Center for Translational Medicine, Department of Medicine, School of Pharmacy, Thomas Jefferson University, Philadelphia, PA, USA.
Cell Cycle. 2012 Feb 1;11(3):475-8. doi: 10.4161/cc.11.3.19059.
AGC kinases, including the three Akt (protein kinase B) isoforms, protein kinase A (PKA) and all protein kinase C (PKC) isoforms, require activation loop phosphorylation (threonine 308 in Akt1) as well as phosphorylation of a C-terminal residue (serine 473 in Akt1) for catalytic activity and phosphorylation of downstream targets. Conversely, phosphatases reverse these phosphorylations. Virtually all cellular processes are affected by AGC kinases, a circumstance that has led to intense scrutiny of the molecular mechanisms that regulate phosphorylation of these kinases. Here, we review a new layer of control of phosphorylation in Akt, PKA and PKC pointing to ATP binding pocket occupancy as a means to decelerate dephosphorylation of these and, potentially, other kinases. This additional level of kinase regulation opens the door to search for new functional motifs for the rational design of non- ATP-competitive kinase inhibitors that discriminate within and between protein kinase families.
AGC 激酶，包括三种 Akt（蛋白激酶 B）同工型、蛋白激酶 A（PKA）和所有蛋白激酶 C（PKC）同工型，需要激活环磷酸化（Akt1 中的苏氨酸 308）以及 C 末端残基磷酸化（Akt1 中的丝氨酸 473）才能发挥催化活性和磷酸化下游靶标。相反，磷酸酶会逆转这些磷酸化。几乎所有的细胞过程都受到 AGC 激酶的影响，这种情况导致人们对调节这些激酶磷酸化的分子机制进行了深入研究。在这里，我们回顾了 Akt、PKA 和 PKC 中磷酸化的新调控层，指出 ATP 结合口袋占据作为一种减缓这些激酶和可能其他激酶去磷酸化的手段。这种额外的激酶调控水平为寻找新的功能基序打开了大门，可用于合理设计非 ATP 竞争性激酶抑制剂，以区分蛋白激酶家族内和家族间的抑制剂。
