Establishment and Analysis of mice disrupted with DNAM-1 gene
DNAM-1基因破坏小鼠的建立及分析
基本信息
- 批准号:10833002
- 负责人:
- 金额:$ 1.86万
- 依托单位:
- 依托单位国家:日本
- 项目类别:Grant-in-Aid for Scientific Research (C)
- 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:
- 关键词:
项目摘要
DNAM-1 is a signal transducing adhesion molecule involved in the cytolytic function mediated by CTL and NK cells. Cross-linking DNAM-1 with anti-DNAM-1 mAb induces cytolysis mediated by CTL and NK cells and also results in tyrosine phosphorylation of the DNAM-1 molecule. We studied regulation of DNAM-1-mediated signaling and adhesion. We report here that specific inhibitors of PKC activity prevented DNAM-1-mediated cytolytic activation of NK cells. Adhesion of DNAM-1 to its ligand does not require divalent cations, such as magnesium or calcium, and is regulated by PKC, as demonstrated by augmentation of DNAM-1 adhesion by PMA and inhibition by specific PKC inhibitors. Mutation of the putative PKC binding site in the cytoplasmic domain of DNAM-1 (SerィイD1329ィエD1 to PheィイD1329ィエD1) prevents ligand binding and PMA-induced serine phosphorylation of the DNAM-1 receptor. These results indicate that PKC phosphorylates SerィイD1329ィエD1 of DNAM-1 and plays a critical role for both DNAM-1 adhesion and signaling.Whereas ligation of DNAM-1 adhesion molecule triggers cytotoxicity mediated by normal NK and T cells, this function was defective in NK cell clones from leukocyte adhesion deficiency syndrome. However, genetic reconstitution of cell surface expression of LFA-1 restored the ability of DNAM-1 to initiate anti-DNAM-1 mAb induced cytotoxicity, indicating a functional relationship between DNAM-1 and LFA-1. Further studies demonstrated that LFA-1 physically associates with DNAM-1 in NK cells and anti-CD3 mAb stimulated T cells, for which serine phosphorylation of DNAM-1 plays a critical role. In addition, cross-linking of LFA-1 induces tyrosine phosphorylation of DNAM-1, for which the fyn protein tyrosine kinase is responsible. These results indicate that DNAM-1 is involved in the LFA-1-mediated intracellular signals.
DNAM-1是一种信号转导粘附分子,参与CTL和NK细胞介导的细胞溶解功能。DNAM-1与抗DNAM-1单抗交联可诱导CTL和NK细胞介导的细胞溶解,并导致DNAM-1分子的酪氨酸磷酸化。我们研究了dnam -1介导的信号和粘附的调节。我们在这里报道PKC活性的特异性抑制剂阻止了dnam -1介导的NK细胞的细胞溶解激活。DNAM-1与其配体的粘附不需要二价阳离子,如镁或钙,并受PKC调节,PMA增强DNAM-1的粘附并被特异性PKC抑制剂抑制。在DNAM-1细胞质区域假定的PKC结合位点(Ser γ γ γ - D1329 γ - D1329 γ - D1)的突变阻止配体结合和pma诱导的DNAM-1受体丝氨酸磷酸化。这些结果表明,PKC磷酸化SerィイD1329ィエDNAM-1 D1和DNAM-1粘附和信号起着至关重要的作用。虽然DNAM-1粘附分子的连接会触发正常NK细胞和T细胞介导的细胞毒性,但这种功能在白细胞粘附缺乏综合征的NK细胞克隆中是缺陷的。然而,LFA-1细胞表面表达的基因重组恢复了DNAM-1启动抗DNAM-1单抗诱导的细胞毒性的能力,表明DNAM-1和LFA-1之间存在功能关系。进一步的研究表明,LFA-1在NK细胞和抗cd3单抗刺激的T细胞中与DNAM-1有物理关联,其中DNAM-1的丝氨酸磷酸化起着关键作用。此外,LFA-1的交联诱导DNAM-1的酪氨酸磷酸化,其中fyn蛋白酪氨酸激酶负责。这些结果表明DNAM-1参与了lfa -1介导的细胞内信号。
项目成果
期刊论文数量(7)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Shibuya, A, et al: "Protein kinase C is involved in the regulation of both signaling and adresion mediated DNAM-1"J. Immunology. 161. 1671-1676 (1998)
Shibuya, A, 等人:“蛋白激酶 C 参与信号传导和邻接介导的 DNAM-1 的调节”J.
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
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- 通讯作者:
Shibuya K., Lanier LL., Phillips JH., Ochs D., Shimizu K., Nakayama E., Nakauchi H., Shibuya A.: "Physical and functional association of LFA-1 with DNAM-1 adhesion molecule."Immunity. 11. 615-623 (1999)
Shibuya K.、Lanier LL.、Phillips JH.、Ochs D.、Shimizu K.、Nakayama E.、Nakauchi H.、Shibuya A.:“LFA-1 与 DNAM-1 粘附分子的物理和功能关联。”
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- 发表时间:
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- 影响因子:0
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- 通讯作者:
Shibuya A., Lanier LL., Phillips JH.: "Protein kinase C is involved in the regulation of both signaling and adhesion mediated by DNAM-1 receptor."J. Immunol.. 161. 1671-1676 (1998)
Shibuya A.、Lanier LL.、Phillips JH.:“蛋白激酶 C 参与 DNAM-1 受体介导的信号传导和粘附的调节。”J.
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- 影响因子:0
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Shibuya K.et al.: "Physical and functional association of LFA-1 with DNAM-1 adhesion molecule"Immunity. 11. 615-623 (1999)
Shibuya K.等人:“LFA-1 与 DNAM-1 粘附分子的物理和功能关联”免疫。
- DOI:
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- 影响因子:0
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Shibuya A.et al.: "Protein-kinase C in involved in the regulation of both signaling and adhesion mediated DNAM-1"J. Immunology. 161. 1671-1676 (1998)
Shibuya A.et al.:“蛋白激酶 C 参与信号传导和粘附介导的 DNAM-1 的调节”J.
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SHIBUYA Akira其他文献
Novel prophylactic and therapeutic approches to GVHD with a monoclonal antibodies against DNAM-1
使用 DNAM-1 单克隆抗体预防和治疗 GVHD 的新方法
- DOI:
- 发表时间:
2009 - 期刊:
- 影响因子:0
- 作者:
KAI Hirayasy;IGUCHI Akiko;WANG Yinan;YAMASHITA Yumi;YASUI Teruhito;KIKUTANI Hitoshi;THARA-HANAOKA Satoko;HONDA Shin-ichiro;SHIBUYA Akira;SHIBUYA Kazuko.;Nabekura T.;鍋倉宰 - 通讯作者:
鍋倉宰
Analysis for the variants of Fcα/μR, a novel Fc receptor for IgA and IgM, expressed in the kidney and testis.
Fcα/μR 变异体的分析,Fcα/μR 是一种新型 IgA 和 IgM Fc 受体,在肾脏和睾丸中表达。
- DOI:
- 发表时间:
2007 - 期刊:
- 影响因子:0
- 作者:
USUI Kenta;HONDA Shin-ichiro;KURITA Naoki;MIYAMOTO Akitomo;CHO Yukiko;TAHARA-HANAOKA Satoko;SHIBUYA Kazuko;SHIBUYA Akira - 通讯作者:
SHIBUYA Akira
Novel prophylactic and therapeutic approches to GVHD with a monoclonal antobodies against DNAM-1
利用 DNAM-1 单克隆抗体预防和治疗 GVHD 的新方法
- DOI:
- 发表时间:
2009 - 期刊:
- 影响因子:0
- 作者:
KAI Hirayasy;IGUCHI Akiko;WANG Yinan;YAMASHITA Yumi;YASUI Teruhito;KIKUTANI Hitoshi;THARA-HANAOKA Satoko;HONDA Shin-ichiro;SHIBUYA Akira;SHIBUYA Kazuko.;Nabekura T. - 通讯作者:
Nabekura T.
SHIBUYA Akira的其他文献
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{{ truncateString('SHIBUYA Akira', 18)}}的其他基金
Development of the therapy for allergic airway hypersensitivity by using a phospholipid liposome
磷脂脂质体治疗过敏性气道超敏反应的开发
- 批准号:
16K15455 - 财政年份:2016
- 资助金额:
$ 1.86万 - 项目类别:
Grant-in-Aid for Challenging Exploratory Research
The immunopathological study on leukocyte adhesion molecule DNAM-1 (CD226)
白细胞粘附分子DNAM-1(CD226)的免疫病理学研究
- 批准号:
21249026 - 财政年份:2009
- 资助金额:
$ 1.86万 - 项目类别:
Grant-in-Aid for Scientific Research (A)
Development of immunotherapy for DNAM-1 as a molecular target in graft-versus-host disease
DNAM-1 免疫疗法作为移植物抗宿主病分子靶标的开发
- 批准号:
19390257 - 财政年份:2007
- 资助金额:
$ 1.86万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Molecular base of the defenses against infection by IgM and IgA
IgM 和 IgA 感染防御的分子基础
- 批准号:
16017215 - 财政年份:2004
- 资助金额:
$ 1.86万 - 项目类别:
Grant-in-Aid for Scientific Research on Priority Areas
Analysis of Mucosal Immunity by the Fc receptor for IgA and IgM
IgA 和 IgM Fc 受体的粘膜免疫分析
- 批准号:
14207024 - 财政年份:2002
- 资助金额:
$ 1.86万 - 项目类别:
Grant-in-Aid for Scientific Research (A)
ANALYSIS OF IMMUNE REGULATION BY ADHESION MOLECULE COMPLEX ON KILLER LYMPHOCYTES
粘附分子复合物对杀伤淋巴细胞免疫调节的分析
- 批准号:
12470111 - 财政年份:2000
- 资助金额:
$ 1.86万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
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