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mTOR pathway 2009

The mTOR (mammalian target of rapamycin) is the pathway I'm working on, and I tried to put some of the recent publications in there. If anybody likes to point out a mistake or has any suggestions, please feel free to do so! This isn't supposed to be a good overview that you'd put in a presentation, rather I tried to put together most of the relevant information I could find, most useful for scientists working on this pathway. There are uncertainties and contradictions, so future work has to be done, especialy regarding the mTorc2 (mTOR complex 2) and its upstream regulators and effectors.

Update v1.01: 28th May 2008 - Amino Acids, Sancak 2008

Update v1.02: 30th May 2008 - Protor->PRR; Ca-dependant; RagGTPase dashed

Update v1.5: 12th June 2008 - New layout; phospho sites; new links

Update v1.6: 8th January 2008 - Revived project, rebuild file from scratch (HDD crash), changed phosphosites and layout, included SGK, PKC, PHLPP, Tel2, PLD1 removed TCTP...

The mammalian target of rapamycin (mTOR) pathway 2009

Bibliography:

  • Gwinn et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Molecular cell (2008) vol. 30 (2) pp. 214-26
  • Huang et al. The TSC1-TSC2 complex is required for proper activation of mTOR complex 2. Molecular and cellular biology (2008) pp.
  • Panasyuk et al. Ribosomal protein S6 kinase 1 interacts with and is ubiquitinated by ubiquitin ligase ROC1. Biochem Biophys Res Commun(2008) pp.
  • Suzuki et al. Tuberous sclerosis complex 2 loss-of-function mutation regulates reactive oxygen species production through Rac1 activation. Biochem Biophys Res Commun (2008) pp.
  • Baba et al. Kidney-Targeted Birt-Hogg-Dube Gene Inactivation in a Mouse Model: Erk1/2 and Akt-mTOR Activation, Cell Hyperproliferation, and Polycystic Kidneys. J Natl Cancer Inst (2008) pp.
  • Bai et al. Rheb activates mTOR by antagonizing its endogenous inhibitor, FKBP38. Science (New York, NY) (2007) vol. 318 (5852) pp. 977-80
  • Yang et al. Expanding mTOR signaling. Cell Res (2007) pp.
  • Pearce et al. Identification of Protor as a novel Rictor-binding component of mTOR complex-2. The Biochemical journal (2007) vol. 405 (3) pp. 513-22
  • Land et al. Hypoxia-inducible factor 1alpha is regulated by the mammalian target of rapamycin (mTOR) via an mTOR signaling motif. The Journal of biological chemistry (2007) vol. 282 (28) pp. 20534-43
  • Guertin et al. Defining the role of mTOR in cancer. Cancer cell (2007) vol. 12 (1) pp. 9-22
  • Manning et al. AKT/PKB signaling: navigating downstream. Cell (2007) vol. 129 (7) pp. 1261-74
  • Abraham et al. The Mammalian target of rapamycin signaling pathway: twists and turns in the road to cancer therapy. Clinical cancer research : an official journal of the American Association for Cancer Research (2007) vol. 13 (11) pp. 3109-14
  • Soulard et al. SnapShot: mTOR signaling. Cell (2007) vol. 129 (2) pp. 434
  • Brognard et al. PHLPP and a second isoform, PHLPP2, differentially attenuate the amplitude of Akt signaling by regulating distinct Akt isoforms. Molecular cell (2007) vol. 25 (6) pp. 917-31
  • Zhang et al. S6K1 regulates GSK3 under conditions of mTOR-dependent feedback inhibition of Akt. Molecular cell (2006) vol. 24 (2) pp. 185-97
  • Baba et al. Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling. Proceedings of the National Academy of Sciences of the United States of America (2006) vol. 103 (42) pp. 15552-7
  • Inoki et al. TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. Cell (2006) vol. 126 (5) pp. 955-68
  • Sabatini. mTOR and cancer: insights into a complex relationship. Nature reviews Cancer (2006) vol. 6 (9) pp. 729-34
  • Shaw et al. Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature (2006) vol. 441 (7092) pp. 424-30
  • Sarbassov et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Molecular cell (2006) vol. 22 (2) pp. 159-68
  • Wullschleger et al. TOR signaling in growth and metabolism. Cell (2006) vol. 124 (3) pp. 471-84
  • Gloire et al. The role of SHIP1 in T-lymphocyte life and death. Biochemical Society transactions (2007) vol. 35 (Pt 2) pp. 277-80
  • Update: 05/28/08: Sancak et al. The Rag GTPases Bind Raptor and Mediate Amino Acid Signaling to mTORC1. Science (New York, NY) (2008) pp.
  • Update: 05/30/08: Gulati et al. Amino acids activate mTOR complex 1 via Ca2+/CaM signaling to hVps34. Cell metabolism (2008) vol. 7 (5) pp. 456-65
  • Update: 06/12/08: Manning. Balancing Akt with S6K: implications for both metabolic diseases and tumorigenesis. The Journal of cell biology (2004) vol. 167 (3) pp. 399-403
  • Update: 06/12/08: Phospho sites: Cellsignal.com
  • Update: 06/12/08: Harrington et al. The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins. The Journal of cell biology (2004) vol. 166 (2) pp. 213-23
  • Update: 06/12/08: Lu et al. Src family protein-tyrosine kinases alter the function of PTEN to regulate phosphatidylinositol 3-kinase/AKT cascades. The Journal of biological chemistry (2003) vol. 278 (41) pp. 40057-66
  • Update: 06/12/08: Huang et al. The TSC1-TSC2 complex: a molecular switchboard controlling cell growth. The Biochemical journal (2008) vol. 412 (2) pp. 179-90
  • Update: 06/12/08: Harvey et al. FOXO-regulated transcription restricts overgrowth of Tsc mutant organs. The Journal of cell biology (2008) vol. 180 (4) pp. 691-6
  • Update: 06/12/08: Sofer et al. Regulation of mTOR and cell growth in response to energy stress by REDD1. Molecular and cellular biology (2005) vol. 25 (14) pp. 5834-45
  • Update: 01/08/09: Sun et al. Phospholipase D1 is an effector of Rheb in the mTOR pathway. Proceedings of the National Academy of Sciences of the United States of America (2008) vol. 105 (24) pp. 8286-91
  • Update: 01/08/09: Yan et al. mTORC2 is the hydrophobic motif kinase for SGK1. The Biochemical journal (2008) vol. 416 (3) pp. e19-21
  • Update: 01/08/09: Facchinetti et al. The mammalian target of rapamycin complex 2 controls folding and stability of Akt and protein kinase C. The EMBO Journal (2008) vol. 27 (14) pp. 1932-43
  • Update: 01/08/09: Takai et al. Tel2 regulates the stability of PI3K-related protein kinases. Cell (2007) vol. 131 (7) pp. 1248-59
  • Update: 01/08/09: Hardie. Neither LKB1 nor AMPK are the direct targets of metformin. Gastroenterology (2006) vol. 131 (3) pp. 973; author reply 974-5
  • Update: 01/08/09: Xie et al. Phosphorylation of LKB1 at serine 428 by protein kinase C-zeta is required for metformin-enhanced activation of the AMP-activated protein kinase in endothelial cells. Circulation (2008) vol. 117 (7) pp. 952-62
  • Update: 01/08/09: Sapkota et al. Phosphorylation of the protein kinase mutated in Peutz-Jeghers cancer syndrome, LKB1/STK11, at Ser431 by p90(RSK) and cAMP-dependent protein kinase, but not its farnesylation at Cys(433), is essential for LKB1 to suppress cell growth. The Journal of biological chemistry (2001) vol. 276 (22) pp. 19469-82
  • Update: 01/08/09: Gwinn et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Molecular cell (2008) vol. 30 (2) pp. 214-26
by Charles Betz
01/08/09. 12:41:00 pm. 953 words, 11729 views. Categories: mTOR key publications ,

23 comments

Comment from: Ced [Visitor]
CedI bet this is a great resource for people working on TOR. As a suggestion, why don't you mark the wiring and components of the pathway with numbers corresponding to your bibliography?
01/08/09 @ 16:40
Comment from: Pazit [Visitor]
PazitI have a feeling that soon making a 2D model will not make sense anymore...
This is getting too complicated!
:)
01/08/09 @ 16:41
Comment from: Charles Betz [Member] Email
Charles BetzCed this is a good idea... thanks, I'll think about how to implement

I guess version 2.0 will require 3D glasses... or a Matrix-like brain connection
01/08/09 @ 16:43
Comment from: Ced [Visitor]
CedAlso, it's starting to look a bit like the flying spaghetti monster!
01/09/09 @ 11:57
Comment from: Charles Betz [Member] Email
Charles Betzhis noodly appendices are all around us
01/09/09 @ 12:00
Comment from: Luci Sandor [Visitor]
Luci SandorI think that Akt has some positive effect on mTORC1, not the negative effect that you show. You are referencing a paper that has in title "Erk1/2 and Akt-mTOR Activation". Also see this: http://www.in-cites.com/papers/DavidMSabatini.html .
03/04/09 @ 02:57
Comment from: Charles Betz [Member] Email
Charles BetzWhere do you see the negative effect? Akt negatively regulates Pras40 which is a negative binding partner of mTORC1, plus it negatively regulates TSC which negatively regulates Rheb which activates mTORC1
did I miss something there?
03/04/09 @ 08:51
Comment from: Luci Sandor [Visitor]
Luci SandorOh, I see. I didn't work out the difference between inhibitor lines that end outside the complex, and inhibitor lines that go inside, to individual components.
03/04/09 @ 13:09
Comment from: Charles Betz [Member] Email
Charles Betzno problem, thanks for the comment though
03/04/09 @ 18:34
Comment from: Richard [Visitor]
RichardHi Charles, I would like to use your interesting illustration in my book on nutrients and body mass. What do you say?
03/16/09 @ 16:39
Comment from: Devaki [Visitor] Email
DevakiHi Charles,
Thanks for the pathway presentation. Indeed, it is handy and have been using it for months that it remains fresh in my memory. Very useful and thanks again for sharing. I like your blog, in general.
I am located in Singapore. In case, if you plan to visit Asia, you are most welcome to the small vibrant country.
03/20/09 @ 03:27
Comment from: rohit trivedi [Visitor]
rohit trivedithis image is simply superb. I am working on this project for past 4 months...n this image makes things more clear and precise...thank you for taking efforts and showing the entire pathway.....
05/14/09 @ 13:28
Comment from: Charles Betz [Member] Email
Charles BetzNo problem... but never take anything for granted... Some interactions may only be important under specific conditions, other may be simply artifacts. The best thing is always to check novel and putative interactors for yourself and compare with the literature
05/14/09 @ 13:31
Comment from: Tania Buchmelter [Visitor]
Tania BuchmelterHello Charles,

I cam across your picture of the mTOR pathway. I would like to use it in a presentation for customers who might be interested in the SIROLIMUS method that Siemens Healthcare Diagnostics has available on their laboratory equipment. The presentation provides a background on Sirolimus, and the pathway is a great depiction of the area that Siro blocks. I don't know for sure how to gain permission to use the picture in my powerpoint. Can you grant me the permission to use the depiction without alteration in my presentation? I will note the link to this article in my presentation.

Thank you,

Tania Buchmelter
Sr. Global Marketing Manager
Siemens Healthcare Diagnostics
05/26/09 @ 22:41
Comment from: Charles Betz [Member] Email
Charles BetzNo Problem, go ahead!
I would be glad for a copy of the presentation though.
05/27/09 @ 08:06
Comment from: Paul Stewart [Visitor]
Paul StewartThank you for this great resource! I am a graduate student in biochemistry and this site has been incredibly helpful.
11/08/09 @ 17:18
Comment from: Margaret Tyson [Visitor]
Margaret TysonThis looks great! Have you any updates on the mTOR pathway for 2010? How verifiable is it? We are looking at the effect of metformin on this pathway and this draws many diagrams together...
06/01/10 @ 18:44
Comment from: Charles Betz [Member] Email
Charles BetzThere will be some major updates but we have to wait for the publication first.
I should put some recent things in there though
06/01/10 @ 18:47
Comment from: Margaret Tyson [Visitor]
Margaret TysonThanks - will you be publishing soon? Do you have a temporary reference for your work?
06/02/10 @ 12:54
Comment from: Charles Betz [Member] Email
Charles BetzI guess I can tell you more in 6 months
06/02/10 @ 12:56
Comment from: Margaret Tyson [Visitor]
Margaret TysonHave you a reference for the existing diagram or is it all the refs given above?
06/02/10 @ 15:36
Comment from: Charles Betz [Member] Email
Charles BetzIt's partly the refs given above, partly data from the numerous good reviews around
06/02/10 @ 15:38
Comment from: Margaret Tyson [Visitor]
Margaret TysonIt's really well worked out. How accurate do you believe it to be?
06/02/10 @ 15:49