TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth
TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth
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DOI：
10.1016/j.cell.2006.06.055
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发表时间：
2006-09-08
期刊：
影响因子：
64.5
通讯作者：
Guan, Kun-Liang
中科院分区：
文献类型：
--
作者：
Inoki, Ken;Ouyang, Hongjiao;Guan, Kun-Liang
肿瘤抑制因子TSC 2的突变导致结节性硬化综合征，这是一种以多组织错构瘤形成为特征的疾病。TSC 2通过充当针对Rheb的GTP酶激活蛋白来抑制细胞生长，从而抑制细胞生长的中央控制器mTOR。在这里，我们发现Wnt通过抑制GSK 3激活mTOR，而不涉及β-连环蛋白依赖性转录。GSK 3通过以依赖于AMPK引发磷酸化的方式磷酸化TSC 2来抑制mTOR通路。雷帕霉素对mTOR的抑制阻断了Wnt诱导的细胞生长和肿瘤发展，这表明雷帕霉素对具有激活的Wnt信号传导的癌症具有潜在的治疗价值。我们的研究结果表明，除了转录激活，Wnt通过激活TSC-mTOR途径刺激翻译和细胞生长。此外，AMPK和GSK 3对TSC 2的连续磷酸化揭示了细胞生长调节中信号整合的分子机制。
Mutation in the TSC2 tumor suppressor causes tuberous sclerosis complex, a disease characterized by hamartoma formation in multiple tissues. TSC2 inhibits cell growth by acting as a GTPase-activating protein toward Rheb, thereby inhibiting mTOR, a central controller of cell growth. Here, we show that Wnt activates mTOR via inhibiting GSK3 without involving beta-catenin-dependent transcription. GSK3 inhibits the mTOR pathway by phosphorylating TSC2 in a manner dependent on AMPK-priming phosphorylation. Inhibition of mTOR by rapamycin blocks Wnt-induced cell growth and tumor development, suggesting a potential therapeutic value of rapamycin for cancers with activated Wnt signaling. Our results show that, in addition to transcriptional activation, Wnt stimulates translation and cell growth by activating the TSC-mTOR pathway. Furthermore, the sequential phosphorylation of TSC2 by AMPK and GSK3 reveals a molecular mechanism of signal integration in cell growth regulation.