Talk:MTOR

Comments

Can we get a little more details on the actual function of mTOR please? The structure is nice and how it assembles is great, but how does it play a role in transduction?

I believe the m stands for metazoan in mTOR. It was discovered in yeast.

The m stands for mammalian; in yeast it is refered to as TOR, in drosophilia dTOR.

m Stands for mechanistic -- see [[1]], its a common misconception. I am not sure about the reason for the change. Consideration should be given to changing the title of this page, or adding an alias link Davebridges (talk) —Preceding undated comment added 14:40, 30 May 2011 (UTC).

Are There Natural or Nutraceutical Inhibitors of mTOR?

If so and if either scientifically verified or suggested, that should definitely be included in the article. (With the proper qualifiers, if verified, say 'verified' if only suggested say 'suggested' prior to any mention of such natural inhibitors.

Sean7phil (talk) 20:47, 28 November 2009 (UTC)

Rapamycin is natural :) I believew curcumin has also been found to inhibit mTOR, but I have to check. Fvasconcellos (t·c) 20:51, 28 November 2009 (UTC)

Split out Interactions

The Interactions section has a huge number of references. Can we split the list (and references) into a separate mTOR interactions article or similar ? Rod57 (talk) 18:26, 6 December 2010 (UTC)

Since this is an issue that also applies to a large number of other Gene Wiki articles, I have copied your question and responded here. Cheers. Boghog (talk) 22:29, 6 December 2010 (UTC)

A line about TOR phenotypes from a mostly-unrelated article

The following may be of some interest in editing this article: "Several aspects of the Atf4 mutant phenotype resemble mice with mutations in components of the target of rapamycin (TOR) pathway. Consistent with the phenotypic similarities, Atf4 null mice have reduced expression of genes that regulate intracellular amino acid concentrations" Atf4 Regulates Obesity, Glucose Homeostasis, and Energy Expenditure --Dan Wylie-Sears 2 (talk) 13:18, 30 May 2011 (UTC)

Misinterpretation?

At the end of the 3rd paragraph in the mTORC1 section, the line reads: "[...] phosphorylation at these sites appears to stimulate mTOR activity". I.e. phosphorylation gives more mTOR activity I looked up the first article it references* and as I understand it, the article actually states the opposite...: "The proposed AKT phosphorylation site (Ser-2448) in mTOR lies within a C-terminal regulatory region, which, when deleted, results in elevated mTOR activity in vitro and in cells (18, 20)" I.e.: no phosphorylation possible gives more mTOR activity.

Did I misunderstand or is the wiki page incorrect?

• Chiang G, Abraham R (2005). "Phosphorylation of mammalian target of rapamycin (mTOR) at Ser-2448 is mediated by p70S6 kinase". J Biol Chem 280 (27): 25485–90. doi:10.1074/jbc.M50170720 — Preceding unsigned comment added by Mrs Often (talk • contribs) 17:03, 26 June 2011 (UTC)

I am not expert on this subject, but what is stated in this Wikipedia article and the Chiang et al. paper do not necessarily contradict each other. The C-terminal regulatory region appears to repress mTOR activity. This repression may be lifted through phosphorylation or deletion of the C-terminal region. Boghog (talk) 19:38, 26 June 2011 (UTC)

mTOR influence on insulin resistance

Not sure where this information should go in this article or even if it should go here, but I was reading a somewhat recent review article titled "Once again on rapamycin‐induced insulin resistance and longevity: despite of or owing to" [2] that talked about high or low concentration of mTOR and insulin resistance resulting in detrimental or beneficial results for the organism/individual depending on the combination. Low mTOR and insulin resistance, visible in caloric restriction, appears to be beneficial and high mTOR and insulin resistance is detrimental and I think associated with type II-diabetes. BreCaitlin (talk) 21:24, 31 January 2013 (UTC)

This is a good idea but it is a bit complicated since mTOR is in two complexes, one of which is generally a positive regulator (mTORC2) and one of which is a negative regulator (mTORC1) of insulin sensitivity. In fact generally I think it would be better for there to be separate mTORC1 and mTORC2 pages, since their roles are generally non-overlapping and not easily explainable from the perspective of the common kinase subunit Davebridges (talk) 08:40, 2 February 2013 (UTC)

Per your suggestion, the mTORC1 and mTORC2 pages have been created. Boghog (talk) 22:12, 2 February 2013 (UTC)

Awesome, thanks. Biosthmors (talk) 18:47, 7 February 2013 (UTC)

Class Project

Hi mTOR editors, this is Bobby, a student in a Signal Transduction class at Saint Louis University. Each student is allowed to pick a topic that they found exciting as well as a topic they felt could expand the current wikipedia knowledge on. This article, along with mTORC1 and mTORC2 are going to be what I am going to be editing for the rest of the semester. If you have any help or input or advice, don't hesitate to leave a comment on my talk page. I am planning on, for the editing, reading upwards of twenty review articles (and perhaps a couple primary articles) about mTOR and its signaling within the cell and using that information to help (hopefully) add to the current knowledge about this protein (these proteins) already supplied on Wikipedia. This is just to help give a heads up that I am working on this.

This article is part of an assignment from Saint Louis University in Spring 2013 (see the course page for more details).

Thanks, Flemingrjf (talk) 03:22, 18 February 2013 (UTC)

Hi Bobby. Your are doing a fantastic job expanding and cleaning up this article as well as mTORC1 and mTORC2. I don't known too much specifically about these two complexes but from my perspective what you have added so far looks great. Cheers. Boghog (talk) 08:29, 17 March 2013 (UTC)

Comments from Gpruett2

First of all, great job editing this article. Your writing style is easy to follow and you are doing a great job organizing this article.

Here are some suggestions I think you should consider (I've broken them up by section):

Introduction

• I would suggest rewording the first sentence to state what mTOR actually is: a kinase. Thus, it would be better to start the article by stating that mTOR is a serine/threonine protein kinase rather than saying that it is encoded by FRAP1.

Sorry for butting in here, but concering the lead sentence in Gene Wiki articles, as discussed here and here, we have tried to make clear that these articles are (1) about both the protein and the gene encoding that protein and (2) not only about the human gene/protein, but also orthologs that exist in other species. The wording that was reached through consensus is perhaps a little awkward, but it is both accurate and concise:

• <recommended UniProt name> is a protein that in humans is encoded by the <approved HUGO gene symbol> gene.

The "that" in the above sentence is non-limiting implying that the protein (and gene) exists in other species besides human. The first sentence defines the scope of the article (protein + gene). The second sentence states that this protein is a kinase. Boghog (talk) 04:25, 27 March 2013 (UTC)

• You should also consider expanding the introduction to basically give an abstract that summarizes the key points of mTOR. This way readers can get a general taste of what they can find later on in the article.

Discovery and history

• Is it really necessary to devote more space to Rapamycin's history than that of mTOR? I ask because in a history/discovery section in an mTOR article, shouldn't mTOR's history be more prominent?

Function

• mTOR is a serine/threonine kinase, thus shouldn’t its function discuss something about phosphorylation?
• The last paragraph seems like it belongs in the history section, not the function section. It doesn't list a function, it lists how certain TORs were discovered.

Complexes

• This section states that mTOR serves as a part of two different complexes, mTORC2 and mTORC1. Shouldn't this be listed under function? In fact, I would suggest incorporating the information in this section under function since it describes mTOR's function for participating in complexes.

Physiological significance

• Does this really belong in the mTOR article. I ask because it seems to focus more on mTORC2 and mTORC1 than mTOR.

Clinical Significance

• Aging

• In this section, the independent groups at the Jackson Laboratory, University of Texas Health Science Center, and the University of Michigan are mentioned. You should probably not mention these groups since Wikipedia seeks to maintain a neutral policy and doesn't want to indorse any groups.

• Alzeihemer’s

• I would suggest making the writing here a little less technical. At the moment it is rather dense. I would suggest limiting the amount of specific experimental results that show the connection between mTOR and Alzeihemer’s. Try to summarize as much as possible.

mTOR inhibitors as therapies

• Should this section be under clinical significance?

Interactions

• Could this be located under function?
• Also does each individual interaction target need so many sources? P70-S6 Kinase has 16 citations by it. Does it really need that many?

General Comments

• Overall the article sections are very well cited; however, there seems to be an overabundance of primary literature. Wikipedia prefers sources more along the lines of review articles. Also, are all of these sources necessary?
• Overall, the article contains good sections. I would recommend going to WikiProject Molecular and Cellular Biology Style Guide for further suggestions on structuring this article.
• However, one section that I would definitely suggest including would be a cell signaling section. For instance, this review article gives a good explanation of how mTOR fits into a signaling pathway that begins with Akt.

I hope you find these suggestions helpful and best of luck with future editing. Gpruett2 (talk) 03:36, 27 March 2013 (UTC)

Comments from Jnims

Great job so far! I've included my suggestions for improvement below as part of our Assignment 7. General and/or article-wide suggestions are first, followed by suggestions for improving specific sections.

General suggestions

• Check in-text links to Wikipedia articles to ensure that they do not result in redirects.
• Add more in-text links to Wikipedia articles.
• Consider adding a Gene(s) section with information about regulation, expression, etc. See these guidelines. Source #2 (Moore et al. 1996) seems like it would be good for this. Be sure to italicize gene names!

Discovery & history section

• This first sentence needs a citation (or a few): "mTOR is considered to be the mammalian target of rapamycin."
• These sentences are slightly awkward: "mTOR is considered to be the mammalian target of rapamycin. Rapamycin was discovered in a soil sample from Easter Island in the 1970s.[5] Researchers studied this sample and found that the bacterium Streptomyces hygroscopicus made an antifungal, which they named rapamycin after the island's name Rapa Nui, which it was called by the locals meaning "navel of the world.""
  • Suggestion: "mTOR is considered to be the mammalian target of rapamycin, a molecule discovered in a soil sample from Easter Island in the 1970s. Researchers studying this sample found that the bacterium Streptomyces hygroscopicus produced an antifungal agent, which they named rapamycin after the locals' name for the island, Rapa Nui, meaning "navel of the world.""
• This sentence could likewise use improvement: "Two of the genes were called targets of rapamycin, or TOR, while the third gene was already characterized to be Fpr1, which is now known to be the yeast ortholog to FKBP12 binding protein in the TOR complexes."
  • Suggestion: "Two of the genes were called targets of rapamycin, or TOR, while the third gene had already been characterized as Fpr1, and is now known to be the yeast ortholog to the FKBP12 binding protein in the TOR complexes."
• Should this word be "as" instead of "at"?: "In 1994, the mammalian target of rapamycin (mTOR) was identified at the rapamycin target in mammals."

Function section

• The meaning of "integrates" is unclear in this sentence; could you provide more information about this particular role of mTOR?: "mTOR integrates the input from upstream pathways, including insulin, growth factors (such as IGF-1 and IGF-2), and amino acids."
• This sentence is rather long and hard to understand; consider dividing it into two or more separate sentences. The inclusion of "genetic and molecular studies" is also unnecessary: "mTOR stands for mammalian Target Of Rapamycin and was named based on the precedent that TOR was first discovered via genetic and molecular studies of rapamycin-resistant mutants of Saccharomyces cerevisiae that identified FKBP12, Tor1, and Tor2 as the targets of rapamycin and provided robust support that the FKBP12-rapamycin complex binds to and inhibits the cellular functions of Tor1 and Tor2."
  • Suggestion: "mTOR, or mammalian target of rapamycin, was named based on the discovery of TOR in rapamycin-resistant mutants of Saccharomyces cerevisiae. Studies of such mutants identified FKBP12, Tor1, and Tor2 as the targets of rapamycin and provided robust support for the theory that the FKBP12-rapamycin complex binds to and inhibits the cellular functions of Tor1 and Tor2."
• As per source #14 (Wullschleger et al 2006), you may want to consider making the role of FKBP12 as a cofactor required for mTOR's function more explicit.

Complexes section

• Add "itself" at the end of these phrases to underscore the presence of mTOR in the complexes: "mTOR Complex 1 (mTORC1) is composed of mTOR," and "mTOR Complex 2 (mTORC2) is composed of mTOR."
  • Thus, the entire sentence containing the first phrase would read, "mTOR Complex 1 (mTORC1) is composed of mTOR itself, regulatory-associated protein of mTOR (Raptor), mammalian lethal with SEC13 protein 8 (MLST8) and the recently identified partners PRAS40 and DEPTOR." The second sentence would look similar.
• The meaning of "partners" is unclear; consider adding more information about what makes them partners: "and the recently identified partners PRAS40 and DEPTOR." Also, I don't see any mention of those two proteins in the two sources you cited (#s 15 and 16). Am I missing something (entirely possible!), or is there a better source that identifies those molecules by name?
• The wording in this sentence could be improved: "This complex is characterized by the classic features of mTOR by functioning as a nutrient/energy/redox sensor and controlling protein synthesis."
  • Suggestion: "This complex embodies the classic functions of mTOR, namely as a nutrient/energy/redox sensor and controller of protein synthesis."
• Remove extra words ("has been shown to") in this sentence, for the sake of brevity: "mTORC2 has been shown to function as an important regulator of the cytoskeleton through its stimulation of F-actin stress fibers, paxillin, RhoA, Rac1, Cdc42, and protein kinase C α (PKCα)."
  • Result: "mTORC2 functions as an important regulator of the cytoskeleton through its stimulation of F-actin stress fibers, paxillin, RhoA, Rac1, Cdc42, and protein kinase C α (PKCα)."
• Are you describing the function of PDK2 here? Please clarify. (There is also an unnecessary space after "serine residue S473" that I would have removed, but there is some wiki markup that I don't recognize and hesitate to edit.): "mTORC2 also appears to possess the activity of a previously elusive protein known as "PDK2". mTORC2 phosphorylates the serine/threonine protein kinase Akt/PKB at a serine residue S473 . Phosphorylation of the serine stimulates Akt phosphorylation at a threonine T308 residue by PDK1 and leads to full Akt activation;[20][21] curcumin inhibits both by preventing phosphorylation of the serine." Also, what do you mean by "inhibits both" in the last sentence?

Clinical significance section

• Remove the unnecessary mentions of the schools in this sentence: "The mTOR inhibitor rapamycin has been confirmed to increase lifespan in mice by independent groups at the Jackson Laboratory, University of Texas Health Science Center, and the University of Michigan.[34]"
  • Instead, you could say: "The mTOR inhibitor rapamycin has been confirmed to increase lifespan in mice by several independent investigators."
• Start this sentence with "However," instead of "But" to avoid an incomplete sentence: "But infusion of leucine into the rat brain has been shown to decrease food intake and body weight via activation of the mTOR pathway."
• The Alzheimer's section could be made clearer by breaking it into more paragraphs by subject, and possibly reorganizing the section to keep information contained within a single paragraph (i.e., have a single paragraph for each of the following: Aβ accumulation, tau accumulation, etc.; this mostly applies to the first two paragraphs). Relating your examples more explicitly to what you call "mTOR signaling hyperactivity in AD brains" would also be helpful.
• To highlight the discrepancy in this finding, consider editing the following sentence: "These in vitro studies suggest that increasing Aβ concentrations increases mTOR signaling; however, significantly large, cytotoxic Aβ concentrations are thought to decrease mTOR signaling."
  • Suggestion: "However, while these in vitro studies suggest that increasing Aβ concentrations increases mTOR signaling, significantly large, cytotoxic Aβ concentrations are thought to have the opposite effect." Maybe also provide a bit more information about this discrepancy, since it seems quite noteworthy.
• Consider changing the words "mTOR activity" to "mTOR's role" in this sentence: "Further evidence for mTOR activity in neurodegeneration comes from recent findings demonstrating that eIF2α-P, an upstream target of the mTOR pathway, mediates cell death in prion diseases through sustained translational inhibition."
  • Thus, the sentence would read, "Further evidence for mTOR's role in neurodegeneration comes from recent findings demonstrating that eIF2α-P, an upstream target of the mTOR pathway, mediates cell death in prion diseases through sustained translational inhibition."
• Change the phrasing of this sentence: "Several groups have proposed that disruptions in autophagy may be a potential source of pathogenesis in protein misfolding diseases, including AD."
  • Suggestion: "Several groups have proposed that disruptions in autophagy may contribute to the pathogenesis of protein misfolding diseases, including AD."
• Edit this sentence: "Perhaps the same treatment may be useful in clearing Aβ deposits as well."
  • Suggestion: "Thus, it is thought that the same treatment may be useful in clearing Aβ deposits."

mTOR inhibitors as therapies section

• Edit these sentences: "Some articles reported that rapamycin can inhibit mTORC1 so that the phosphorylation of GS(glycogen synthase) can be increased in skeletal muscle. This discovery represents a potential novel therapeutic approach for glycogen storage diseases that involve glycogen accumulation in muscle."
  • Suggestion: "The discovery that rapamycin can inhibit mTORC1 such that phosphorylation of glycogen synthase (GS) is increased in skeletal muscle could represent a novel therapeutic approach for glycogen storage diseases that involve the accumulation of glycogen in muscle."
• "Some" what? Specify what these compounds are: "Some (e.g. temsirolimus, everolimus) are beginning to be used in the treatment of cancer."
• This sentence should either be expanded upon or removed: "Ridaforolimus is another mTOR inhibitor, currently in clinical development."

Please let me know if you have any questions. Good luck! Jnims (talk) 00:28, 23 April 2013 (UTC)

Comments from Dr.saptarshi

This is part of a discussion in response to Flemming's comment in my discussion page. I am copy pasting part of my response from there since I believe that discussion should belong to this page:

mTOR is quite a huge topic and deserves a big introduction. Probably so does mTORC1 & mTORC2 if they were stand alone. But since they are not stand alone, you can insert some sort of statement at the top: "for a broad introduction on this topic please see the article mTOR" to avoid too much repeatition of the same in the mTORC1 article and also at the bottom use the ==See also== to direct the readers/collaborators.

Writing in wikipedia is usually very satisfying when you see your article grow and also your reference list grows. But I caution you guys that mTOR is a huge and still unfolding topic and a lot of it is still left to be addressed in these articles. As for example the following may not have been adequately addressed

Role of mTOR in

• cell size regulation
• organism size regulation
• mechano transduction
• Cell cycle progression;
• Cancer therapy. currently its use in transplant rejection is covered but it has not not gone into its use in Cancer therapy. When you cover that, please also try to address how mTOR inhibition works in some cancers but paradoxically fails or worsens some other cancers;
• In the signaling part you need to address the interrelation between mTORC1 & 2.

May be you can try to organize the headings as subheadings ===Cellular level effects=== and ===Organism level effects=== under a bigger heading of ==Pathophysiological significance== instead of physiological significance. You might say that the wikiproject Cell and molecular biology itself does not have its general format, but that itself could also be improved.

Good luck and happy wiki-ing ;) --Dr.saptarshi (talk) 06:06, 23 April 2013 (UTC)

Peer Review comments from MChapman5

• I would suggest breaking the Alzheimer's section up into several sub-categories. This section is really text heavy and may be easier to read if you could divide it.
• In the section "Interactions," do you think organizing the data into a chart/table would be better for the article's organization?
• Would a picture of the MTORC1 and MTORC2 pathways be acceptable in those sections? Or do you think it's better to have the reader click over to their main articles? They may just want a visualization which could be provided here.
• The leading section seems a little short. You may want to add in a couple of sentences detailing the physiological significances and the clinical significances since you talk about them in your main article.
• Great contribution on this page! I'm going to go ahead and make some comments on the MTORC1 and MTORC2 articles as well. MChapman5 (talk) 06:52, 30 April 2013 (UTC)