Institute of Medical Genetics, Medical University of Vienna, Währinger Strasse 10, 1090, Vienna, Austria.
Amino Acids. 2012 Jun;42(6):2251-6. doi: 10.1007/s00726-011-0965-4. Epub 2011 Jun 28.
The protein kinase p70 S6K1 is regulated in response to cytokines, nutrients and growth factors, and plays an important role in the development of a variety of human diseases. Mammalian target of rapamycin (mTOR) is known to phosphorylate and thereby activate p70 S6K1. p70 S6K1 phosphorylates different cytoplasmic and nuclear substrates involved in the regulation of protein synthesis, cell cycle, cell growth and survival. Recently, we have shown that mTOR-mediated phosphorylation of p70 S6K1 at T389 also regulates its nucleocytoplasmic localization. Since this phosphorylation is associated with its kinase activity the question whether p70 S6K1 phosphorylation or kinase activity is essential for its proper localization remained elusive. Recently, the chemical compound PF-4708671 has been demonstrated to block p70 S6K1 kinase activity while inducing its phosphorylation at T389. This potential of PF-4708671 to separate p70 S6K1 activity from its T389 phosphorylation allowed us to demonstrate that the proper nucleocytoplasmic localization of this kinase depends on its mTOR-mediated phosphorylation but not on its kinase activity. These findings provide important insights into the regulation of p70 S6K1 and allow a more detailed understanding of subcellular enzyme localization processes.
蛋白激酶 p70 S6K1 可响应细胞因子、营养物质和生长因子而被调控，在多种人类疾病的发生发展中发挥着重要作用。已知哺乳动物雷帕霉素靶蛋白（mTOR）可磷酸化并激活 p70 S6K1。p70 S6K1 可磷酸化参与调控蛋白质合成、细胞周期、细胞生长和存活的不同细胞质和核内底物。最近，我们发现 mTOR 介导的 p70 S6K1 在 T389 的磷酸化也可调控其核质定位。由于这种磷酸化与激酶活性相关，p70 S6K1 的磷酸化或激酶活性对于其正确定位是否必不可少的问题仍未得到解答。最近，化合物 PF-4708671 已被证明可阻断 p70 S6K1 激酶活性，同时诱导其在 T389 处磷酸化。PF-4708671 将 p70 S6K1 的活性与其 T389 磷酸化分离的这种潜力使我们能够证明该激酶的正确核质定位取决于其 mTOR 介导的磷酸化，而不取决于其激酶活性。这些发现为 p70 S6K1 的调控提供了重要的见解，并允许更详细地了解细胞内酶定位过程。
