Focus on molecules: Akt (PKB).
Focus on molecules: Akt (PKB).
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关注分子：Akt (PKB)。
DOI：
10.1016/j.exer.2010.06.016
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发表时间：
2011
影响因子：
3.4
通讯作者：
Kazlauskas,Andrius
中科院分区：
文献类型：
--
作者：
Ruan,Guo-Xiang;Kazlauskas,Andrius
丝氨酸 (Ser)/苏氨酸 (Thr) 激酶 Akt，也称为蛋白激酶 B (PKB)，属于 AGC（cAMP 依赖性、cGMP 依赖性和蛋白激酶 C）激酶家族。在人类中，存在三个 Akt 基因：Akt1（NM_005163、NM_001014432、NM_001014431；3 个剪接变体编码相同的蛋白质）、Akt2（NM_001626）和 Akt3（NM_005465、NM_181690；2 个剪接变体编码更长的蛋白质） （Akt3.1）和较短的（Akt3.2）亚型）。Akt 蛋白包含 N 端 pleckstrin 同源 (PH) 结构域、短螺旋区域、Ser/Thr 特异性激酶结构域和 C 端疏水调节结构域（图 1A）。 Akt2的活化激酶结构域的晶体结构如图1B所示。 Akt 的激活始于配体（例如生长因子）与其细胞表面受体的结合，从而激活磷脂酰肌醇 (PtdIns) 3-激酶 (PI3K)。 PI3K 磷酸化 PtdIns (4, 5) P2 (PIP2)，生成 PtdIns (3, 4, 5) P3 (PIP3)。 PIP3 的水平还受到 PTEN（10 号染色体上删除的磷酸酶和张力蛋白同源物）的调节，PTEN 使 PIP3 去磷酸化生成 PIP2（图 1C）。 PIP3 的积累是 Akt 激活的关键步骤，因为它通过与 Akt 和 PDK1（3-磷酸肌醇依赖性蛋白激酶 1）的 PH 结构域相互作用将其募集到质膜上。 PDK1 在激酶结构域中的保守 Thr 残基处磷酸化 Akt，从而稳定激酶的激活环（图 1C）。 Akt 的完全激活需要调节域中保守 Ser 残基的磷酸化，这是由 mTOR 复合物 2 (mTORC2) 介导的（至少在某些条件下）（Sarbassov 等，2005）（图 1C）。一旦激活，Akt 就会从质膜上解离。
The serine (Ser)/threonine (Thr) kinase Akt, also known as protein kinase B (PKB), belongs to the AGC (cAMP-dependent, cGMP-dependent and protein kinase C) kinase family. In humans, there are three Akt genes: Akt1 (NM_005163, NM_001014432, NM_001014431; the 3 splice variants encode the same protein), Akt2 (NM_001626), and Akt3 (NM_005465, NM_181690; the 2 splice variants encode a longer (Akt3. 1) and a shorter (Akt3. 2) isoform).Akt proteins contain an N-terminal pleckstrin homology (PH) domain, a short helical region, a Ser/Thr specific kinase domain, and a C-terminal hydrophobic regulatory domain (Fig. 1A). A crystal structure of activated kinase domain of Akt2 is shown in Fig. 1B. Activation of Akt begins with the binding of a ligand (eg, growth factor) to its cell surface receptor, which activates phosphatidylinositol (PtdIns) 3-kinase (PI3K). PI3K phosphorylates PtdIns (4, 5) P2 (PIP2) to generate PtdIns (3, 4, 5) P3 (PIP3). The level of PIP3 is also regulated by PTEN (phosphatase and tensin homologue deleted on chromosome 10) that dephosphorylates PIP3 to generate PIP2 (Fig. 1C). Accumulation of PIP3 is a key step in activation of Akt because it recruits Akt and PDK1 (3-phosphoinositide-dependent protein kinase 1) to the plasma membrane by interacting with their PH domains. PDK1 phosphorylates Akt at a conserved Thr residue in the kinase domain, which stabilizes the activation loop of the kinase (Fig. 1C). Full activation of Akt requires phosphorylation at a conserved Ser residue in the regulatory domain, which is mediated (at least under certain conditions) by mTOR Complex 2 (mTORC2)(Sarbassov et al., 2005)(Fig. 1C). Once activated, Akt can dissociate from the plasma membrane.