Akt regulates growth by directly phosphorylating Tsc2
Akt regulates growth by directly phosphorylating Tsc2
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DOI：
10.1038/ncb840
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发表时间：
2002-09-01
影响因子：
21.3
通讯作者：
Xu, T
中科院分区：
文献类型：
--
作者：
Potter, CJ;Pedraza, LG;Xu, T
丝氨酸/苏氨酸激酶Akt（也称为蛋白激酶B（PK B））调节细胞生长的直接机制尚不清楚。在这里，我们报告说，果蝇Akt/PKB刺激生长的磷酸化结节性硬化症复合物2（TSC 2）肿瘤抑制和抑制形成的TSC 1-TSC 2复合物。我们发现，Akt/PKB直接磷酸化果蝇Tsc 2在体外的保守残基，丝氨酸924和苏氨酸1518。这些位点的突变使得Tsc 2对Akt/PKB信号传导不敏感，增加了细胞内Tsc 1-Tsc 2复合物的稳定性。在体内刺激Akt/PKB信号传导显著增加细胞生长/大小，破坏Tsc 1-Tsc 2复合物并扰乱Tsc 1和Tsc 2的不同亚细胞定位。此外，所有Akt/PKB生长信号被缺乏Akt磷酸化位点的Tsc 2突变体的表达阻断。因此，Tsc 2似乎是Akt在介导胰岛素信号传导途径的生长信号中的关键靶标。
The direct mechanism by which the serine/threonine kinase Akt (also known as protein kinase B (PKB)) regulates cell growth is unknown. Here, we report that Drosophila melanogaster Akt/PKB stimulates growth by phosphorylating the tuberous sclerosis complex 2 (Tsc2) tumour suppressor and inhibiting formation of a Tsc1-Tsc2 complex. We show that Akt/PKB directly phosphorylates Drosophila Tsc2 in vitro at the conserved residues, Ser 924 and Thr 1518. Mutation of these sites renders Tsc2 insensitive to Akt/PKB signalling, increasing the stability of the Tsc1-Tsc2 complex within the cell. Stimulating Akt/PKB signalling in vivo markedly increases cell growth/size, disrupts the Tsc1-Tsc2 complex and disturbs the distinct subcellular localization of Tsc1 and Tsc2. Furthermore, all Akt/PKB growth signals are blocked by expression of a Tsc2 mutant lacking Akt phosphorylation sites. Thus, Tsc2 seems to be the critical target of Akt in mediating growth signals for the insulin signalling pathway.