Bayascas Jose R
Institut de Neurociències & Departament de Bioquiacute;mica i Biologia Molecular, Universitat Autònoma de Barcelona, Barcelona, Spain.
Cell Cycle. 2008 Oct;7(19):2978-82. doi: 10.4161/cc.7.19.6810. Epub 2008 Oct 18.
The 3-phosphoinositide-dependent protein kinase-1 (PDK1) mediates the cellular effect of insulin and growth factors by activating a group of kinases including PKB/Akt, S6K, RSK, SGK and PKC isoforms. PDK1 possesses two regulatory domains namely a Pleckstrin Homology (PH) domain that binds to the phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P(3)] second messenger, and a substrate binding site termed the PIF-pocket. Employing a combination of biochemical, structural and mouse knock-in approaches we have been able to define the roles that the regulatory domains on PDK1 play. We have established that binding of PDK1 to PtdIns(3,4,5)P(3) is essential for efficient activation of PKB isoforms as well as for maintaining normal cell size and insulin sensitivity. In contrast, the PIF-substrate binding pocket of PDK1 is not required for PKB activation, but is necessary for PDK1 to activate all of its other substrates.
3-磷酸肌醇依赖性蛋白激酶-1（PDK1）通过激活包括蛋白激酶B/蛋白激酶B（PKB/Akt）、核糖体S6激酶（S6K）、p90核糖体S6激酶（RSK）、血清和糖皮质激素诱导激酶（SGK）以及蛋白激酶C（PKC）亚型在内的一组激酶来介导胰岛素和生长因子的细胞效应。PDK1具有两个调节结构域，即与磷脂酰肌醇-3,4,5-三磷酸[PtdIns(3,4,5)P3]第二信使结合的普列克底物蛋白同源（PH）结构域，以及一个称为PIF口袋的底物结合位点。通过结合生化、结构和小鼠基因敲入方法，我们已经能够确定PDK1上调节结构域所起的作用。我们已经确定，PDK1与PtdIns(3,4,5)P3的结合对于有效激活PKB亚型以及维持正常细胞大小和胰岛素敏感性至关重要。相比之下，PDK1的PIF底物结合口袋对于PKB激活不是必需的，但对于PDK1激活其所有其他底物是必需的。
