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Functional analysis of Tec family kinases in normal hematopoiesis and hematological disease.

Tec 家族激酶在正常造血和血液疾病中的功能分析。

基本信息

批准号：
13671081
负责人：
YAMASHITA Yoshihiro
金额：
$ 2.3万
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：
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-13671081/
关键词：
Sak kinase Tec kinase tyrosine phosphorylation PEST sequence 造血前駆細胞 BRDG1 ドッキング蛋白 PHドメイン B細胞抗原受容体(BCR)CREB

项目摘要

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基因编码一种推定的丝氨酸-苏氨酸激酶，其与Plk/波罗家族成员同源。尽管Sak蛋白被认为参与细胞生长机制，但努力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），可通过细胞因子受体、淋巴细胞表面抗原、异源三聚体G蛋白连接受体和整联蛋白的刺激而激活。为了阐明Tec在体内的功能，我们尝试利用酵母双杂交筛选Tec的第二信使。其中一种TEC结合蛋白被证明是Sak。在人肾293细胞中，Sak被Tec磷酸化，并且仅在Tec存在下检测到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活性有效地保护Sak免受“PEST”序列依赖性蛋白水解。PEST序列的内部缺失导致Sak蛋白的稳定，这些突变体的表达对细胞生长具有抑制作用。我们的数据共同支持一个新的作用，Sak在PTK介导的信号通路中发挥作用。