Studies on control mechanism of protein phosphatases ds a network system of information

信息网络系统中蛋白磷酸酶调控机制的研究

• 批准号: 10480162
• 负责人: KIKUCHI Kunimi
• 金额: $ 7.68万
• 依托单位: HOKKAIDO 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 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-10480162/
• 关键词: protein phosphatase; phosphotyrosine phosphatase; dual specificity phosphatase; PTPε; tautomycetin; cell differentiation; IL-6; apoptosis; チロシンホスファタ-ゼ; セリンホスファタ-ゼ; 2重基質特異性ホスファタ-ゼ; PTPεC; インヒビター4; トウトマイシン; 癌化; 2重特異性ホスファターゼ

Our results are summarized as follows:1. Regulation of cytokine signaling by PTPεC(1) PTPεC strongly suppressed IL-6-induced M1 differentiation in PTPεC activity-dependent manner. This suppression is due to suppression of JAK-activation.(2) This suppression by PTPεC was observed in STAT-activation through IL6R and IL10R, but not in those via IFNα/βR and IFNγR.2. Structure and function of a novel dual specificity phosphatase, MKP-7(1) MKP-7 has Rhodariese domain, catalytic domain, NLS, and NES.(2) Substrate specificity is in the order ot JNK>p38>>ERK.(3) MKP-7 is a shuttle protein between cytosol and nucleus.3. Structure and function of a novel PP1-inhibitor, 1-4(1) 1-4 strongly inhibits PP1, IC_<50> being 0.2 nM.(2) 1-4interacts with PP1C on at least three sites.4. Structure-function relationship of tautomycin and its related compounds(1) Different moieties of tautomycin are involved in protein phosphatase inhibition and induction of apoptosis.(2) Tautomycetin is found to be a strong and specific inhibitor for PP1.

主要研究结果如下：1. PTPεC对细胞因子信号的调节（1）PTPεC以PTPεC活性依赖的方式强烈抑制IL-6诱导的M1分化。这种抑制是由于抑制JAK激活。(2)PTPεC对IL 6 R和IL 10 R介导的STAT激活有抑制作用，而对IFNα/βR和IFNγ R介导的STAT激活无抑制作用。MKP-7是一种新型的双特异性磷酸酶，其结构和功能如下：（1）MKP-7具有Rhodariese结构域、催化结构域、NLS和内斯。(2)底物特异性顺序为JNK>p38>>ERK。(3)MKP-7是细胞质与细胞核之间的穿梭蛋白.新型PP 1抑制剂1-4（1）1-4的结构与功能<50>研究(2)1- 4与PP 1C至少在三个位点上相互作用.互变霉素及其相关化合物的构效关系（1）互变霉素的不同结构部分参与蛋白磷酸酶抑制和诱导细胞凋亡。(2)发现互变霉素是PP 1的强且特异性的抑制剂。

项目成果

Shinya Mitsuhashi: "The spiroketals containing a benzyloxymethyl moiety at C8 position showed the most potent apoptosis-inducing activity"Bioorganic & Medicinal Chemistry Letter. 9(14). 2007-2012 (1999)

Shinya Mitsuhashi：“在 C8 位点含有苄氧基甲基部分的螺缩酮显示出最有效的细胞凋亡诱导活性”Bioorganic

Shinya Mitsuhashi: "Development of an assay method for activities of serine/threonine protein phosphatase type 2B(calcineurin) in crude extracts"Analytical Biochemistry. 278(2). 192-197 (2000)

Shinya Mitsuhashi：“粗提物中丝氨酸/苏氨酸蛋白磷酸酶 2B 型（钙调神经磷酸酶）活性测定方法的开发”分析生物化学。

Nobuhiro Tanuma: "Distinct promoters control transmembrane and cytosolic protein tyrosine phosphatase ε expression during macrophage differentiation"European Journal of Biochemistry. 259(1-2). 46-54 (1999)

Nobuhiro Tanuma：“不同的启动子控制巨噬细胞分化过程中的跨膜和胞质蛋白酪氨酸磷酸酶 ε 表达”，《欧洲生物化学杂志》259(1-2) (1999)。

Kunimi Kikuchi: "New apoptosis-inducing agents : Thyrsiferyl 23-acetate, tautomycin, and their related compounds"Drugs of the Future. 25(5). 501-507 (2000)

Kunimi Kikuchi：“新型细胞凋亡诱导剂：Thyrsiferyl 23-acetate、tautomycin 及其相关化合物”未来药物。

Nobuhiro Tanuma: "Distinct promoters control transmembrane and cytosolic protein tyrosine phosphatase ε expression during macrophage differentiation"Eurpean Journal of Biochemistry. 259(1-2). 44-46 (1999)

Nobuhiro Tanuma：“不同的启动子控制巨噬细胞分化过程中的跨膜和胞浆蛋白酪氨酸磷酸酶 ε 表达”欧洲生物化学杂志 259(1-2) (1999)。