Characterization of S6K2, a novel kinase homologous to S6K1
Characterization of S6K2, a novel kinase homologous to S6K1
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DOI：
10.1038/sj.onc.1202894
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发表时间：
1999-09-09
期刊：
影响因子：
8
通讯作者：
Blenis, J
中科院分区：
文献类型：
--
作者：
Lee-Fruman, KK;Kuo, CJ;Blenis, J
雷帕霉素是一种免疫抑制剂，其通过抑制mTOR的功能来拮抗细胞增殖。mTOR：FKBP 12：雷帕霉素复合物通过抑制细胞周期进程所必需的下游靶标来阻断G1/S转换。一种这样的靶标是p70（S6 k1）（S6 K1），其是一种丝氨酸/苏氨酸激酶，其被mTOR：FKBP 12：雷帕霉素复合物灭活，并且由于其磷酸化核糖体蛋白S6的能力而与翻译控制相关联。在目前的工作中，我描述了一个新的S6 K1同源物，p54 S6激酶2（p54（S6 K2）/S6 K2）的克隆和表征。与S6 K1类似，S6 K2被有丝分裂原和组成型活性PI 3 K激活，并被雷帕霉素和渥曼青霉素抑制。观察到PDK 1激活S6 K1和S6 K2之间的差异，表明这些同源物的调节存在潜在差异。S6 K1（-/-）ES细胞中S6 K2活性和S6磷酸化均未发生变化，提示S6 K2在体内S6磷酸化中可能起作用。有趣的是，我们发现了两种亚型的S6 K2被定位到不同的细胞室;较小的形式驻留在洗涤剂可溶性部分，而较大的形式被发现在颗粒部分。我们的研究结果表明存在一个雷帕霉素敏感蛋白激酶家族，可能参与S6磷酸化、翻译控制和mTOR信号转导。
Rapamycin is an immunosuppressant which antagonizes cellular proliferation by inhibiting the function of mTOR. The mTOR:FKBP12:rapamycin complex blocks G1/S transition by inhibiting downstream targets essential for cell cycle progression. One such target is p70(S6k1) (S6K1), a serine/threonine kinase which is inactivated by the mTOR:FKBP12: rapamycin complex, and which has been linked to translational control by virtue of its ability to phosphorylate the ribosomal protein S6. In the current work, me describe cloning and characterization of a novel S6K1 homolog, p54 S6 kinase 2 (p54(S6k2)/S6K2). Similar to S6K1, S6K2 is activated by mitogens and by constitutively active PI3K, and is inhibited by rapamycin as well as wortmannin. Differences between activation of S6K1 and S6K2 by PDK1 were observed, suggesting potential differences in the regulation of these homologs. Strikingly, S6K2 activity and S6 phosphorylation were both intact in S6K1(-/-)ES cell, indicating a possible role for S6K2 in in vivo S6 phosphorylation. Interestingly, we found two isoforms of S6K2 which are localized to distinct cellular compartments; the smaller form resides in the detergent-soluble fraction, whereas the larger form is found in the particulate fraction. Our findings demonstrate the existence of a family of rapamycin-sensitive protein kinases potentially involved in S6 phosphorylation, translational control, and transduction of mTOR signals.