Rheb通过拮抗其内源性抑制剂FKBP38来激活mTOR。
Rheb activates mTOR by antagonizing its endogenous inhibitor, FKBP38.
作者信息
Bai Xiaochun, Ma Dongzhu, Liu Anling, Shen Xiaoyun, Wang Qiming J, Liu Yongjian, Jiang Yu
机构信息
Department of Pharmacology, University of Pittsburgh School of Medicine, E1357 Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15213, USA.
出版信息
Science. 2007 Nov 9;318(5852):977-80. doi: 10.1126/science.1147379.
The mammalian target of rapamycin, mTOR, is a central regulator of cell growth. Its activity is regulated by Rheb, a Ras-like small guanosine triphosphatase (GTPase), in response to growth factor stimulation and nutrient availability. We show that Rheb regulates mTOR through FKBP38, a member of the FK506-binding protein (FKBP) family that is structurally related to FKBP12. FKBP38 binds to mTOR and inhibits its activity in a manner similar to that of the FKBP12-rapamycin complex. Rheb interacts directly with FKBP38 and prevents its association with mTOR in a guanosine 5'-triphosphate (GTP)-dependent manner. Our findings suggest that FKBP38 is an endogenous inhibitor of mTOR, whose inhibitory activity is antagonized by Rheb in response to growth factor stimulation and nutrient availability.
雷帕霉素的哺乳动物靶点mTOR是细胞生长的核心调节因子。其活性受Rheb（一种类Ras小GTP酶）调节，以响应生长因子刺激和营养物质可用性。我们发现，Rheb通过FKBP38调节mTOR，FKBP38是FK506结合蛋白（FKBP）家族的成员，在结构上与FKBP12相关。FKBP38与mTOR结合并以类似于FKBP12-雷帕霉素复合物的方式抑制其活性。Rheb直接与FKBP38相互作用，并以鸟苷5'-三磷酸（GTP）依赖的方式阻止其与mTOR结合。我们的研究结果表明，FKBP38是mTOR的内源性抑制剂，其抑制活性在生长因子刺激和营养物质可用性的响应中被Rheb拮抗。
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