Fc receptor signal initiation mechanisms at lipid rafts

脂筏上的 Fc 受体信号启动机制

• 批准号: 13670451
• 负责人: SUZUKI Takeshi
• 金额: $ 2.56万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670451/
• 关键词: Fc receptor; src family kinases; lipid rafts; SH3 domain; FcγRIIb; Fc受容体; FcrRIIb; C末端Srcキナーゼ

Antigen receptors, consists of T and B cell receptors and those for Fc portion of Immunoglobulines (Fc receptors for Igs) play central roles in the initial step of immune regulation. It was assumed that receptor engagement is sensed and converted by Src family kinases (SFKs) to cell-inner events. To elucidate the SFK specificity, we introduced novel strategies and established their requirement and specificity in Fc, and c-Kit and Integrin receptors. Notably, SFKs responsible for Fc receptor signaling are all modified with palmitic acid, and they reside in a membrane domain referred to as 'lipid rafts'. We have also shown that special lipid raft-coalescence is an upstream event to SFK activation. It could be assumed that raft-coalescence provides a field for SFKs transactivate on another. We are searching for the molecule(s) responsible for Fc receptor-mediated lipid raft assembly. Next we have cloned two novel molecules interacting with a SFK, Lyn. One possess RING domain and another is a huge adaptor protein possessing putative Grb2 and PI3K binding sites and GAP domain. Third, we are investigating functional differences in polymorphic forms of negatige regulatory Fc receptor for IgG (FcγRIIb), one of which (rare allele) is genetically linked to systemic lupus erythematodes.

抗原受体由 T 细胞和 B 细胞受体以及免疫球蛋白 Fc 部分受体（Igs 的 Fc 受体）组成，在免疫调节的初始步骤中发挥核心作用。假设 Src 家族激酶 (SFK) 感知受体结合并将其转化为细胞内部事件。为了阐明 SFK 特异性，我们引入了新策略并确定了它们在 Fc、c-Kit 和整合素受体中的要求和特异性。值得注意的是，负责 Fc 受体信号传导的 SFK 均经过棕榈酸修饰，并且它们驻留在称为“脂筏”的膜结构域中。我们还表明，特殊的脂筏合并是 SFK 激活的上游事件。可以假设筏合并为 SFK 在另一个上反式激活提供了一个场所。我们正在寻找负责 Fc 受体介导的脂筏组装的分子。接下来，我们克隆了两种与 SFK Lyn 相互作用的新分子。一个具有 RING 结构域，另一个是一个巨大的接头蛋白，具有推定的 Grb2 和 PI3K 结合位点以及 GAP 结构域。第三，我们正在研究 IgG 阴性调节 Fc 受体 (FcγRIIb) 多态性的功能差异，其中之一（罕见等位基因）与系统性红斑狼疮有遗传相关。

项目成果

Ueda S., Honda Z., et al.: "Critical roles of c-kit tyrosine residues"Blood. 99. 3342-3349 (2002)

Ueda S.、Honda Z. 等人：“c-kit 酪氨酸残基的关键作用”血液。

Kono H., Suzuki T., et al.: "Spatial Raft coalescence represents an initial step in FcγR signaling"The Journal of Immunology. 169. 193-203 (2002)

Kono H.、Suzuki T.等人：“空间筏聚结代表了 FcγR 信号传导的初始步骤”《免疫学杂志》169. 193-203 (2002)。

Ueda S, Mizuki M, Ikeda H, Tsujimura T, Matsumura I, Nakano K, Daino H, Honda Z, Sonoyama J, Shibayama H, Sugahara H, Machii T and Kanakura Y: "Critical roles of c-Kit tyrosine residues 567 and 719 in stem cell factor-induced chemotaxis : contribution of

Ueda S、Mizuki M、Ikeda H、Tsujimura T、Matsumura I、Nakano K、Daino H、Honda Z、Sonoyama J、Shibayama H、Sugahara H、Machii T 和 Kanakura Y：“c-Kit 酪氨酸残基 567 和

Kono H, Suzuki T, Yamamoto K, Okada M, Yamamoto T and Honda Z: "Spatial raft coalescence represents an initial step in Fc gamma R signaling"J. Immunol.. 169. 193-203 (2002)

Kono H、Suzuki T、Yamamoto K、Okada M、Yamamoto T 和 Honda Z：“空间筏合并代表了 Fc gamma R 信号传导的第一步”J.

Kono H., Suzuki T., et al.: "Spatial Raft Coalescence Represents an initial step in FcR signaling"The Journal of Immunology. 169. 193-203 (2002)

Kono H.、Suzuki T. 等人：“空间筏聚结代表 FcR 信号传导的初始步骤”《免疫学杂志》。