Akt regulates growth by directly phosphorylating Tsc2

被引:751
作者
Potter, CJ [1 ]
Pedraza, LG [1 ]
Xu, T [1 ]
机构
[1] Yale Univ, Sch Med, Boyer Ctr Mol Med, Dept Genet,Howard Hughes Med Inst, New Haven, CT 06536 USA
关键词
D O I
10.1038/ncb840
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
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收藏
页码:658 / 665
页数:8
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