Dynamic regulation of Src-family tyrosine kinases by CD45

CD45 对 Src 家族酪氨酸激酶的动态调节

• 批准号: 13680731
• 负责人: KATAGIRI Tatsuo
• 金额: $ 1.98万
• 依托单位: TOYAMA MEDICAL AND PHARMACEUTICAL UNIVERSITY
• 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-13680731/
• 关键词: B cell reseptor signal; Lipid Raft; GEM; CD45; PTP; PTK; Src-family PTK; Lyn

Initiation of immune responses is determined by activation of Src-family protein tyrosine kinases (Src-PTKs) upon antigen receptor ligation. Activity of Src-PTKs is regulated, among others, by tyrosine phosphorylation of two tyrosine residues: the autophosphorylation and COOH-terminal negative regulatory sites. CD45, the prototypic receptor-type protein tyrosine phosphatase, has been shown to be a major regulator of Src-PTKs. The precise way in which CD45 exerts its effect is still controversial, however. Our earlier studies showed that CD45 inhibits Lyn activity in a B cell line by dephosphorylating both the autopfibsphorylation and negative regulatory tyrosine residues, and that B cell receptor (BCR) ligation induces phosphorylation of both regulatory sites, suggesting CD45 action on Lyn is diminished upon BCR ligation. In this presentation, we report that in contrast to most studies reported thus far, negative regulation by CD45 is generally operative in B cells, and that some CD45 is constitutively associated with glycolipid-enriched microdomains (GEMs), where it inhibits Src-PTK activity. Upon BCR ligation, however, CD45 dissociates from GEMs within 1 min, leading to activation of Src-PTKs, and then subsequently re-associates with the GEMs within 60 min. CD45 is not involved in the regulation of movement of IgM, Src-PTKs and Csk with respect to GEMs. We propose that the primary role of GEM-associated CD45 is inhibition of Src-PTKs, and that its dynamic behavior of CD45 determines the level of Src-PTK activation and the cell fate.

免疫应答的启动是由抗原受体连接后的Src家族蛋白酪氨酸激酶(Src-PTKs)的激活决定的。除其他外，Src-PTKs的活性通过两个酪氨酸残基的酪氨酸磷酸化来调节：自磷酸化和COOH末端的负调控位点。CD45是典型的受体样蛋白酪氨酸磷酸酶，已被证明是Src-PTKs的主要调节因子。然而，CD45发挥作用的确切方式仍存在争议。我们早期的研究表明，CD45通过去磷酸化自体纤维蛋白和负调控酪氨酸残基来抑制B细胞系LYN的活性，而B细胞受体(BCR)连接诱导这两个调控位点的磷酸化，这表明CD45在BCR连接后对LYN的作用减弱。在这份报告中，我们报告了与迄今报道的大多数研究相反，CD45的负调控通常在B细胞中起作用，一些CD45与糖脂丰富的微域(GEMS)结构性相关，在那里它抑制Src-PTK的活性。然而，在BCR连接后，CD45在1分钟内从宝石上解离，导致Src-PTK的激活，然后在60分钟内与宝石重新结合。CD45不参与调节IgM、Src-PTKs和CSK相对于宝石的运动。我们认为GEM相关的CD45的主要作用是抑制Src-PTKs，CD45的动态行为决定了Src-PTK的激活水平和细胞命运。

项目成果

Mizuno K., Tagawa Y., Mitomo K., Watanabe N., Katagiri T., Ogimoto M. & Yakura H.: "Src homology region 2 domain-containing phosphatase 1 positively regulates B cell receptor-induced apoptosis by modulating association of B cell linker protein with Nck an

水野 K.、田川 Y.、三友 K.、渡边 N.、片桐 T.、荻本 M.

Mizuno Kazuya: "Src homology region 2 domain-containing phosphatase 1 positively regulates B cell receptor-induced apoptosis by modulating association of B cell linker protein with Nck and activation of c-Jun NH2-terminal kinase"The Journal of Immunology.

Mizuno Kazuya：“包含 Src 同源区 2 结构域的磷酸酶 1 通过调节 B 细胞接头蛋白与 Nck 的关联以及 c-Jun NH2 末端激酶的激活，正向调节 B 细胞受体诱导的细胞凋亡”《免疫学杂志》。