Regulatory mechanism on B cell antigen receptor-mediated signal transduction and gene expression.

B细胞抗原受体介导的信号转导和基因表达的调控机制。

• 批准号: 11470088
• 负责人: WATANABE Takeshi
• 金额: $ 9.28万
• 依托单位: KYUSHU UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B).
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11470088/
• 关键词: Lyn kinase; gene targeting; autoantibody; tyrosine phosphorylation; Negative regulation; phosphataseu; Ly49; Akt; トランスジェニックマウス; 自己免疫性貧血; B1細胞; 抗原受容体シグナル; SHP1; 2; PITPnm; Golgi膜

B cell antigen receptor (BCR)-mediated signals play a crucial role in determination and regulation of B cell differentiation or apoptotic cell death. In the present study, we focus on the roles of Lyn kinase and phosphatidylinositol signal pathway in regulation of B1 cell activation. Mice obtained from crossing Lyn kinase-deficient mice with transgenic mice carrying heavy and light chain genes encoding for autoantibody to erythrocytes showed abnormal increase and maturation of B1 cells. We found that signals from co-stimulatory receptors such as CD5, CD72 and FcγRIIB play as crucial negative regulators for BCR-mediated signal transduction. These receptors possess ITIM motif on cytoplasmic tail. We found Lyn kinase is an essential kinase for tyrosine phosphorylation of those ITIM, to which SHP-1 recruits rapidly. Recruitment of SHP-1 shut off BCR-mediated signals by de-phosphorylation. Therefore, B1 cells show minimum response against BCR-mediated antigen stimulation. Lyn kinase is thus obligatory for the SHP-1 recruitment to the phosphorylated ITIM on CD5, CD73 and FcγRIIB.The transgenic mice carrying heavy and light chain genes encoding for autoantibody to erythrocytes did not develop hemolytic anemia because of those strong negative regulation. Lack of Lyn kinase, however, eliminated these negative regulation. Lyn-negative transgenic mice thus developed autoimmune hemolytic anemia. Furthermore, we found another co-receptor that showed negative regulation for BCR-mediated signaling. It is Ly49. The Ly49 is known as a negative regulator on NK cells, which binds to MHC class I.Ly49 was detected on B1 cells but not on B2 cells. Throsine phosphorylation of Ly49 was induced by Lyn kinase and SHP-1 recruits to the phosphorylated Ly49. These results clearly indicated that Lyn kinase plays an essential role in negative regulation of autoreactive B1 cells and prevention of autoantibody production.

B细胞抗原受体（BCR）介导的信号在决定和调节B细胞分化或凋亡性细胞死亡中起关键作用。本研究主要探讨林恩激酶和磷脂酰肌醇信号通路在B1细胞活化调控中的作用。将林恩激酶缺陷小鼠与携带编码红细胞自身抗体的重链和轻链基因的转基因小鼠杂交获得的小鼠显示B1细胞异常增加和成熟。我们发现来自共刺激受体如CD 5、CD 72和FcγRIIB的信号在BCR介导的信号转导中起着关键的负调节作用。这些受体在胞质尾区具有ITIM基序。我们发现林恩激酶是ITIM酪氨酸磷酸化的一种必需激酶，SHP-1可迅速募集到ITIM。SHP-1的募集通过去磷酸化关闭了BCR介导的信号。因此，B1细胞对BCR介导的抗原刺激的反应最小。因此，林恩激酶是SHP-1募集到CD 5、CD 73和FcγRIIB上的磷酸化ITIM的必需性激酶。由于这些强的负调控，携带编码抗红细胞自身抗体的重链和轻链基因的转基因小鼠没有发生溶血性贫血。然而，缺乏林恩激酶，消除了这些负调控。因此，Lyn-negative转基因小鼠发生自身免疫性溶血性贫血。此外，我们还发现了另一种对BCR介导的信号传导具有负调控作用的辅助受体。这是Ly 49。Ly 49被认为是NK细胞的负调节因子，它与MHC I类结合。Ly 49在B1细胞上被检测到，但在B2细胞上未检测到。Ly 49的苏氨酸磷酸化由林恩激酶诱导，SHP-1募集到磷酸化的Ly 49。这些结果清楚地表明，林恩激酶在自身反应性B1细胞的负调节和自身抗体产生的预防中起着重要作用。

项目成果

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T.Masaki,H.Yoshimitsu,S.Chiba T.Watanabe,and T.Sakata: "Targeted disruption of histamine H1 receptor attenuated reglatory effect of leptin on feeding behavior, adiposity and UCP family expression in mice."Deabetes. (In press).

T.Masaki、H.Yoshimitsu、S.Chiba T.Watanabe 和 T.Sakata：“有针对性地破坏组胺 H1 受体可减弱瘦素对小鼠进食行为、肥胖和 UCP 家族表达的调节作用。”糖尿病。

Y.Nagata,T.watanabe,et al: "Activation of hematopoietic progenitor kinase-1 by erythropoietin."Blood. 93. 3347-3354 (1999)

Y.Nagata、T.watanabe 等：“促红细胞生成素激活造血祖细胞激酶 1”。血液。

H.Ochi,and T.Watanbe: "Negative regulation of BCR-mediated signaling in B-1 cells through CD5 and Ly49 coreceptors via Lyn kinase activity."Intern, Immunol.. 12. 1417-1423 (2000)

H.Ochi 和 T.Watanbe：“通过 CD5 和 Ly49 辅助受体通过 Lyn 激酶活性对 B-1 细胞中 BCR 介导的信号传导进行负调节。”Intern，Immunol.. 12. 1417-1423 (2000)

D.Marguet,L.Baggio,T.Kobayashi,A-H.Bernard,U.Ribel,T.Watanabe, et.al.: "Enhanced insulin secretion and improved glucose tolerance in mice lacking CD26,."Proc.Natl.Acad.Sci.USA. 97. 6874-6879 (2000)

D.Marguet、L.Baggio、T.Kobayashi、A-H.Bernard、U.Ribel、T.Watanabe 等人：“缺乏 CD26 的小鼠中胰岛素分泌增强并改善葡萄糖耐量”，Proc.Natl.Acad。