Investigation of Tec family of protein-tyrosine kinases in hematopoiesis and hematological disorders.

蛋白酪氨酸激酶 Tec 家族在造血和血液疾病中的研究。

• 批准号: 15591023
• 负责人: YAMASHITA Yoshihiro
• 金额: $ 2.24万
• 依托单位: Jichi Medical School
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15591023/
• 关键词: Sak kinase; Tec kinsase; tyrosine phosphorylation; PEST sequence

The murine sak gene encodes a putative serine-threonine kinase which is homologous to the members of the Plk/Polo family. Although Sak protein is presumed to be involved in cell growth mechanism, efforts have failed to demonstrate its kinase activity. Little has been, therefore, elucidated how Sak is regulated and how Sak contributes to cell proliferation. Tec is a cytoplasmic protein-tyrosine kinase(PTK) which becomes activated by the stimulation of cytokine receptors, lymphocyte surface antigens, heterotrimeric G protein-linked receptors, and integrins. To clarify the in vivo function of Tec, we have tried to isolate the second messengers of Tec by using the yeast two-hybrid screening. One of such Tec-binding proteins turned out to be Sak. In human kidney 293 cells, Sak became tyrosine-phosphorylated by Tec, and the serine-threonine kinase activity of Sak was detected only under the presence of Tec, suggesting Sak to be an effector molecule of Tec. In addition, Tec activity efficiently protects Sak from the "PEST" sequence-dependent proteolysis. Internal deletion of the PEST sequences led to the stabilization of Sak proteins, and expression of these mutants acted suppressive to cell growth. Our data collectively supports a novel role of Sak acting in the PTK-mediated signaling pathway.

鼠 sak 基因编码与 Plk/Polo 家族成员同源的推定丝氨酸-苏氨酸激酶。尽管推测 Sak 蛋白参与细胞生长机制，但未能证明其激酶活性。因此，很少有人阐明 Sak 是如何调节的以及 Sak 如何促进细胞增殖。 Tec 是一种细胞质蛋白酪氨酸激酶 (PTK)，在细胞因子受体、淋巴细胞表面抗原、异三聚体 G 蛋白连接受体和整合素的刺激下被激活。为了阐明Tec的体内功能，我们尝试通过酵母双杂交筛选来分离Tec的第二信使。 Sak 就是其中一种 Tec 结合蛋白。在人肾293细胞中，Sak被Tec酪氨酸磷酸化，并且仅在Tec存在下才检测到Sak的丝氨酸-苏氨酸激酶活性，表明Sak是Tec的效应分子。此外，Tec 活性可有效保护 Sak 免受“PEST”序列依赖性蛋白水解作用。 PEST 序列的内部删除导致 Sak 蛋白的稳定，并且这些突变体的表达抑制细胞生长。我们的数据共同支持 Sak 在 PTK 介导的信号通路中发挥的新作用。

项目成果

He H.et al.: "The Tyr-Kinase Inhibitor AG879, That Blocks the ETK-PAK1 Interaction, Suppresses the RAS-Induced PAK1 Activation and Malignant Transformation"Cancer Biol Ther.. 3. 96-101 (2004)

He H.等人：“The Tyr-Kinase Inhibitor AG879, That Blocks the ETK-PAK1 Interaction, Suppresses the RAS-Induced PAK1 Activation and Malignant Transformation”Cancer Biol Ther. 3. 96-101 (2004)

DNA microarray analysis of dysplastic morphology associated with acute myeloid leukemia.

与急性髓系白血病相关的发育不良形态的 DNA 微阵列分析。

• 发表时间: 2004
• 期刊: Exp Hematol. 32
• 作者: Numata;A.;Shimoda;K.;Kamezaki;K.;Haro;T.;Kakumitsu;H.;Shide;K.;Kato;K.;Miyamoto;T.;Yamashita;Y.;Oshima;Y.;Nakajima;H.;Iwama;A.;Aoki;K.;Takase;K.;Gondo;H.;Mano;H.;Harada;M.;He H.et al.;Kaneda R. et al.;Tsutsumi C. et al.
• 通讯作者: Tsutsumi C. et al.

DNA microarray analysis of dysplastic morphology associated with acute myeloid leukemia

急性髓性白血病相关发育异常形态的 DNA 微阵列分析

• 发表时间: 2004
• 期刊: Exp Hematol 32
• 作者: Tsutsumi;C.;Ueda;M.;Miyazaki;Y.;Yamashita;Y.;Choi;Y.L.;Ota;J.;Kaneda;R.;Koinuma;K.;Fujiwara;S.;Kisanuki;H.;Ishikawa;M.;Ozawa;K.;Tomonaga;M.;Mano;H.
• 通讯作者: H.

Ueno S.et al.: "DNA microarray analysis of in vivo progression mechanism of heart failure"Biochem Biophys Res Commun.. 307. 771-777 (2003)

Ueno S.等：“心力衰竭体内进展机制的DNA微阵列分析”Biochem Biophys Res Commun.. 307. 771-777 (2003)

High-throughput screening of genome fragments bound to differentially acetylated histones

• DOI: 10.1111/j.1365-2443.2004.00804.x
• 发表时间: 2004-12-01
• 期刊: GENES TO CELLS
• 影响因子: 2.1
• 作者: Kaneda, R;Toyota, M;Mano, H
• 通讯作者: Mano, H