Department of Pathology, Harvard Medical School, Dana-Farber/Harvard Cancer Center, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 2012 Jun 26;109(26):10581-6. doi: 10.1073/pnas.1202810109. Epub 2012 Jun 11.
Elevating Akt activation is an obvious clinical strategy to prevent progressive neuronal death in neurological diseases. However, this endeavor has been hindered because of the lack of specific Akt activators. Here, from a cell-based high-throughput chemical genetic screening, we identified a small molecule SC79 that inhibits Akt membrane translocation, but paradoxically activates Akt in the cytosol. SC79 specifically binds to the PH domain of Akt. SC79-bound Akt adopts a conformation favorable for phosphorylation by upstream protein kinases. In a hippocampal neuronal culture system and a mouse model for ischemic stroke, the cytosolic activation of Akt by SC79 is sufficient to recapitulate the primary cellular function of Akt signaling, resulting in augmented neuronal survival. Thus, SC79 is a unique specific Akt activator that may be used to enhance Akt activity in various physiological and pathological conditions.
升高 Akt 的激活水平显然是预防神经疾病中神经元进行性死亡的一种临床策略。然而，由于缺乏特异性的 Akt 激活剂，这一努力受到了阻碍。在这里，我们通过基于细胞的高通量化学遗传学筛选，鉴定出一种小分子 SC79，它可抑制 Akt 的膜转位，但出人意料的是，它能在细胞质中激活 Akt。SC79 特异性结合 Akt 的 PH 结构域。与 SC79 结合的 Akt 采用一种有利于被上游蛋白激酶磷酸化的构象。在海马神经元培养系统和缺血性中风的小鼠模型中，SC79 诱导的 Akt 在细胞质中的激活足以重现 Akt 信号通路的主要细胞功能，从而增加神经元的存活。因此，SC79 是一种独特的特异性 Akt 激活剂，可用于增强各种生理和病理条件下 Akt 的活性。
