance of mature B cells through functional coupling with c-Rel. 相似文献
9.
Variations in the core region of hepatitis C virus genomes in patients with chronic hepatitis 总被引:1,自引:0,他引:1
Summary In each infected patient, the population of hepatitis C virus is composed of quasispecies that differ in their nucleotide sequences. Among regions in hepatitis C virus genomes, nucleotide sequences of the hypervariable region have been shown to change quickly during the course of infection. It is not known, however, whether these variations exist in the core region that has recently been suggested to contain human lymphocyte antigen class 1 restricted sites for cytotoxic T cell recognition. To clarify this, RNA was extracted from the plasma of four patients with chronic hepatitis C. After cDNA synthesis, DNA fragments that contain the core region were amplified by the polymerase chain reaction and the diversity of the core region was analyzed by the single strand conformation polymorphism analysis. Using this method, single or multiple DNA bands were observed in each patient, and representative bands showed different nucleotide sequences. Comparison of single strand conformation polymorphism patterns revealed that the population of quasispecies changed during the course of chronic infection. These changes were more remarkable in patients with high serum alanine aminotransferase levels than those with low serum alanine aminotransferase levels. Thus, sequential variations exist in the core region of hepatitis C virus in same individuals, and the population of quasispecies as determined by the sequence of the core region changes during the course of infection, which might be related to cytopathic effects of hepatitis C virus. 相似文献
10.
Naoya Sakamoto Nobuyuki Enomoto Masayuki Kurosaki Fumiaki Marumo Chifumi Sato 《Journal of medical virology》1994,42(1):103-108
Hepatitis C virus (HCV) infection is characterized by persistence of liver inflammation that often leads to end-stage liver disease, although the mechanisms are not fully understood. A hyper-variable region (HVR) has been reported in the E2/NS1 region of the HCV genome, in which striking diversity is found among different HCV isolates. To investigate the association of the HVR alterations with the clinical courses of HCV infection, a longitudinal analysis of the HVR in patients with acute HCV infection was carried out. Plasma samples were obtained at several times in three patients with acute hepatitis C. Plasma RNA was extracted and reverse transcribed, and DNA fragments that included the HVR were amplified by PCR. The sequences of the HVR were directly determined from the PCR products by the dideoxy chain termination method, from which amino acid sequences were deduced. In all cases, plasma HCV-RNA disappeared with the improvement of the initial alanine aminotransferase (ALT) elevation, but HCV-RNA reappeared about 1 year later with or without deterioration of the hepatitis. In a case of sporadic acute hepatitis, the HCV in the recurrent phase had seven amino acid substitutions in the HVR compared with that in the acute phase, although no amino acid changes were noted during the initial acute phase. In a case of posttransfusion hepatitis, a marked difference was observed between the acute and the recurrent phases, with an amino acid homology of 30% (8/27). The mutation rate of the HVR had a tendency to accelerate as the HCV infection progressed to the chronic stage. In conclusion, the HVR changes serially during the course of acute HCV infection, and these HVR changes may play a part in the chronicity of HCV infection. © 1994 Wiiey-Liss, Inc. 相似文献