TOR action in mammalian cells and in Caenorhabditis elegans.
TOR action in mammalian cells and in Caenorhabditis elegans.
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DOI：
10.1007/978-3-642-18930-2_8
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发表时间：
2004
影响因子：
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通讯作者：
Samuel Long;F. Müller;J. Avruch
中科院分区：
文献类型：
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作者：
Samuel Long;F. Müller;J. Avruch
p70 S6 激酶 (p70 S6K) 是哺乳动物细胞中第一个被证明可被雷帕霉素抑制的信号元件。哺乳动物细胞中 p70 S6K 的活性主要通过 1A 型 PI-3 激酶的激活，通过细胞外氨基酸（尤其是亮氨酸）和受体酪氨酸激酶 (RTK) 的信号上调。氨基酸/雷帕霉素敏感输入和 PI-3 激酶输入是共显性的，但在很大程度上是独立的，因为 p70 S6K 催化结构域侧翼的氨基末端和羧基末端非催化序列的缺失使激酶对雷帕霉素和氨基酸撤出的抑制不敏感，而该 p70 S6K 突变体仍然对 RTK 的激活和渥曼青霉素的抑制有反应。在分子水平上，p70 S6K活性的这种双重控制可归因于两个p70 S6K位点的磷酸化：Ptd Ins 3,4,5P3依赖性激酶1 (PDK1)在激活环上的Thr处磷酸化p70 S6K，而mTOR磷酸化位于催化结构域的疏水基序羧基末端的Thr。这两种磷酸化共同产生了 p70 S6K 的强烈、积极的协同激活，因此每种磷酸化对于生理调节都是不可或缺的。与 RTK 一样，p70 S6K 出现在后生动物进化的早期，并且代表了一个重要位点，在该位点，更古老的营养响应 TOR 途径与控制细胞生长的 RTK/PI-3 激酶途径汇合。在果蝇中观察到 p70 S6K 的双重调节；然而，这种趋同性在秀丽隐杆线虫中尚不明显，其中胰岛素受体（InsR）途径的营养激活负向调节多尔发育和寿命，而TOR途径通过不同于p70 S6K的效应器调节总体mRNA翻译，如在酵母中。 C. elegansTOR 和 InsR 通路没有表现出哺乳动物细胞中所见的交叉或汇聚调节。将营养充足性与 TOR 活性相结合的因素的性质仍有待发现，RTK 影响哺乳动物细胞中 TOR 活性的机制也需要进一步研究。 RTK 控制的一种途径涉及结节性硬化症复合体，而 C 中不存在这种复合体。线虫，但对于果蝇和高等后生动物非常重要。
The p70 S6 kinase (p70 S6K) was the first signaling element in mammalian cells shown to be inhibited by rapamycin. The activity of the p70 S6K in mammalian cell is upregulated by extracellular amino acids (especially leucine) and by signals from receptor tyrosine kinases (RTKs), primarily through activation of the type 1A PI-3 kinase. The amino acid-/rapamycin-sensitive input and the PI-3 kinase input are codominant but largely independent, in that deletion of the amino-terminal and carboxy-terminal noncatalytic sequences flanking the p70 S6K catalytic domain renders the kinase insensitive to inhibition by both rapamycin and by withdrawal of amino acids, whereas this p70 S6K mutant remains responsive to activation by RTKs and to inhibition by wortmannin. At a molecular level, this dual control of p70 S6K activity is attributable to phosphorylation of the two p70 S6K sites: The Ptd Ins 3,4,5P3-dependent kinasel (PDK1) phosphorylates p70 S6K at a Thr on the activation loop, whereas mTOR phosphorylates a Thr located in a hydrophobic motif carboxyterminal to the catalytic domain. Together these two phosphorylations engender a strong, positively cooperative activation of p70 S6K, so that each is indispensable for physiologic regulation. Like RTKs, the p70 S6K appears early in metazoan evolution and comes to represent an important site at which the more ancient, nutrient- responsive TOR pathway converges with the RTK/PI-3 kinase pathway in the control of cell growth. Dual regulation of p70 S6K is seen inDrosophila; however, this convergence is not yet evident inCaenorhabditis elegans, wherein nutrient activation of the insulin receptor (InsR) pathway negatively regulates dauer development and longevity, whereas the TOR pathway regulates overall mRNA translation through effectors distinct from p70 S6K, as in yeast. TheC. elegansTOR and InsR pathways show none of the cross- or convergent regulation seen in mammalian cells. The nature of the elements that couple nutrient sufficiency to TOR activity remain to be discovered, and the mechanisms by which RTKs influence TOR activity in mammalian cells require further study. One pathway for RTK control involves the tuberous sclerosis complex, which is absent inC. elegans, but of major importance inDrosophilaand higher metazoans.