Rheb binds tuberous sclerosis complex 2 (TSC2) and promotes S6 kinase activation in a rapamycin- and farnesylation-dependent manner
Rheb binds tuberous sclerosis complex 2 (TSC2) and promotes S6 kinase activation in a rapamycin- and farnesylation-dependent manner
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DOI：
10.1074/jbc.c300226200
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发表时间：
2003-08-29
影响因子：
4.8
通讯作者：
Quilliam, LA
中科院分区：
文献类型：
--
作者：
Castro, AF;Rebhun, JF;Quilliam, LA
最近，结节性硬化症复合体2（TSC 2）肿瘤抑制基因产物已被鉴定为mTOR和核糖体S6激酶上游蛋白质合成的负调节剂。由于TSC 2与GTP酶激活蛋白Rap 1的同源性，我们研究了Ras/Rap 1相关的GTP酶是否可能参与这一过程。发现TSC 2在体外与Rheb-GTP结合并在体内降低Rheb GTP水平。Rheb的过表达而不是Rap 1的过表达以雷帕霉素依赖的方式促进S6激酶的激活，表明Rheb在mTOR的上游起作用。Rheb诱导S6磷酸化的能力也受到法尼基转移酶抑制剂的抑制，这表明Rheb可能是这种药物的Ras独立抗肿瘤特性的原因。
Recently the tuberous sclerosis complex 2 (TSC2) tumor suppressor gene product has been identified as a negative regulator of protein synthesis upstream of the mTOR and ribosomal S6 kinases. Because of the homology of TSC2 with GTPase-activating proteins for Rap1, we examined whether a Ras/Rap-related GTPase might be involved in this process. TSC2 was found to bind to Rheb-GTP in vitro and to reduce Rheb GTP levels in vivo. Over-expression of Rheb but not Rap1 promoted the activation of S6 kinase in a rapamycin-dependent manner, suggesting that Rheb acts upstream of mTOR. The ability of Rheb to induce S6 phosphorylation was also inhibited by a farnesyl transferase inhibitor, suggesting that Rheb may be responsible for the Ras-independent anti-neoplastic properties of this drug.