Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase
Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase
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DOI：
10.1073/pnas.0405659101
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发表时间：
2004-09-14
影响因子：
11.1
通讯作者：
Blenis, J
中科院分区：
文献类型：
--
作者：
Roux, PP;Ballif, BA;Blenis, J
多发性硬化症（TSC）是由两种肿瘤抑制基因TSC 1或TSC 2（分别编码hamartin和tuberin）突变引起的遗传性疾病。雷帕霉素和错构蛋白形成复合物，其抑制雷帕霉素的哺乳动物靶标（mTOR）的信号传导，所述mTOR是细胞生长和增殖的关键营养传感器和调节剂。磷脂酰肌醇3-激酶（PI 3 K）通过Akt磷酸化块茎蛋白使肿瘤抑制复合物失活并增强mTOR信号传导。重要的是，由佛波酯和Ras亚型介导的细胞转化在缺乏Akt活化的情况下促进肿瘤发生，所述佛波酯和Ras亚型不良地活化PI 3 K。在这项研究中，我们发现佛波醇酯和激活的Ras也诱导了块茎素的磷酸化，并与营养传感途径合作来调节mTOR效应子，如p70核糖体S6激酶1（S6 K1）。丝裂原活化蛋白激酶（MAPK）激活的激酶，p90核糖体S6激酶（RSK）1，被发现相互作用和磷酸化的调节位点，Ser-1798，位于进化保守的C末端的块茎蛋白。Ser-1798的RSK 1磷酸化抑制了块茎蛋白/错构瘤蛋白复合物的肿瘤抑制功能，导致mTOR信号传导至S6 K1增加。总之，我们的数据揭示了Ras/MAPK和PI 3 K通路会聚在肿瘤抑制因子tuberin上以抑制其功能的调节机制。
Tuberous sclerosis complex (TSC) is a genetic disorder caused by mutations in either of the two tumor suppressor genes TSC1 or TSC2, which encode hamartin and tuberin, respectively. Tuberin and hamartin form a complex that inhibits signaling by the mammalian target of rapamycin (mTOR), a critical nutrient sensor and regulator of cell growth and proliferation. Phosphatidylinositol 3-kinase (PI3K) inactivates the tumor suppressor complex and enhances mTOR signaling by means of phosphorylation of tuberin by Akt. Importantly, cellular transformation mediated by phorbol esters and Ras isoforms that poorly activate PI3K promote tumorigenesis in the absence of Akt activation. In this study, we show that phorbol esters and activated Ras also induce the phosphorylation of tuberin and collaborates with the nutrient-sensing pathway to regulate mTOR effectors, such as p70 ribosomal S6 kinase 1 (S6K1). The mitogen-activated protein kinase (MAPK)-activated kinase, p90 ribosomal S6 kinase (RSK) 1, was found to interact with and phosphorylate tuberin at a regulatory site, Ser-1798, located at the evolutionarily conserved C terminus of tuberin. RSK1 phosphorylation of Ser-1798 inhibits the tumor suppressor function of the tuberin/hamartin complex, resulting in increased mTOR signaling to S6K1. Together, our data unveil a regulatory mechanism by which the Ras/MAPK and PI3K pathways converge on the tumor suppressor tuberin to inhibit its function.