Study of B cell antigen receptor (BCR)-mediated signal transduction pathway

B细胞抗原受体（BCR）介导的信号转导通路研究

• 批准号: 10470087
• 负责人: SAKAGUCHI Nobuo
• 金额: $ 6.53万
• 依托单位: Kumamoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10470087/
• 关键词: rapamycin; S6 kinase; mTor; protein synthesis pathway; Iga; MB-1; B cell antigen receptor; gene knock out mice; 抗体産生; CD40; 抗原レセプター; 胚中心; セントロサイト; モノクロナール抗体; B細胞異常; 抗体レパートリー

We identified a novel phosphoprotein of BCR mediated signal transduction as a coprecipitated molecule with Iga (MB-1). The cDNA clone showed a unique structure and named it alpha4 as a fourth component associated with MB-1 protein. The yeast homologue (Tap42) was isolated by the other group and was found to be a critical molecule of the growth factor mediated signal transduction of rapamycin-sensitive pathway. The alpha4/Tap42 is now known as a major signal transduction molecule of rapamycin sensitive pathway leading to protein synthesis probably through the activation of S6 kinase activity.We prepared the gene knock out mice and found that the alpha4 is essential for the growth especially at the embryonal development. By the conditional targeting strategy using Cre-lox P system we could delete the alpha4 locus on the X chromosome and show that alpha4 is also essential for the growth of mature B cells stimulated with BCR crosslinking. Here, we could clearly demonstrate that alpha4 is involved in the BCR-mediated signal transduction of rapamycin sensitivity for the protein synthesis. We will further study the biological function of alpha4 related pathway in the immune system.

我们鉴定了一种新的BCR介导的信号转导的磷蛋白，作为与伊加（MB-1）的共沉淀分子。该cDNA克隆显示出独特的结构，并将其命名为α 4作为与MB-1蛋白相关的第四组分。另一个研究小组分离到的酵母同源物Tap 42是生长因子介导的雷帕霉素敏感信号转导途径的关键分子。α 4/Tap 42是雷帕霉素敏感途径的主要信号转导分子，可能通过激活S6激酶活性而导致蛋白质合成，我们制备了基因敲除小鼠，发现α 4对生长尤其是胚胎发育至关重要。通过使用Cre-lox P系统的条件靶向策略，我们可以删除X染色体上的α 4基因座，并且表明α 4对于用BCR交联刺激的成熟B细胞的生长也是必需的。在这里，我们可以清楚地证明，α 4参与BCR介导的信号转导的雷帕霉素敏感性的蛋白质合成。我们将进一步研究α 4相关通路在免疫系统中的生物学功能。

项目成果

S. Inui: "A lymphocyte signal transduction molecule alpha4 associates with the catalytic subunit of hosphatase 2A and acts as a new target of rapamycin." BLOOD. 92. 539-546 (1998)

S. Inui：“淋巴细胞信号转导分子 α4 与磷酸酶 2A 的催化亚基结合，并充当雷帕霉素的新靶点。”

S.Inui: "Introduction of human CD40 gene with immunoglobulin enhancer and promoter creates mice with a population of human CD40+ early B lineage cells in the bone marrow." Transgenics. 5. 1-10 (1998)

S.Inui：“将人类 CD40 基因与免疫球蛋白增强子和启动子一起引入，可以在小鼠的骨髓中产生一群人类 CD40 早期 B 谱系细胞。”

Seiji Inui: "Introduction of human CD40 gene with immunoglobulin enhancer and promoter creates mice with a population of human CD40^+ early B lineage cells in the bone marrow."Transgenics. 2. 347-356 (1999)

Seiji Inui：“将人类 CD40 基因与免疫球蛋白增强子和启动子一起引入，在小鼠骨髓中产生了一群人类 CD40^ 早期 B 谱系细胞。”转基因。

Naomi Kuwata, Hideya Igarashi, Takafumi Ohmura, Shinichi Aizawa, and Nobuo Sakaguchi: "Absence of expression of RAG1 in peritoneal B-1 cells detected by knocking into RAG1 locus with green fluorescent protein gene."J. Immunol.. 163. 6355-6359 (1999)

Naomi Kuwata、Hideya Igarashi、Takafumi Ohmura、Shinichi Aizawa 和 Nobuo Sakaguchi：“通过用绿色荧光蛋白基因敲入 RAG1 位点，检测到腹膜 B-1 细胞中 RAG1 不表达。”J.

Seiji Inui, Hideki Sanjo, Kazuhiko Maeda, and Nobuo Sakaguchi: "A lymphocyte signal transduction molecule alpha4 associates with the catalytic subunit of phosphatase 2A and acts as a new target of rapamycin." BLOOD. 92. 539-546 (1998)

Seiji Inui、Hideki Sanjo、Kazuhiko Maeda 和 Nobuo Sakaguchi：“淋巴细胞信号转导分子 α4 与磷酸酶 2A 的催化亚基结合，并作为雷帕霉素的新靶标。”