哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)是一种丝氨酸/苏氨酸蛋白激酶，在细胞生长、分化、增殖、迁移和存活上扮演重要角色。雷帕霉素常用于组织移植排斥，先前有研究证实TOR是雷帕霉素的靶标，后来又有发现TOR有抗癌效果。2002年在酵母中发现的雷帕霉素不敏感的TOR信号途径（rapamycin-insensitive TOR pathway），并没有将此蛋白革名，反而使人们更加确信mTOR存在于两种完全不同的多蛋白复合体—— mTORC1和mTORC2中。
最近两篇热点封面介绍说两个实验室发现一种哺乳动物mTORC2，即雷帕霉素不敏感复合体。马萨诸塞州理工研究所David Sabatini实验室发现新的结合蛋白Rictor。在一篇补充文章中，瑞士Basel大学Michael Hall研究小组发现mTORC2在酵母和人类中是保守的，也包括Rictor。一篇后继文章中，Sabatini实验室发现与mTORC2有关的第二个激酶——PDK2（PDK2引起Akt/PKB第473位丝氨酸磷酸化）丢失。
Akt/PKB是癌症研究的关键靶标，因此越发将TORC2推向焦点。Sabatini说：“因为Akt是如此一个有名的激酶，在癌症和糖尿病中作用很多，许多人都开始研究（mTORC2）。”这有利于弄清mTORC2的调节机制以及设计特异的抑制剂。
耶鲁大学苏兵说：“TORC1和TORC2复合体是新出现的概念，非常有趣。”mTOR结合蛋白似乎定义了两条不同的途径。
在发现Rictor以前，已经证实mTOR与蛋白Raptor结合，形成后来被称为mTORC1的复合物，调节细胞生长。Rictor的出现提示了mTOR具有其它功能。“我们先前没有推测过Rictor的作用，”Sabatini说，但是“偶然观察”到RNAi将果蝇中TOR沉默，Rictor可以影响Akt/PKB的磷酸化。
苏兵说这是一个特大发现，“S473被普遍用作Akt活性的抑制剂，但是长期以来都不清楚引起此位点磷酸化的激酶是哪种。”确实，TOR同一性进入了白热化讨论。
近期涌现的研究结果支持mTORC2是忽略的激酶。比如，苏兵实验室最近敲除小鼠mTORC2的另一个成分——mSIN1，发现Akt/PKB的S473的磷酸化受到抑制。范德比尔特大学Mark Magnuson小组最近敲除小鼠的Rictor，得到了相似的结果。
Magnuson说：“仍有一些大问题，比如mTORC2不同组分的作用是什么？”Hall认为未知因素还包括mTORC2的上下游物质。敲除mTORC2，对于许多已知的Akt/PKB靶标，如GSK3、TSC2和S6K没有作用，只是会影响Forkhead转录因子Foxo1和Foxo3。这些提示mTORC2只是影响Akt/PKB的特定部分，不是全部活性。
因为mSIN1和Rictor被敲除的小鼠是胚胎致死的，加大了研究的困难程度。Rictor敲除的小鼠胚胎发育开始时正常，在E11.5天死亡，没有任何形态学差异，只有胎盘缺陷和细胞恶化。Magnuson由此产生疑问：“单单的Akt磷酸化能够解释这些表型吗？”
雷帕霉素何去何从？
雷帕霉素受到越来越多的重视，被认为是潜在的治疗癌症药物，但是mTORC2的出现提示雷帕霉素似乎只是抑制mTOR的部分功能。寻找mTOR特异抑制剂开始引发新的研究热潮。苏兵说人们已经拭图用各种方法阻断mTOR2途径，但是不能期望通过mTOR1阻断细胞基础的能量代谢功能。
Sabatini实验室最近在研究使雷帕霉素作用于mTORC2更长久的物质时发现，在几种细胞中雷帕霉素可以降低mTORC2的表达量。“这是矛盾的但也是光明的，”Sabatini说，因为这个现象提示雷帕霉素有望用于一些细胞中阻断Akt。
从上世纪80年代观察到雷帕霉素的抗肿瘤作用，到现在寻找mTOR的侧面，Hall说，“一种很重要的物质这么久都没有被弄清，是一种很有魅力的挑战。”
英文原文：
For mTOR, Clarification and Confusion
The mammalian target of rapamycin (mTOR) was already an established player in cell growth
Size and Shape: An evolving model of the mTOR signaling network posits two major branches. Rapamycin sensitive mTORC1 regulates cell size, and mTORC2, through actin organization, regulates cell shape.
when a discovery late in 2004 stepped up interest in the molecule. TOR was originally found as a target to rapamycin, a drug used to suppress tissue-graft rejection, that was also found to have some tantalizing antitumor effects. The discovery of a rapamycin-insensitive TOR pathway in 2002 in yeast didn't quash the name of the protein, but rather led to the realization that mTOR exists in two distinct multiprotein complexes, mTORC1 and mTORC2.
In the Hot Papers featured here, two labs discovered a mammalian component of mTORC2, the rapamycin-insensitive complex. David Sabatini's lab at the Massachusetts Institute of Technology found the new binding protein Rictor. In a complementary paper, Michael Hall's group at the University of Basel showed mTORC2 to be conserved in yeast and mammals, and to also include Rictor. Then, in a follow-up paper, Sabatini's lab discovered that the mTORC2 appears to be the missing second kinase, PDK2, which phosphorylates serine 473 (S473) on Akt/PKB.
Akt/PKB is a crucial target in cancer research, pushing TORC2 further into the spotlight. "Because Akt is such a famous kinase and it has so many different roles in cancer and diabetes, a lot of people are now running into [mTORC2]" says Sabatini. Consequently, the push is on to figure out how mTORC2 is regulated, what other functions it might have, and to design specific drugs to inhibit it.
Debated Kinase Found?
"TORC1 and TORC2 complexes are new emerging concepts that are very exciting," says Bing Su of Yale University. It is particularly interesting, he adds, that mTOR's binding partner seems to define two distinct pathways.
Before the discovery of Rictor, it was known that mTOR binds to the protein Raptor, forming what was later to be called mTORC1 and regulating cell growth. But with Rictor on the scene, it soon became apparent that mTOR had other functions. "We originally had no guesses what Rictor did," says Sabatini, but "a chance observation" showed that RNAi on Drosophila TOR and Rictor could affect Akt/PKB phosphorylation.
This was a huge find, says Su. "S473 has been widely used as an indicator of Akt activity, but which kinase phosphorylated this site has been unknown for a very long time." Indeed, the identity had been hotly debated.
Recent results back up mTORC2 as this missing kinase. For example, Su's lab recently knocked out a new mTORC2 component, mSIN1, in mice, finding that this inhibits S473 phosphorylation on Akt/PKB. Mark Magnuson's group at Vanderbilt University recently knocked out Rictor in mice with similar results on Akt/PKB. "There are still huge unanswered questions," says Magnuson, "like what are the functions of the different components of mTORC2?"
Hall agrees, adding that it's also unclear what's exactly upstream and downstream of mTORC2. Knocking out mTORC2 had no effect on several well-known Akt/PKB targets, such as GSK3, TSC2, and S6K, and affected only the Forkhead transcription factors Foxo1 and Foxo3. 4,5 This suggests that mTORC2 might affect only Akt/PKB specificity and not overall activity. "We so far know enough to [say] that mTORC2 is of fundamental importance," Hall says, "but I think what we know is only the tip of the iceberg."
Indeed, mSIN1 and Rictor knockout mice are embryonic lethal, making study difficult. Rictor knockouts begin to develop normally and then die at day E11.5 without gross structural differences, but with placental defects and indications of cellular degeneration. This led Magnuson to ask: "Does the phosphorylation of simply Akt explain this phenotype? I'm not sure we know that."
Whither Rapamycin?
Rapamycin received a lot of attention as a possible cancer treatment drug, but with the discovery of mTORC2, rapamycin appears to only inhibit some mTOR functions. The search for mTORC2-specific inhibitors is therefore garnering a lot of attention, says Su. "It makes a lot of sense to try to block the mTORC2 pathway," he adds. "You may not want to even block fundamental energy or metabolism functions of cells through mTORC1."
Sabatini says he thinks we haven't heard the last from rapamycin. His lab recently looked into what prolonged exposure to rapamycin does to mTORC2, finding that it can reduce mTORC2 levels over time in some cell types. "This is still controversial but looks promising," says Sabatini, since it suggests that rapamycin might be useful for blocking Akt in some cells.
Building from observations that began in the 1980's with the tumor-fighting abilities of rapamycin, to now seeing a different side of mTOR, Hall says, "It's fascinating that something that seems so important now, went undiscovered for so long."
