Novel role of the small GTPase Rheb: Its implication in endocytic pathway independent of the activation of mammalian target of rapamycin
Novel role of the small GTPase Rheb: Its implication in endocytic pathway independent of the activation of mammalian target of rapamycin
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DOI：
10.1093/jb/mvi046
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发表时间：
2005-03-01
影响因子：
2.7
通讯作者：
Katada, T
中科院分区：
文献类型：
--
作者：
Saito, K;Araki, Y;Katada, T
从酵母到人类保守的Ras同源GTdR heb似乎不仅参与细胞生长，而且参与营养摄取。最近的生化分析表明，结节性硬化症复合物（TSC），一种GTP酶激活蛋白（GAP），使Rheb失活，磷脂酰肌醇3 '-激酶（PI 3 k）-Akt/PKB激酶途径通过抑制GAP介导的失活激活Rheb。尽管哺乳动物雷帕霉素靶蛋白（mTOR）激酶与Rheb的下游靶蛋白有关，但Rheb的直接效应子和确切功能尚未完全阐明。在这里，我们确定了Rheb在培养细胞中的表达诱导大的细胞质空泡的形成，其特征在于晚期内吞（晚期内体和溶酶体样）成分。空泡的形成需要GTP形式的Rheb，但不需要下游mTOR激酶的激活。这些结果表明，Rheb调节内吞运输途径独立于先前鉴定的mTOR途径。这两个Rheb依赖性信号通路的生理作用进行了讨论，在营养吸收和细胞生长或细胞周期的进展。
The Ras-homologous GTPase Rheb that is conserved from yeast to human appears to be involved not only in cell growth but also in nutrient uptake. Recent biochemical analysis revealed that tuberous sclerosis complex (TSC), a GTPase-activating protein (GAP), deactivates Rheb and that phosphatidylinositol 3'-kinase (PI3k)-Akt/PKB kinase pathway activates Rheb through inhibition of the GAP-mediated deactivation. Although mammalian target of rapamycin (mTOR) kinase is implicated in the downstream target of Rheb, the direct effector(s) and exact functions of Rheb have not been fully elucidated. Here we identified that Rheb expression in cultured cells induces the formation of large cytoplasmic vacuoles, which are characterized as late endocytic (late endosome- and lysosome-like) components. The vacuole formation required the GTP form of Rheb, but not the activation of the downstream mTOR kinase. These results suggest that Rheb regulates endocytic trafficking pathway independent of the previously identified mTOR pathway. The physiological roles of the two Rheb-dependent signaling pathways are discussed in terms of nutrient uptake and cell growth or cell cycle progression.