PRAS40 is a target for mammalian target of rapamycin complex 1 and is required for signaling downstream of this complex
PRAS40 is a target for mammalian target of rapamycin complex 1 and is required for signaling downstream of this complex
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DOI：
10.1074/jbc.m704406200
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发表时间：
2007-08-24
影响因子：
4.8
通讯作者：
Proud, Christopher G.
中科院分区：
文献类型：
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作者：
Fonseca, Bruno D.;Smith, Ewan M.;Proud, Christopher G.
通过雷帕霉素复合物1（mTORC 1）的哺乳动物靶标的信号传导受氨基酸和胰岛素的正调控。PRAS 40与mTORC 1（包含raptor）相关，但不与mTORC 2相关。PRAS 40与猛禽相互作用，这需要PRAS 40中完整的TOR信号（TOS）基序。与含TOS基序的蛋白质如eIF 4 E结合蛋白1（4 E-BP 1）一样，PRAS 40是mTORC 1磷酸化的底物。与此相一致的是，细胞的氨基酸饥饿或用雷帕霉素处理改变了PRAS 40的磷酸化。PRAS 40结合14-3-3蛋白，这需要氨基酸和胰岛素。PRAS 40与14-3-3蛋白的结合被TSC 1/2（mTORC 1的负调节剂）抑制，并以雷帕霉素敏感的方式被Rheb刺激。这证实PRAS 40是mTORC 1调节的靶标。小干扰RNA介导的PRAS 40敲低损害氨基酸和胰岛素刺激的4 E-BP 1磷酸化和S6磷酸化。然而，这对Akt或TSC 2（Akt底物）的磷酸化没有影响。这些数据将PRAS 40置于mTORC 1的下游，但其效应物（如S6 K1和4 E-BP 1）的上游。
Signaling through the mammalian target of rapamycin complex 1 (mTORC1) is positively regulated by amino acids and insulin. PRAS40 associates with mTORC1 (which contains raptor) but not mTORC2. PRAS40 interacts with raptor, and this requires an intact TOR-signaling (TOS) motif in PRAS40. Like TOS motif-containing proteins such as eIF4E-binding protein 1 (4E-BP1), PRAS40 is a substrate for phosphorylation by mTORC1. Consistent with this, starvation of cells of amino acids or treatment with rapamycin alters the phosphorylation of PRAS40. PRAS40 binds 14-3-3 proteins, and this requires both amino acids and insulin. Binding of PRAS40 to 14-3-3 proteins is inhibited by TSC1/2 (negative regulators of mTORC1) and stimulated by Rheb in a rapamycin-sensitive manner. This confirms that PRAS40 is a target for regulation by mTORC1. Small interfering RNA-mediated knockdown of PRAS40 impairs both the amino acid- and insulin-stimulated phosphorylation of 4E-BP1 and the phosphorylation of S6. However, this has no effect on the phosphorylation of Akt or TSC2 (an Akt substrate). These data place PRAS40 downstream of mTORC1 but upstream of its effectors, such as S6K1 and 4E-BP1.