Meeting Highlights


Meeting Highlights

Welcome Meeting Attendees

Jan 29 2009 12:13PM

Science Signaling Editors

In the past, the editors have placed meeting highlights in the Open Forum on Cell Signaling. To keep that as a place to discuss any topic related to cell signaling and to group comments and brief reports from meetings together, the editors started this new forum.

Any meeting attendee, from keynote speakers to students, are invited to submit comments about sessions, individual talks, or entire meetings or conferences that were of particular interest. If you attended a meeting that already has an entry, just choose "Post a Response" to enter your comments. If you want to start a thread on a new meeting, then choose "Start a New Topic". Make sure the title of the comments includes the name of the meeting for the first entry.

Poster Award Winners from "Visualizing Immune System Complexity"

May 15 2009 6:57AM

Nancy R. Gough

Science Signaling sponsored a poster competition at the EMBO workshop, "Visualizing Immune System Complexity," 15-17 January 2009. Co-organizer Michael L. Dustin (Skirball Institute, NY) provided a Meeting Report with highlights from the meeting (1). This meeting was organized to follow the "3rd Luminy Advanced Course in Immunology," which provided instruction and hands-on experience for students from around the world.

The meeting was organized such that theoretical approaches to understanding the immune system were presented first and the talks proceeded from the nano- and molecular scale to the cellular level to the tissue level and finally the entire organism. In addition to posters, there were a mixture of longer talks by senior investigators and shorter talks selected from the poster submissions, which were mostly presented by more junior scientists. The meeting covered a very broad range of topics in immunology with talks highlighting the dynamics of molecular complexes in cells to the movement of immune cells in the body and covered cells in both the adaptive and innate immune system. Approaches to understanding the immune systems were presented by computational biologists and those using modeling, those studying the interaction between cells and cellular responses in vitro, as well as those applying the latest imaging techniques to study immune cells in vivo. Although many different approaches and methodologies were presented, an recurrent them was the application of live-cell imaging in vitro and in vivo, which is revealing how dynamic the immune system is at the molecular level, as well as at the cellular and tissue levels.

The editors of Science Signaling would like to extend congratulations to the poster award winners. These young scientists submitted poster presentations that were selected by the scientific committee to present as short talks. Of the more than 50 posters submitted, nine were selected for short talks and three students were selected to win the competition sponsored by Science Signaling.

Stephane Oddos, a student in Dan Davis's lab at the Imperial College of London, was the first place winner for his presentation describing high-speed high-resolution imaging of intercellular immune synapses. By combining optical tweezers with confocal microscopy, they examined natural killer cell immune synapses and T cell immune synapses. On the NK cells, they observed long filopodial-like extensions containing the activating receptor KIR. At the T cell immune synapse, they observed the dynamic movement of proteins at the center of the immune synapse and found spatial segregation of microclusters of signaling molecules. His work was presented in the session entitled "Visualizing the Complexity at the Cellular Level (II)."

Rachel Evans, a student in Nancy Hogg's lab at the London Research Institute, won second place for her work on signaling by the integrin LFA-1 in migrating T cells. With confocal microscopy and immunofluorescence and biochemical and siRNA assays, they showed that LFA-1 and the kinases ZAP-70 and Lck associate and are involved in T cell migration. Her work was presented in the session "Visualizing Immune System Complexity at the Molecular Level (II)."

Stefanie Siegert, a student in Sanjiv Luther's lab at the University of Lausanne, won third place for her work in reconstructing a lymph node in vitro. They have created an immortalized mouse T zone reticular cell line and have grown these cells in a collagen-containing sponge where the cells form a characteristic reticular network. The goal is to have an ex vivo experimental system in which immune cells can be introduced and exposed to various conditions and then more easily monitored than can be done in vivo. For example, T cells and dendritic cells could be introduced into this in vitro lymph node to study T cell priming events. Her work was presented in the session entitled "Visualizing Immune System Complexity in the Whole Organism."

  1. M. L. Dustin, Visualizing Immune System Complexity. Sci. Signal. 2, mr4 (2009). [Abstract] [Full Text]

Lily Jan Honored at Neuroscience Meeting

Nov 23 2009 6:34AM

Science Signaling Editors

The editors congratulate Science Signaling Editorial Board member Lily Jan on receiving the Ralph W. Gerard Prize in Neuroscience. This annual award recognizes outstanding contributions to the field of neuroscience and was awarded to Lily Jan and Yuh Nung Jan on 20 October 2009 at the Society for Neuroscience annual meeting in Chicago, Illinois.

Joseph Schlessinger Honored at the American Association for Cancer Research (AACR) Annual Meeting

Apr 29 2010 8:14AM

Science Signaling Editors

The editors congratulate Science Signaling Editorial Board member Joseph Schlessinger on receiving the Pezcoller Foundation-AACR International Award for Cancer Research. This annual award recognizes an active scientist who has made a major contribution to basic or translational cancer research. Schlessinger accepted the award on 19 April 2010 at the AACR 101st Annual Meeting in Washington, DC.

Highlights from Cell Signaling Networks 2011

Jan 27 2012 11:07AM

Nancy R. Gough

In October 2011, organizers Fernando López-Casillas, José Vázquez-Prado, and Teresa Hernández-Sotomayor assembled an impressive cast of scientists to present their work and insights into the progressing field of signal transduction. The CSN 2011 meeting was a joint effort of the 13th International Union of Biochemistry and Molecular Biology (IUBMB) Conference, the 1st Panamerican Association for Biochemistry and Molecular Biology (PABMB) Conference and the 3rd Meetings of the Signal Transduction Branch and Oxidative Stress Branches of the Sociedad Mexicana de Bioquímica (SMB) and took place on 22-27 October 2011 in Mérida, Mexico, an area of Mexico rich in Mayan culture. As one of the organizers explained, Mérida was chosen because one of the goals of the IUBMB is to be the "science Robin Hood" and take science where it is well developed to places where it is less so.

The talks included overviews of major emerging themes in signaling research, as well as detailed, specific presentations during the concurrent sessions. Many of the speakers gave excellent overviews in their areas of expertise, as well as describing some of their newer work, which made the meeting a great one for younger scientists who are still learning the field and for the established scientists interested in the latest findings. Over the course of the next few weeks, I will post some of my notes with highlights from selected plenary symposia. Other attendees are encouraged to fill in any gaps by submitting their own comments on topics from the meeting that are not covered here or who took away a different message from one of the talks or posters.

Click "Next Message" to read the posted highlights.

Just click "Post a Response" to submit. Submission requires free registration.

Selected Symposia Related to Signaling in Disease at CSN 2011

Jan 30 2012 10:21AM

Nancy R. Gough

Joan Massagué (Memorial Sloan-Kettering Cancer Center, New York, NY) kicked off the scientific meeting by discussing his lab’s work on the role of transforming growth factor β (TGF-β) in stem cells and cancer. He argues that in embryonic stem cells, certain master regulators of cell fate are “poised” for response to TGF-β stimulation, but not fully inaccessible. This is in contrast to “homeostatic” genes, which are fully accessible. TGF-β signaling is mediated through activation of transcriptional regulators of the Smad family. Most Smads interact with the common Smad, Smad4, but TRIM33 is an alternative to Smad4 in some protein complexes containing Smad2 or Smad3 (Smad2/3), leading to complex combinatorial gene regulation profiles. Some genes require both TRIM33-Smad2/3 and Smad4-Smad2/3 complexes for activation, whereas others and require only one or the other. The master regulatory genes require both complexes.

In addition to Smads, TRIM33 also binds acetylated and methylated histones at “poised” genes. Separate TRIM33-Smad2/3 and Smad4-Smad2/3 complexes bind to the promoters of master regulator genes, and it appears that the TRIM33-Smad2/3 complex promotes binding of the Smad4-Smad2/3 complex. Thus, TRIM33 and Smad4 appear to coordinately activate master regulators of cell fate. This may relate to cancer in that TGF-β may act as a tumor suppressor by promoting differentiation and thus eliminating “stemness.” In some cancers, the cancer cells exhibit corruption of the pathway through which TGF-β promotes differentiation to act as a tumor supporessor and instead allows TGF-β signaling to promote cell survival and metastasis. Therefore, it would be better to target the genes that enable the cells to be stimulated by TGF-β, rather than TGF-β itself.

Related Reading
Q. Xi, Z. Wang, A. I. Zaromytidou, X. H. Zhang, L. F. Chow-Tsang, J. X. Liu, H. Kim, A. Barlas, K. Manova-Todorova, V. Kaartinen, L. Studer, W. Mark, D. J. Patel, J. Massagué, A poised chromatin platform for TGF-β access to master regulators. Cell 147, 1511-1524 (2011). [PubMed]

T. Oskarsson, S. Acharyya, X. H. Zhang, S. Vanharanta, S. F. Tavazoie, P. G. Morris, R. J. Downey, K. Manova-Todorova, E. Brogi, J. Massagué, Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs. Nat Med. 17, 867-874 (2011). [PubMed]

J. Massagué, TGFβ in cancer. Cell 134, 215-230 (2008). [PubMed]

W. He, D. C. Dorn, H. Erdjument-Bromage, P. Tempst, M. A. Moore, J. Massagué, Hematopoiesis controlled by distinct TIF1γ and Smad4 branches of the TGFβ pathway. Cell 125, 929-941 (2006). [PubMed]

Related Resources in Science Signaling
L. Mishra, K. Kitisin, T. Saha, T. Blake, N. Golestaneh, M. Deng, C. Kim, Y. Tang, K. Shetty, B. Mishra, TGF-β signaling in development. Sci. Signal. (Connections Map in the Database of Cell Signaling, as seen 20 January 2012). [Canonical Pathway]

A. Atfi, R. Baron, p53 brings a new twist to the Smad signaling network. Sci. Signal. 1, pe33 (2008). [Abstract] [Full Text]


Gokhan Hotamisligil (Harvard School of Public Health, Boston, MA) talked about obesity, which he called “the 21st century’s chronic disease plague,” emphasizing the relationship between inflammation and obesity. He calls the kind of inflammatory response associated with obesity “metainflammation”, because it is associated with the general condition of reduced metabolic activity, rather than localized swelling, redness, and heat associated with classical inflammation.

Obesity is associated with increased (tumor necrosis factor-α) TNF-α production by fat cells and stromal cells. When the gene encoding TNF-α is knocked out, mice exhibit improved glucose tolerance; and when inflammatory signaling is inhibited in human patients, there is also improved glucose handling. Insulin receptor signaling is inhibited by (i) classic inflammatory mediators, like TNF-α and IL-1, (evolutionarily this may be because an infected animal needs to redirect nutrients and metabolic processes to fighting infection, not cell growth and other processes responsive to insulin), (ii) nutrients, which stimulate inflammatory signaling and the inflammasome directly, and (iii) internal stress as indicated by the endoplasmic reticulum (ER) stress response, also called the unfolded protein response (UPR).

UPR is activated in obese animals, especially in the liver. UPR is connected to inflammatory signaling through the kinases JNK and IKK. Limited clinical trials suggest that alleviation of UPR may be helpful in treating diabetes. Analysis of protein abundance in livers from lean and obese mice suggests that the ER chaperone adaptive response may be defective, because there are more components of lipid synthesis machinery and autophagic degradation machinery in the obese animal livers without a concomitant increase in ER chaperones.

Analysis of the abundance of the lipids in lean and obese mouse livers showed that the ratio of phosphatidylcholine (PC) to phosphatidylethanolamine (PE) was higher in the obese animals. This altered lipid composition could affect the activities of integral membrane proteins, like calcium channels and the ER-localized calcium pump SERCA. When the PC/PE ratio is too high, SERCA is inhibited in vitro and in vivo. Treatments that reduce the PC/PE ratio or induce expression of an alternate isoform of SERCA (SERCA2b) result in improved glucose tolerance, reduced UPR, and better calcium handling in the liver ER.

Related Reading
L. P. Bechmann, R. A. Hannivoort, G. Gerken, G. S. Hotamisligil, M. Trauner, A. Canbay, The interaction of hepatic lipid and glucose metabolism in liver diseases. J. Hepatol. Epub ahead of print 13 Dec 2011. [PubMed]

S. Fu, L. Yang, P. Li, O. Hofmann, L. Dicker, W. Hide, X. Lin, S. M. Watkins, A. R. Ivanov, G. S. Hotamisligil, Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity. Nature 473, 528-531 (2011). [PubMed]

F. Engin, G. S. Hotamisligil, Restoring endoplasmic reticulum function by chemical chaperones: An emerging therapeutic approach for metabolic diseases. Diabetes Obes Metab. Suppl 2, 108-115 (2010). [PubMed]

G. S. Hotamisligil, Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell 140, 900-917 (2010). [PubMed]

Related Resources in Science Signaling
Y. Qiu, T. Mao, Y. Zhang, M. Shao, J. You, Q. Ding, Y. Chen, D. Wu, D. Xie, X. Lin, X. Gao, R. J. Kaufman, W. Li, Y. Liu, A Crucial Role for RACK1 in the Regulation of Glucose-Stimulated IRE1 Activation in Pancreatic β Cells. Sci. Signal. 3, ra7 (2010). [Abstract] [Full Text]

D. L. Eizirik, M. Cnop, ER Stress in Pancreatic β Cells: The Thin Red Line Between Adaptation and Failure. Sci. Signal. 3, pe7 (2010). [Abstract] [Full Text]

V. Mieulet, L. Yan, C. Choisy, K. Sully, J. Procter, A. Kouroumalis, S. Krywawych, M. Pende, S. C. Ley, C. Moinard, R. F. Lamb, TPL-2–mediated activation of MAPK downstream of TLR4 signaling is coupled to arginine availability. Sci. Signal. 3, ra61 (2010). [Abstract] [Full Text]


M. Angela Nieto (Instituto de Neurociencias, San Juan de Alicante, Spain) presented an overview of the role of the transcription factor Snail in epithelial-to-mesenchymal transition (EMT) and how Snail may contribute to cancer. Snail controls EMT during development and becomes reactivated in invasive cells in tumors (both in mouse models and in human cancers), where it represses E-cadherin expression. EMT is "reversible" in the embryo – some cells can undergo EMT, migrate to their destinations, then undergo MET (mesechymal-to-epithelial transition), and this phenotype switching can happen multiple times. EMT is also important for wound healing and tissue regeneration.

Snail has been implicated in renal failure and fibrotic kidney disease. Human patients with renal fibrosis have very high amounts of Snail in the kidney. Removing Snail specifically in the kidneys markedly reduced kidney inflammation and fibrosis in a mouse model of obstructive ureter disease. Snail activation in the adult kidney is associated with altered cellular morphology, induction of markers of mesenchyme and of renal fibrosis, and can lead to renal failure. If fibrosis is triggered by Snail induction in mice and then Snail induction is stopped, the fibrosis in the kidney is reduced and organ function improves. Thus, Snail is involved in both cancer invasivenes and diseases associated with tissue fibrosis.

Related Reading
M. A. Nieto, Epithelial-Mesenchymal Transitions in development and disease: old views and new perspectives. Int J Dev. Biol. 53, 1541-1547 (2009). [PubMed]

A. Boutet, M. A. Esteban, P. H. Maxwell, M. A. Nieto, Reactivation of Snail genes in renal fibrosis and carcinomas: a process of reversed embryogenesis? Cell Cycle. 6, 638-642 (2007). [PubMed]

Boutet A, De Frutos CA, Maxwell PH, Mayol MJ, Romero J, Nieto MA, Snail activation disrupts tissue homeostasis and induces fibrosis in the adult kidney. EMBO J. 25, 5603-5613 (2006). [PubMed]

Related Resources in Science Signaling
D. Iliopoulos, C. Polytarchou, M. Hatziapostolou, F. Kottakis, I. G. Maroulakou, K. Struhl, P. N. Tsichlis, MicroRNAs differentially regulated by Akt isoforms control EMT and stem cell renewal in cancer cells. Sci. Signal. 2, ra62 (2009). [Abstract] [Full Text]

S. Stinson, M. R. Lackner, A. T. Adai, N. Yu, H.-J. Kim, C. O’Brien, J. Spoerke, S. Jhunjhunwala, Z. Boyd, T. Januario, R. J. Newman, P. Yue, R. Bourgon, Z. Modrusan, H. M. Stern, S. Warming, F. J. de Sauvage, L. Amler, R.-F. Yeh, D. Dornan, TRPS1 Targeting by miR-221/222 Promotes the Epithelial-to-Mesenchymal Transition in Breast Cancer. Sci. Signal. 4, ra41 (2011). [Abstract] [Full Text]

A. Ruiz i Altaba, Hedgehog signaling and the Gli code in stem cells, cancer, and metastases. Sci. Signal. 4, pt9 (2011). [Abstract] [Full Text] [Slideshow]

S. Stinson, M. R. Lackner, A. T. Adai, N. Yu, H.-J. Kim, C. O’Brien, J. Spoerke, S. Jhunjhunwala, Z. Boyd, T. Januario, R. J. Newman, P. Yue, R. Bourgon, Z. Modrusan, H. M. Stern, S. Warming, F. J. de Sauvage, L. Amler, R.-F. Yeh, D. Dornan, miR-221/222 targeting of Trichorhinophalangeal 1 (TRPS1) promotes epithelial-to-mesenchymal transition in breast cancer. Sci. Signal. 4, pt5 (2011). [Abstract] [Full Text] [Slideshow]

Y.-G. Yoo, J. Christensen, J. Gu, L. E. Huang, HIF-1α mediates tumor hypoxia to confer a perpetual mesenchymal phenotype for malignant progression. Sci. Signal. 4, pt4 (2011). [Abstract] [Full Text] [Slideshow]


J. Silvio Gutkind (National Institute of Dental and Craniofacial Research, Bethesda, MD) described his lab’s work on targeting virally-encoded G protein-coupled receptors (GPCRs) or chemokine receptor signaling as a means to target cancer. GPCRs and G proteins can be oncogenes, and . vViruses, such as Kaposi's sSarcoma-associated hHerpesvirus (KSHV), encode active vGPCRs. KPSV is a common tumor-inducing virus in immune-compromised patients. The KSHV vGPCR activates the target of rapamycin (TOR) pathway through phosphoinositide 3-kinase γ (PI3Kγ), and blocking this pathway with rapamycin reduced tumor growth.

Chemokine receptors are GPCRs and can be used by cancer cells to mediate migration. The receptor CXCR4 is a GPCR that promotes migration toward a source of its chemokine ligand, SDF-1. In cancer cells, the promigratory signal may occur through atypical G protein coupling - that is, these receptors may couple to a different G protein than the one they typically use in noncancerous or other cells. His lab used G protein receptors activated solely by artificial ligands (Gi RASSL) to identify a pathway from CXCR4 to the Rho kinase ROCK through Gα12/13, which promoted migration of cancer cells. Based on studies with xenografted tumors in mice, disruption of this pathway may be effective at preventing metastasis. Some of this work was published in the 20 September 2011 issue of Science Signaling.

Related Reading
D. Martin, R. Galisteo, A. A. Molinolo, R. Wetzker, E. Hirsch, J. S. Gutkind, PI3Kγ mediates kaposi's sarcoma-associated herpesvirus vGPCR-induced sarcomagenesis. Cancer Cell 19, 805-813 (2011). [PubMed]

A. Sodhi, R. Chaisuparat, J. Hu, A. K. Ramsdell, B. D. Manning, E. A. Sausville, E. T. Sawai, A. Molinolo, J. S. Gutkind, S. Montaner, The TSC2/mTOR pathway drives endothelial cell transformation induced by the Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor. Cancer Cell 10, 133-143 (2006). [PubMed]

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H. Yagi, W. Tan, P. Dillenburg-Pilla, S. Armando, P. Amornphimoltham, M. Simaan, R. Weigert, A. A. Molinolo, M. Bouvier, J. S. Gutkind, A synthetic biology approach reveals a CXCR4-G13-Rho signaling axis driving transendothelial migration of metastatic breast cancer cells. Sci. Signal. 4, ra60 (2011). [Abstract] [Full Text]

J. S. Gutkind, A. M. VanHook, Science Signaling podcast: 20 September 2011. Sci. Signal. 4, pc19 (2011). [Abstract] [Podcast]

E. Slinger, D. Maussang, A. Schreiber, M. Siderius, A. Rahbar, A. Fraile-Ramos, S. A. Lira, C. Söderberg-Nauclér, M. J. Smit, HCMV-encoded chemokine receptor US28 mediates proliferative signaling through the IL-6–STAT3 axis. Sci. Signal. 3, ra58 (2010). [Abstract] [Full Text]

C. T. Veldkamp, C. Seibert, F. C. Peterson, N. B. De la Cruz, J. C. Haugner, III, H. Basnet, T. P. Sakmar, B. F. Volkman, Structural basis of CXCR4 sulfotyrosine recognition by the chemokine SDF-1/CXCL12. Sci. Signal. 1, ra4 (2008). [Abstract] [Full Text]


Richard Flavell (Yale University School of Medicine) described an elegant genetic dissection of the role of the innate immune signaling pathway mediated by inflammosomes in regulation of the intestinal microflora. Nod-like receptors (NLRs) constitute an intracellular arm of the innate immune system that detects the consequences of pathogen infection or cellular damage. The Nod family includes NOD (nucleotide-binding oligomerization domain), IPAF (ICE protease activating factor), and NLRP (Nod-like receptor protein) and in mammals there are more than 35 genes encoding members of this family. Nod proteins have a leucine-rich repeat (LRR), a nucleotide-binding domain, and a protein interaction domain (either a pyrin domain or a caspase recruitment domain) and, through the formation of the inflammasome, they activate caspase 1, which in turn activates the proinflammatory mediators interleukin-1β (IL-1β) and IL-18. For example, NLRP3 is an NLR with a pyrin domain that recognizes viral and bacterial pathogens, Plasmodium, and fungi, as well as environmental toxins (silica, asbestos, the vaccine adjuvant alum) and endogenous mediators (ATP, uric acid, b-amyloid, cholesterol crystals, DNA, and RNA).

After this introduction to the inflammasome and the NLRs, he discussed his lab’s investigation into the role of NLRP6 and the inflammasome in the regulation of the response to intestinal microbes. The intestinal microflora are essential for metabolism, nutrient absorption, and production of vitamins. They found that mice deficient in NLRP6 or the inflammasome response exhibited an altered intestinal flora that could be spread to wild-type mice housed in the same cage. This altered intestinal flora made the mice more susceptible to chemically induced colitis.

Using an elegant genetic analysis, he defined a pathway in the colonic epithelium from NLRP6 to the inflammasome to caspase 1 to IL-18, which was important for regulating the bacterial composition of the intestine. When wild-type mice were housed with mice in which this pathway was compromised, the wild-type mice became more susceptible to chemically induced colitis. The inflammasome-compromised mice transmitted “contagious” colitis to their wild-type cage mates (remember that mice are coprophagic). The bacteria responsible for the transmissible colitis were determined through sequence analysis.

Related Reading
E. Elinav, T. Strowig, J. Henao-Mejia, R. A. Flavell, Regulation of the antimicrobial response by NLR proteins. Immunity 34, 665-679 (2011). [PubMed]

E. Elinav, T. Strowig, A. L. Kau, J. Henao-Mejia, C. A. Thaiss, C. J. Booth, D. R. Peaper, J. Bertin, S. C. Eisenbarth, J. I. Gordon, R. A. Flavell, NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 145, 745-757 (2011). [PubMed]

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E. M. Adler, Allies from within. Sci. Signal. 1, ec204 (2008). [Abstract]

K. L. Mueller, A gut feeling. Sci. Signal. 3, ec194 (2010) [Abstract]

W.-J. Lee, Bacterial-modulated signaling pathways in gut homeostasis. Sci. Signal. 1, pe24 (2008). [Abstract] [Full Text]

Highlights of Selected Talks Related to Posttranslational Modifications in Cell Signaling

Feb 6 2012 7:48AM

Nancy R. Gough

Tony Hunter (Salk Institute for BiologicalStudies) provided an overview of protein phosphorylation and other posttranslational modificationsthat are important for mediating signal transduction and cellular regulation. He discussed the effect of cancer-associated mutations in kinases and how to decide whether these are good candidates for development of inhibitors. Itturns out that many are tumor suppressors and, therefore,not good candidates for the development of inhibitors foroncogenic therapies.

Another theme of his talk was the chemistry ofphosphorylation and why this posttranslational modificationis particularly suitable for biological systems. He notedthat it is important to recognize that phosphomimeticmutations in proteins may not always truly mimicphosphorylated residues due to major differences in the chemistry. He also reminded the audience that kinases canwork in reverse and that it is the high ATP/ADP ratio inbiological systems that drives the reaction in thedirection of protein phoshorylation and not ATP generation through dephosphorylation of the protein.

Related Reading
J. Brognard, Y. W. Zhang, L. A. Puto, T. Hunter, Cancer- associated loss-of-function mutations implicate DAPK3 as atumor-suppressing kinase. Cancer Res.71, 3152-3161 (2011). [PubMed]

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A. S. Little, K. Balmanno, M. J. Sale, S. Newman, J. R.Dry, M. Hampson, P. A. W. Edwards, P. D. Smith, S. J. Cook,Amplification of the Driving Oncogene, KRAS or BRAF,Underpins Acquired Resistance to MEK1/2 Inhibitors inColorectal Cancer Cells. Sci. Signal.4, ra17 (2011). [Abstract] [Full Text]

R. B. Corcoran, D. Dias-Santagata, K. Bergethon, A. J.Iafrate, J. Settleman, J. A. Engelman, BRAF GeneAmplification Can Promote Acquired Resistance to MEKInhibitors in Cancer Cells Harboring the BRAF V600EMutation. Sci. Signal. 3,ra84 (2010). [Abstract] [Full Text]

N. R. Gough, J. F. Foley, Focus Issue: Systems Analysisof Protein Phosphorylation. Sci. Signal.3, eg6 (2010). [Abstract] [Full Text]

A. Moritz, Y. Li, A. Guo, J. Villén, Y. Wang, J.MacNeill, J. Kornhauser, K. Sprott, J. Zhou, A. Possemato,J. M. Ren, P. Hornbeck, L. C. Cantley, S. P. Gygi, J. Rush,M. J. Comb, Akt-RSK-S6 Kinase Signaling Networks Activatedby Oncogenic Receptor Tyrosine Kinases. Sci.Signal. 3, ra64 (2010). [Abstract] [Full Text]

GeraldHart (Johns Hopkins Medical School) described theposttranslational modification of O-GlcAcylation and the crosstalk between this modification and phosphorylation. O- GlcNAcylation is a reversible modification mediated by O- GlcNAc transferase (OGT), which adds this modification totarget proteins, and glycanase, which removes it. This areaof biology is relatively understudied because of thetechnical challenges associated with detecting this modification; thus, relatively little is known about theregulation of the enzymes that control this modification,and few large-scale studies of the occurrence of thismodification and its biological consequences have been done. It is likely that the dynamic turnover of this modificationis more important than the absolute stoichometry of themodification.

O-GlcNAcylation is regulated by nutrient status, and theO-GlcAcylation of proteins is often reciprocal withphosphorylation. For example, in RNA polymerase II, thereare initially many O-GlcNAc groups added to the C-terminaldomain, and these have to be removed and then replaced withphosphate groups for the polymerase to mediatetranscription. Histones are also O-GlcNAcylated, and atleast one modification is located where the histonecontacts DNA, begging the question of whether this could beanother part of the histone code. A dynamic interplay between O-GlcNAcylation and phosphorylation occurs duringthe cell cycle. O-GlcNAcylation of kinases can change theirspecificity or kinetics as compared to the phosphorylated form of the kinase.

Related Reading
M. K. Tarrant, H.-S. Rho, Z. Xie, Y. L. Jiang, C. Gross, J. Qian, Y. Ichikawa, T. Matsuoka, N. Zachara, F. Etzkorn, G. W. Hart, J.-S. Jeong, S. Blackshaw, H. Zhu, P. A. Cole, Regulation of CK2 by phosphorylation and O-GlcNAcylation revealed by semisynthesis. Nat. Chem. Biol.. 2012 Jan 22. doi: 10.1038/nchembio.771. [Epub ahead of print] [PubMed]

K. Sakabe, Z. Wang, G. W. Hart, β-N-acetylglucosamine (O-GlcNAc) is part of the histone code. Proc. Natl. Acad. Sci. U.S.A. 107, 19915-19920 (2010). [PubMed]

N. E. Zachara, K. Vosseller, G. W. Hart, Detection andanalysis of proteins modified by O-linked N- acetylglucosamine. Current ProtocolsProtein Sci. UNIT 12.8.1-12.8.33 (2011). [PubMed]

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D. Mariappa, K. Sauert, K. Mariño, D. Turnock, R.Webster, D. M. F. van Aalten, M. A. J. Ferguson, H.- A. J.Müller, Protein O-GlcNAcylation Is Required for Fibroblast Growth Factor Signaling in Drosophila. Sci. Signal. 4, ra89 (2011). [Abstract] [Full Text]

Z. Wang, N. D. Udeshi, C. Slawson, P. D. Compton, K.Sakabe, W. D. Cheung, J. Shabanowitz, D. F. Hunt, G. W.Hart, Extensive Crosstalk Between O-GlcNAcylation and Phosphorylation Regulates Cytokinesis. Sci. Signal. 3, ra2 (2010). [Abstract] [Full Text]

D. C. Love, J. A. Hanover, The Hexosamine SignalingPathway: Deciphering the "O-GlcNAc Code". Sci. STKE 2005, re13(2005). [Abstract] [Full Text]

Federico Mayor, Jr.  (Universidad Autónoma de Madrid) presented results from his lab's investigation into the functions of G protein-coupled receptor (GPCR) kinase 2 (GRK2), especially on those functions that are not related to desensitization of GPCRs. He described how GRK2 may contribute to epithelial cell migration by promoting histone deacetylase 6 (HDAC6)-mediated deactylation of tubulin; phosphorylation of HDAC6 by GRK2 promotes its deacetylase activity. The ability of GRK2 to target HDAC6 is regulated by extracellular signal regulated kinase (ERK)1/2 in response to epidermal growth factor (EGF). It appears that EGF signaling redirects GRK2 away from GPCRs and toward HDAC6, which enhances cell motility. However, the role of GRK2 in chemoattraction may be more complex, because GRK2 activity toward chemokine receptors initially decreases migration. Thus, open questions remain regarding whether there is a temporal aspect to GRK2 signaling or whether GRK2 is serving as an integrator of multiple signals.

GRK2 has also been implicated in vasculogenesis andangiogenesis. When GRK2 is reduced in mice (GRK2+/-), TGF-β signaling is shifted tofavor that mediated by the TGF-β receptor ALK5. Thus,GRK2 appears to serve as a switch in the TGF-βcascade. GRK+/- and GRK2-/- mice show impaired angiogenesis duringdevelopment, which may explain the embryonic lethality ofthe knockout animals and also the impaired angiogenesis ofxenografted tumors.

Related Reading
V. Lafarga, I. Aymerich, O. Tapia, F. Mayor Jr, P.Penela, A novel GRK2/HDAC6 interaction modulates cell spreading and motility. EMBO J. 2011 Dec23. doi: 10.1038/emboj.2011.466. [Epub ahead of print] [PubMed]

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K. N. Nobles, K. Xiao, S. Ahn, A. K. Shukla, C. M. Lam,S. Rajagopal, R. T. Strachan, T.-Y. Huang, E. A. Bressler,M. R. Hara, S. K. Shenoy, S. P. Gygi, R. J. Lefkowitz, Distinct Phosphorylation Sites on the β2-Adrenergic Receptor Establish a Barcode That Encodes Differential Functions of β-Arrestin. Sci. Signal. 4, ra51 (2011). [Abstract] [Full Text]

Highlights from the Society for Neuroscience Meeting 2012

Oct 31 2012 8:31AM

Nancy R. Gough

This year's meeting of the Society for Neuroscienceoccurred October 13-17 in New Orleans. Lily Jan (a member of theScience Signaling Board of Reviewing Editors) and herhusband Yuh Nung Jan received the 2012 Gruber Neuroscience Prize. They presented a historical review of theirlaboratory's work in neurodevelopment and dendritic structureand function studies (Y. N. Jan) and in channel cloning andbiology (L. Jan). In their 40 years, they have trained 128students and postdoctoral fellows and have contributed to ourunderstanding of the molecular mechanisms of neuraldevelopment and regulation of synaptic activity.

Highlights from Understanding Signaling Pathways in Cancer

Nov 20 2012 2:04PM

Leslie K Ferrarelli

On November 6th 2012, the Koch Institute at MIT and its sponsoring partner Cell Signaling Technology hosted a symposium entitled "UnderstandingSignaling Pathways in Cancer." Speaking to a standing room only crowd,leaders in the field of cell signaling research shared recent findings and developments. The main themes of the day focused on the role thatinterconnected signaling networks play in cancer metabolism and resistance to chemotherapeutics. Many speakers presented data showing how cancercells can dynamically rewire their signaling networks after drug-targetedkinase inhibition, which renders these cells resistant to continuedinhibitor use. Another theme was how nutrient sensing through mammaliantarget of rapamycin (mTOR) and other enzymes maintains metabolichomeostasis, and how these mechanisms are altered in cancer cells.Together, the presentations at the symposium highlighted just how critical it is that we tease out the complexity of cellular signaling if we are tohave a fighting chance against cancer.

Rewiring Signaling Networks to Evade Chemotoxicity

Nov 21 2012 9:57AM

Leslie K. Ferrarelli

Michael Yaffe (Koch Institute at MIT), organizer of the symposium, highlighted the shortcomings of the traditional approach to translating signaling knowledge into clinical therapies. He likened cell signaling networks to electrical circuitry: The phospho group is the current, and the kinase-driven phosphorylation cascades are the voltage. Electricians would not measure the current and voltage and assume that they know how the circuitry works or how to manipulate it; however, many current cancer strategies are based on monitoring one or a few phosphorylation events and targeting a single kinase without having knowledge of the entire network. These highly specific, kinase-directed strategies often ultimately fail, resulting in the rapid emergence of a drug-resistant tumor. Yaffe described how using a sequential approach to combination therapies exploited the ability of cancer cells to rewire their signaling circuitry by first "herding" the cells down a selected pathway with kinase inhibitors and then "clobbering" them with a lethal secondary hit, for example with a DNA-damaging agent.

Joan Brugge (Harvard Medical School), highlighting her laboratory’s work with three-dimensional (3D) cultures of ovarian cancer, described the resistance mechanisms in cancer. Exposure of tumor cells, growing as 3D spheroids with an internal group of cells that do not contact the extracellular matrix and an external layer of cells that contact extracellular matrix, to a phosphoinositide 3-kinase (PI3K) inhibitor resulted in death of the internal cells, but survival of the cells contacting the extracellular matrix. Subsequently, the outer cells exhibited network rewiring that allowed them to invade the tumor cavity and re-establish cells inside the tumor cavity, which could possibly represent not only a resistance mechanism, but also a mechanism for metastasis. She further described how an overlooked consequence of kinase inhibition is the loss of inhibitory feedback loops, thus activating adaptive antiapoptotic signaling and growth factor pathways. Brugge suggested that phosphoproteomic analysis of cancer cells after drug treatment may reveal specific combination therapies that could prevent cancer cells from mounting the adaptive response to kinase inhibition. Her work highlights the importance of targeting both and the signaling kinase and the adaptive stress response.

Jeffrey Settleman (Genentech) emphasized the importance of nongenetic means of chemotherapy resistance, that is resistance that does not involve genetic mutation. Culturing cancer cells for long periods in the presence of specific kinase inhibitors can produce drug-resistant clones, which have altered epigenetic chromatin modifications. He speculated that there may be intermediate states of drug resistance that can be reversed and that these may represent therapeutic "windows of opportunity." Thus, drugs that reverse or prevent these epigenetic changes (such as deacetylation and methylation) may be effective complements to kinase inhibition in treating cancer and reducing resistance. He also showed that the presence of various growth factors can influence the efficacy of kinase inhibitors in producing cell death of cultured cancer cells. Because secreted growth factors can be measured in plasma and these may represent mechanisms for subverting the toxicity of the targeted therapy, analysis of growth factor concentrations in patient’s circulation may present an opportunity for personalized treatment strategies. By targeting not only the kinase to which the cancer cells are “addicted” but other growth factor pathways that may rescue the cells from kinase inhibition, more effective combinations tailored to the individual may be created.

Michael Comb (President and CEO of Cell Signaling Technology) discussed current efforts to characterize the human "kinome," the array of posttranslational modifications and understand how these changes affect signaling networks. The initial studies involved analysis of phosphorylation in signaling pathways using antibodies specific for particular phosphorylated motifs to screen for changes in protein phosphorylation in response to kinase inhibition. Recent work has focused on other posttranslational modifications and how these change in response to kinase inhibition. Current efforts use a bidirectional approach, combining both DNA sequencing and protein mass spectrometry to identify the mutational changes and posttranslational modifications that converge on signaling pathways in cancer and disease.

Related Reading

M.J. Lee, A.S. Ye, A.K. Gardino, A.M. Heijink, P.K. Sorger, G. MacBeath, M.B. Yaffe, Sequential application of anticancer drugs enhances cell death by rewiring apoptotic signaling networks. Cell 149, 780-794 (2012). [PubMed]

J. T. Erler, R. Linding. Network medicine strikes a blow against breast cancer. Cell 149, 731-733 (2012). [PubMed]

J.R. Cantor, D.M. Sabatini, Cancer cell metabolism: One hallmark, many faces. Cancer Discovery 2, 1-18 (2012). [PubMed]

T. Muranen, L.M. Selfors, D.T. Worster, M.P. Iwanicki, L. Song, F.C. Morales, S. Gao, G.B.Mills, J.S. Brugge, Inhibition of PI3K/mTOR leads to adaptive resistance in matrix-attached cancer cells. Cancer Cell 21, 227-239 (2012). [PubMed]

R. Katayama, A.T. Shaw, T.M. Khan, M. Mino-Kenudson, B.J. Solomon, B. Halmos, N.A. Jessop, J.C. Wain, A. Tien Yeo, C. Benes, L. Drew, J.C. Saeh, K. Crosby, L.V. Sequist, A.J. Iafrate, J.A. Engelman, Mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers. Sci Transl Med. 4, 120ra17 (2012). [PubMed]

Related Resources in Science Signaling

B. Kholodenko, M. B. Yaffe, W. Kolch, Computational approaches for analyzing information flow in biological networks. Sci. Signal. 5, re1 (2012). [Abstract] [Full Text]

D.T. Worster, T. Schmelze, N.L. Solimini, E.S. Lightcap, B. Millard, G.B. Mills, J.S. Brugge, J.G. Albeck, Akt and ERK control the proliferative response of mammary epithelial cells to the growth factors IGF-1 and EGF through the cell cycle inhibitor p57Kip2. Sci. Signal. 5, ra19 (2012). [Abstract] [Full Text]

R.B. Corcoran, D. Dias-Santagata, K. Bergethon, A.J. Iafrate, J. Settleman, J.A. Engelman, BRAF gene amplification can promote acquired resistance to MEK inhibitors in cancer cells harboring the BRAF V600E mutation. Sci. Signal. 3, ra84 (2010). [Abstract] [Full Text]

A. Moritz, Y. Li, A. Guo, J. Villén, Y. Wang, J. MacNeill, J. Kornhauser, K. Sprott, J. Zhou, A. Possemato, J. M. Ren, P. Hornbeck, L. C. Cantley, S. P. Gygi, J. Rush, M. J. Comb, Akt-RSK-S6 kinase signaling networks activated by oncogenic receptor tyrosine kinases. Sci. Signal. 3, ra64 (2010). [Abstract] [Full Text]

P.A. Kiberstis. Smart Drugs, Smarter Tumors. Sci STKE 387, tw180 (2007). [Abstract]

J.F. Foley. Triple Therapy Targets Tumors. Sci. Signal. 5, ec291 (2012). [Abstract]

E.M. Adler, N.R. Gough. Focus Issue: Rendering Resistance Futile. Sci. Signal. 4, eg3 (2011). [Abstract] [Full Text]

Computational Approaches to Cancer Therapy

Nov 29 2012 10:56AM

Leslie K. Ferrarelli

Rune Linding (Technical University of Denmark) stated that we need to not consider the individual “node” in the network as the drug target, but rather we should consider the "network" as the drug target. To this end, his lab has been developing computational approaches to integrating genomic data and proteomic data to understand signaling networks in normal and disease states. Recognizing that traditional tumor sequencing identifies many "passenger" mutations, which do not drive the cancer and which cloud the identification of cancer drivers, Linding and colleagues have developed algorithms and online tools, such as NetworKIN and NetPhorest. Using these tools and genomics data, researchers can analyze the massive amounts of proteomics data and make predictions about the effects of kinase mutations on the structure and dynamics of the network. The key—but also the major challenge—to understanding the dynamic changes in signaling networks that drive cancer is to analyze data from tissue early during its carcinogenic transformation, because the early changes that drive cancer initiation are difficult to detect after the accumulation of other mutations in later stages of the disease.

Douglas Lauffenburger (MIT) is using a different approach that he referred to as “cue-signal-response” analysis, to model pathway dynamics. His lab’s approach relies on principle component analysis and uses partial least-squares discriminant analysis modeling to understand complex signaling networks and how their dysregulation contributes to complex diseases, such as inflammatory bowel disease. This method can be used to investigate how specific kinase mutations or inhibitors affect multiple signaling pathways through crosstalk. In the case of cancer, this computational approach may ultimately enable the identification of effective therapeutic targets on the basis of the genetic profile of the tumor. Diseases under investigation with collaborators in multiple institutions include chronic intestinal inflammation, endometriosis, Alzheimer’s disease, and AIDS.

Related Reading

P. Creixell, E. M. Schoof, J. T. Erler, R. Linding, Navigating cancer network attractors for tumor-specific therapy. Nat Biotechnol. 30, 842-848 (2012). [PubMed]

K. S. Lau, V. Cortez-Retamozo, S. R. Philips, M. J. Pitet, D. A. Lauffenburger, K. M. Haigis, Multi-scale in vivo systems analysis reveals the influence of immune cells on TNF-α-induced apoptosis in the intestinal epithelium. PLoS Biol. 10, e1001393 (2012). [PubMed]

Related Resources in Science Signaling

M. L. Miller, L. J. Jensen, F. Diella, C. Jørgensen, M. Tinti, L. Li, M. Hsiung, S. A. Parker, J. Bordeaux, T. Sicheritz-Ponten, M. Olhovsky, A. Pasculescu, J. Alexander, S. Knapp, N. Blom, P. Bork, S. Li, G. Cesareni, T. Pawson, B. E. Turk, M. B. Yaffe, S. Brunak, R. Linding, Linear Motif Atlas for Phosphorylation-Dependent Signaling. Sci. Signal. 1, ra2 (2008). [Abstract] [Full Text]

C. S. H. Tan, B. Bodenmiller, A. Pasculescu, M. Jovanovic, M. O. Hengartner, C. Jørgensen, G. D. Bader, R. Aebersold, T. Pawson, R. Linding, Comparative Analysis Reveals Conserved Protein Phosphorylation Networks Implicated in Multiple Diseases. Sci. Signal. 2, ra39 (2009). [Abstract] [Full Text]

I. J. Farkas, T. Korcsmáros, I. A. Kovács, Á. Mihalik, R. Palotai, G. I. Simkó, K. Z. Szalay, M. Szalay-Beko, T. Vellai, S. Wang, P. Csermely, Network-Based Tools for the Identification of Novel Drug Targets. Sci. Signal. 4, pt3 (2011). [Abstract] [Full Text]

K. S. Lau, A. M. Juchheim, K. R. Cavaliere, S. R. Philips, D. A. Lauffenburger, K. M. Haigis, In vivo systems analysis identifies spatial and temporal aspects of the modulation of TNF-α–induced apoptosis and proliferation by MAPKs. Sci. Signal. 4, ra16. (2011). [Abstract] [Full Text]

N. R. Gough, W. Wong, Focus Issue: The Evolution of Complexity. Sci. Signal. 3, eg5 (2010). [Abstract] [Full Text]

Linking Cancer and Metabolism

Dec 7 2012 12:44PM

Leslie K. Ferrarelli

Lewis Cantley (Weill Cornell Medical College) divided his talk into three parts: an introduction to the mTOR pathway, a discussion of the role of AMPK and Akt in regulation of metabolism, and a discussion of why type II diabetes may be associated with increased cancer risk. It seems that in metabolism and cell growth, all roads lead to mammalian target of rapamycin (mTOR). In particular, the mTOR complex 1 (mTORC1) functions as a critical logic gate so that cells only grow when there are sufficient nutrients (sensed through the Rag proteins to activate mTOR), growth factors [sensed by receptor tyrosine kinases (RTKs) that signal through phosphoinositide 3-kinase (PI3K) to activate mTOR], and ATP [sensed by AMP-regulated kinase (AMPK)]. Cantley noted that 80% of mutated genes currently identified in cancers encode signaling proteins involved in the RTK-PI3K-Akt-Ras-AMPK-mTOR pathway, and that PI3K-driven cancers are dependent on enhanced glucose metabolism. In this pathway, Akt and AMPK function in opposition to produce long-term effects on metabolism and growth that are mediated through changes in transcription. In contrast, for the acute regulation of metabolism, Akt and AMPK work in concert. He then described his lab’s work on a molecular mechanism through which AMPK inhibits degradation of glucose transporters during periods of acute energy stress. Although the mTOR network holds a key to cancer treatment, learning how to effectively target it is challenging, due to the multiple pathways through which mTOR can be activated and the rewiring that occurs in cancer cells.

Intriguingly, the high association of cancer with type II diabetes may be rooted in the misguided (albeit well-intentioned) treatment of patients with insulin to overcome insulin resistance. In many type II diabetes patients, circulating insulin and the related hormone IGF-1 are high because of the adaptive changes resulting from the loss of tissue responsiveness to insulin. Because insulin drives PI3K signaling, treatment of diabetes with insulin would provide a tremendous growth signal to the tumor cells. To limit this cancer-diabetes connection, better strategies for treating type II diabetes are to target metabolism, such as AMPK, a component of the mTOR pathway, or to target proteins that improve the tissue responsiveness to insulin, such as the transcriptional regulator PPARγ.

David Sabatini (Whitehead Institute, MIT) continued the theme of complexity in the mTOR network by showing that mTOR is not only regulated by most, if not all, external cues (such as nutrients, growth factors, mitogens, and hormones), but in turn regulates numerous key metabolic and growth pathways. He described his lab’s efforts to understand how the Rag family of guanosine triphosphatases (GTPases) enable mTORC1 activation by amino acids and described how mTORC1 makes the lysosome an intracellular metabolic-sensing organelle. The Rag proteins function as a complex, containing either Rag A or B with either Rag C or D, and the specific activated GTPase affects the function of the complex. For example, RagB-GDP/RagD-GTP does not bind to mTORC1, but RagB-GTP/RagD-GDP does. In the presence of amino acids, Rag proteins recruit mTORC1 to the surface of lysosomes, where the other GTPase that activates mTORC1 in response to both growth factors and sufficient energy supplies is found. Rag proteins themselves may shuttle on and off the lysosome, and the four possible states of this dimeric complex may be involved in its ability to recruit and transport mTORC1 to the lysosome. His lab is investigating how amino acids stimulate the lysosomally localized mTORC1 using isolated lysosome preparations. His lab is also trying to understand the connection between lysosomal function, mTORC1, and autophagy by examining RagA-GTP knock-in mice, which die postnatally and cannot initiate autohpagy, suggesting that autophagy is required to produce cell nutrients prior to suckling. Thus, not only is mTORC1 central to cancer metabolism, but is likely also critical for early postnatal survival through regulation of metabolism by influencing lysosomal activity and autophagy.

William Kaelin (Dana-Farber Cancer Institute) highlighted work in "oncometabolites," which are products of metabolism that can promote cancer. He described the conundrum that the transcription factor hypoxia-inducible factor 1α (HIF-1α), which enables cells to adapt to a low oxygen environment, is typically considered oncogenic, but in some cancers HIF-1α appears to function as a tumor suppressor. In particular, cancers with mutant forms of isocitrate dehydrogenase (IDH), which would produce large amounts of 2-hydroxyglutarate (2-HG), exhibit reduced abundance of HIF-1α. 2-HG affects the activity of enzymes in the 2-oxoglutarate-dependent dioxygenase family, which includes the histone demethylase JmjC and the prolyl hydroxylase PHD (also known as EGLN) family, the latter of which reduce the abundance of HIF-1α protein by marking it for proteasomal degradation. 2-HG is not the only “oncometabolite”; in cancers with mutations in various metabolic enzymes, such as succinate dehydrogenase (SDH), fumarate hydratase (FH), or isocitrate dehydrogenase (IDH), large amounts of endogenous metabolites accumulate (fumarate, succinate, and 2-HG, respectively) and these each influence carcinogenesis or cancer cell metabolism to confer a growth advantage.

Related Reading

H. Ying, A. C. Kimmelman, C. A. Lyssiotis, S. Hua, G. C. Chu, E. Fletcher-Sananikone, J. W. Locasale, J. Son, H. Zhang, J. L. Coloff, H. Yan, W. Wang, S. Chen, A. Viale, H. Zheng, J. H. Paik, C. Lim, A. R. Guimaraes, E. S. Martin, J. Chang, A. F. Hezel, S. R. Perry, J. Hu, B. Gan, Y. Xiao, J. M. Asara, R. Weissleder, Y. A. Wang, L. Chin, L. C. Cantley, R. A. DePinho, Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell 149, 656-70 (2012). [PubMed].

L. Bar-Peled, L. D. Schweitzer, R. Zoncu, D. M. Sabatini, Ragulator is a GEF for the RAG GTPases that signal amino acid levels to mTORC1. Cell 150, 1196-1208 (2012). [PubMed].

W. G. Kaelin, Jr. Cancer and altered metabolism: potential importance of hypoxia-inducible factor and 2-oxoglutarate-dependent dioxygenases. Cold Spring Harb Symp Quant Biol. 76, 335-45 (2011). [PubMed].

P. Koivunen, S. Lee, C. G. Duncan, G. Lopez, G. Lu, S. Ramkissoon, J. A. Losman, P. Joensuu, U. Bergmann, S. Gross, J. Travins, S. Weiss, R. Looper, K. L. Ligoon, R. G. Verhaak, H. Yan, W. G. Kaelin, Jr. Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation. Nature 483, 484-488 (2012). [PubMed].

Related Resources in Science Signaling

A. Roczniak-Ferguson, C. S. Petit, F. Froehlich, S. Qian, J. Ky, B. Angarola, T. C. Walther, S. M. Ferguson. The Transcription Factor TFEB Links mTORC1 Signaling to Transcriptional Control of Lysosome Homeostasis. Sci. Signal. 5, ra42. (2012). [Abstract] [Full Text].

N. R. Gough Focus Issue: Demystifying mTOR Signaling. Sci. Signal. 2, eg5. (2009). [Abstract] [Full Text].

D. A. Guertin, D. M. Sabatini, The Pharmacology of mTOR Inhibition. Sci. Signal. 2, pe24 (2009). [Abstract] [Full Text].