Editorial GuideCell Biology

2011: Signaling Breakthroughs of the Year

Science Signaling  03 Jan 2012:
Vol. 5, Issue 205, pp. eg1
DOI: 10.1126/scisignal.2002787


The editors of Science Signaling are pleased to start 2012 with our 10th compilation of the most exciting cell signaling research to emerge in the previous year. The Signaling Breakthroughs list is selected from articles nominated by members of the Science Signaling Editorial Board as providing major advances in cell signaling, particularly those that were unexpected or likely to open up new avenues of research. This edition includes breakthroughs in the structural analysis of signaling proteins, technological advances in imaging, and insights into the mechanisms controlling gene expression, immune function, and the cellular response to stress.

This 10th annual edition of Signaling Breakthroughs of the Year includes a portrait of the β-adrenergic receptor in action, unexpected twists in the regulation of gene expression, new insights into immune function, intriguing developments in our understanding of the mechanisms whereby cells sense and respond to stress, and exciting technological advances in neuroscience and calcium imaging. We thank all of the scientists who provided nominations this year; researchers providing nominations that survived the selection process included: K. Mark Ansel (University of California, San Francisco), Ivan Dikic (Goethe University Medical School, Germany), Henrik Dohlman (University of North Carolina Chapel Hill, USA), David Fruman (University of California, USA), Toby Gibson (European Molecular Biology Laboratory, Germany), Donald L. Gill (Temple University School of Medicine, USA), Katsuhiko Mikoshiba (RIKEN Brain Science Institute, Japan), Solomon Snyder (Johns Hopkins University, USA), and Eric Vivier (Centre d'Immunologie de Marseille-Luminy, France).

G protein–coupled receptors (GPCRs, also known as seven-transmembrane receptors) constitute a large family of membrane receptors that transduce many cellular responses to hormones and neurotransmitters and mediate sight, smell, and taste. Moreover, GPCRs provide targets for numerous clinically relevant drugs. Identified on the basis of their physiological roles and pharmacological properties, and intensively studied through a series of technological advances—from radioligand binding, to purification and reconstitution, to cloning and structural analyses—GPCRs are among the most well studied of signaling proteins. β2 adrenergic receptors have provided a model of GPCR signaling for some 40 years, illustrating the classic paradigm of GPCR activation of a heterotrimeric guanine nucleotide–binding protein (G protein), in which the nucleotide-binding α-subunit (Gα) exchanges GDP for GTP and the heterotrimer dissociates into Gα-GTP and βγ subunits, enabling their interaction with downstream effectors. However, the structural basis whereby an agonist-bound GPCR activates its cognate G protein in the ternary complex of agonist, receptor, and G protein has remained unclear. Both Dohlman and Mikoshiba nominated research by Brian Kobilka and his colleagues that used a combination of x-ray crystallography and electron microscopy to visualize the β2 adrenergic receptor bound to Gs (the G protein that stimulates adenylyl cyclase) (Fig. 1), providing an unparalleled view of GPCR signaling (1–3). As Dohlman noted, “This much-anticipated structure represents the first-ever snapshot of a transmembrane signaling complex. Importantly it is the nucleotide-free form of the G protein, ‘caught in the act’ so to speak, as it is being activated by the receptor.… The work is also a testament to the power of perseverance and cooperation, as it is the culmination of a 2-decade-long effort by a diverse team of collaborating scientists from across the globe.”

Fig. 1

Structure of the β2 adrenergic receptor bound to Gs. β2 adrenergic receptor, green; ligand, red, blue, and gray; Gα, gold; Gβ, light blue; Gγ, purple.


Toby Gibson also nominated research in which structural analysis provided new insights into cell signaling mechanisms, in this case work by Mouilleron et al. showing how changes in actin polymerization status can be translated into changes in gene expression (4). Actin exists in cells as an equilibrium between monomers (G-actin) and polymeric filaments (F-actin); consequently, signals that promote actin polymerization—and thereby changes in cell shape and motility—will decrease the concentration of G-actin. The transcriptional coactivator MRTF-A (myocardin-related transcription factor A) binds to G-actin monomers. Analyses of the crystal structure of complexes between G-actin and the MRTF-A actin-binding domain enabled Mouilleron et al. to determine how increases in G-actin concentration promote the cytoplasmic sequestration of MRTF-A, preventing its activation of target genes.

Structural insights into the basis of actin-mediated regulation of transcription were far from the only intriguing twist on the regulation of gene expression that made it onto this year’s list of signaling breakthroughs. Fruman, Gibson, Ansel, and Snyder all provided nominations in this area: Breakthroughs involved gene regulation in eukaryotes and bacteria and in disease and development.Nominated research ranged from therapeutic strategies targeting bromodomain-containing proteins, which bind to acetylated histones to modify chromatin structure and thereby facilitate transcription, to an apparently novel mode of translation.

Noting that MYC is one of the most prominent oncogenes in human cancer but that, unfortunately, Myc does not present a classic “druggable” target, Fruman nominated research by Dawson et al. (5), Delmore et al. (6), Mertz et al. (7), and Zuber et al. (8) that identified an alternative mode of interfering with Myc function: “Four papers this year provided a major breakthrough by describing small molecules that suppress Myc expression (5–8). These compounds interfere with the binding of BET bromodomain-containing proteins to transcriptional complexes at the promoter of MYC and other genes of relevance to cancer. Two different BET inhibitors had efficacy in models of blood cancers. These findings could have major impact on the treatment of cancer.”

One of last year’s signaling breakthroughs concerned the identification of a role for transcribed pseudogenes in enhancing the expression of the bona fide partner gene by providing a competing target for inhibitory microRNAs. In a second nomination, Fruman identified research supporting the hypothesis that endogenous RNAs (mRNAs, transcribed pseudogenes, and long noncoding RNAs) containing common microRNA response elements (MREs) form a transcriptome-wide regulatory network by competing for a limited pool of regulatory microRNAs (9). In making this nomination, for work by Karreth et al. (10), Sumazin et al. (11), and Tay et al. (12), Fruman explained how such competing endogenous RNA (ceRNA) networks may function and highlighted their potential implications for cancer. “It has been known for some time that specific microRNAs suppress expression of multiple mRNAs that share consensus MREs in the 3-UTR. Genes targeted by miRNAs do not necessarily encode proteins in a common pathway or cellular function.… three papers showed that mRNAs targeted by common miRNAs can serve as competitors, or ‘sponges,’ that regulate each other’s expression (10–12). This is a remarkable conceptual breakthrough with tremendous implications. The papers focused on cancer and showed that expression of the PTEN tumor suppressor is regulated by multiple competing endogenous RNAs (ceRNAs). The genes encoding these ceRNAs can act as tumor suppressors because their loss facilitates miRNA-mediated downregulation of PTEN. This function is dependent on the 3’-UTR but independent of the protein coding function of the message. It should now be recognized that any gene knockout or silencing approach can lead to spurious assignment of tumor suppressor or oncogenic function to the protein product of a gene, if it has an important function in the ceRNA network.” Although the implications for cancer pathogenesis are clear, physiological functions for ceRNAs are emerging as well. For his last entry in this series, Fruman nominated a paper by Cesana et al. implicating a muscle-specific long noncoding RNA in regulating the timing of muscle differentiation, by competing for microRNAs that repress two transcription factors involved in myogenic differentiation (13).

The next pair of papers, nominated by Gibson, shifted the focus from regulation of gene expression in eukaryotes to gene regulation in prokaryotes: “It has often been said that the bacterial cell is ‘just a bag of enzymes.’ I would like to select two papers that together highlight how absurd this notion is in the way it dismisses the potential for sophisticated regulatory systems in prokaryotes. … A picture is starting to emerge whereby sophisticated and networked signaling systems monitoring multiple cell state parameters can have both very broad and very targeted effects on prokaryotic gene regulation.” The first paper, by Nurmohamed et al. (14), provided a direct link between bacterial metabolism and RNA stability by showing that the tricarboxylic acid cycle intermediate citrate bound to and modulated the activity of the Escherichia coli nuclease polynucleotide phosphorylase (PNPase), a component of an RNA degrading complex called the degradosome (14). Conversely, loss of PNPase activity had wide-ranging effects on metabolism. The second paper, by Nevo-Dinur et al., challenged the prevailing view that, in bacteria, transcription and translation are strictly coupled, with protein localization depending solely on targeting signals within the protein itself, by showing spatial targeting of E. coli mRNAs to the appropriate cellular domains independent of their translation (15).

Returning to eukaryotes, Ansel drew our attention to an unexpected mechanism through which translation is regulated during embryonic development. He nominated a paper by Kondrashov et al. (16) showing that a core component of the ribosome—Ribosomal Protein L38—selectively regulated the translation of a subset of mRNA transcripts, including several encoding Hox proteins, thereby playing an unexpected role in vertebrate tissue patterning. Snyder, in one of several nominations made in conjunction with his junior colleagues Jing Xe, Juan Sbodio, and Bindu Paul, nominated research describing an unusual mode of translation that may contribute to the pathology of certain neurodegenerative disorders. As he explained, “Several neurodegenerative diseases, especially Huntington’s Disease, are associated with CAG repeats, which code for polyglutamine stretches. Zu et al. (17) report that CAG expansion constructs express polyglutamine and other repeat proteins in the absence of an ATG start codon. This appears to represent a novel mode of protein translation and may be responsible for the accumulation of misfolded proteins in diverse neurodegenerative conditions.”

Most secreted and membrane proteins are folded within the lumen of the endoplasmic reticulum (ER); accumulation of unfolded or misfolded proteins in the ER—which can, of course, occur independently of CAG repeat expansion—elicits a stress response called the unfolded protein response (UPR). As part of the UPR, the ER transmembrane protein Ire1 senses stress to initiate signaling pathways that lead to the restoration of ER homeostasis or—that failing—the apoptotic death of the cell. But, what, precisely, is the stress signal that activates Ire1? Dikic nominated work of Gardner and Walter (18) revealing that, in yeast, the unfolded proteins themselves bind directly to Ire1 to stimulate its oligomerization and activation. Protein folding, like ER processes, depends on calcium present in the ER. A different ER transmembrane protein, STIM1 (stromal interaction molecule 1), was identified as a calcium sensor that stimulates calcium influx when ER stores become depleted. Gill nominated work by Xiao et al. (19) showing that STIM1 is also activated by changes in temperature, which, together with previous research, suggests that STIM proteins may act as general sensors of cell stress: “This finding represents a remarkable and unexpected sensing property of STIM proteins. These proteins were originally discovered as sensors of calcium within the lumen of ER, undertaking an extraordinary translocation event into ER-plasma membrane junctions … to effect crucial communication with Orai calcium entry channels. The work of Ardem Patapoutian’s lab showed that modestly increased temperature is sensed by STIM proteins to activate them without the depletion of intracellular calcium stores. However, at the higher temperature, the coupling to activate Orai channels is prevented, suggesting either that temperature is a mechanism for priming the channels to become activated when temperature decreases to normal, or that, at the higher temperature, the uncoupling process protects cells from becoming over-activated…. The process may have major implications for signaling in lymphocytes during fever. Also, there are broader implications for STIM proteins functioning as more general sensors of cellular stress, responding to not only calcium stress and temperature stress, but also sensing stress due to reactive oxygen species, hypoxia, and acidification.”

Calcium is, of course, well known for its role in cell signaling; Mikoshiba nominated a paper identifying a role for another divalent cation—magnesium—in signaling in immune cells. Li et al. (20) determined that an X-linked human T cell immunodeficiency was associated with mutation of the gene encoding the magnesium transporter MAGT1. Functional analyses indicated that MAGT1 deficiency was associated with decreased magnesium influx following T cell receptor (TCR) stimulation, as well as impaired TCR-dependent activation of phospholipase Cγ1 and calcium influx. Thus, magnesium appears to play a crucial role as an intra­cellular second messenger in T cell signaling.

Vivier and Dikic also provided nominations for breakthroughs in our understanding of immune function. The intestine, like other epithelia that provide barriers between the host and the environment, contains specialized lymphocytes that help maintain epithelial function and localized defenses. Vivier nominated work by Li et al. (21) and Kiss et al. (22) showing that activation of the aryl hydrocarbon receptor in a subset of innate intestinal lymphocytes by nutrients found in plants promotes their expansion, thereby contributing to intestinal immune defenses (23) (Fig. 2). Ubiquitination is a posttranslational modification in which the small protein ubiquitin is attached to a target protein; ubiquitination can involve a single moiety (monoubiquitination) or various types of ubiquitin chains, with different forms of ubiquitination eliciting different responses. Dikic, in work he described as “the most surprising signaling discovery in the ubiquitin field in 2011,” nominated research by Gerlach et al. (24) and Tokunaga et al. (25) demonstrating that linear ubiquitin chains play a central role in regulating inflammation and the innate immune response. Thus, mice deficient in a component of the linear ubiquitin chain assembly complex (LUBAC) experience an inflammatory phenotype involving chronic proliferative dermatitis characterized by inflammatory skin lesions (24–26).

Fig. 2

Ligands derived from phytochemicals found in cruciferous vegetables activate the aryl hydrocarbon receptor to promote intestinal immune defenses.


The next set of nominations swung from signaling in defense to signaling in disease. Dohlman nominated a paper by Chakir et al. implicating RGS (regulator of G protein signaling) proteins targeting Gαi in the restoration of cardiac function by cardiac resynchronization therapy (27). “Heart failure patients with ventricular dyssynchrony show improvement with a form of electrical stimulation therapy designed to resynchronize the heart by pacing both sides at once. The therapy lowers mortality but does so in a seemingly paradoxical manner, by making weak hearts perform more work. The work of David Kass and colleagues reveals that resynchronizing the heart improves its function by increasing the expression of RGS2 and RGS3. RGS proteins have long been known to accelerate inactivation of G proteins by stimulating their intrinsic GTPase activity. These findings reveal RGS proteins as appealing therapeutic targets in heart failure. More broadly, the findings represent an example of reverse engineering—where a successful clinical therapy is deconstructed to identify key molecular changes that then point to future therapies.”

Signaling aficionados have long been familiar with such modes of cell death as apoptosis, necrosis, and autophagy. The next nomination, by Snyder, concerns parthanatos, a distinct form of cell death that has been implicated in various pathological conditions, including the excitoxic cell death that occurs downstream of NMDA-type glutamate receptors and contributes to various disorders of the brain. Snyder nominated a paper by Andrabi et al. (28) identifying a protein induced in response to NMDA receptor activation that inhibits parthanotos, providing a potential therapeutic approach to treating neurologic disorders associated with excitoxic cell death. “Valina and Ted Dawson pioneered the notion that poly(ADP)ribose (PAR) mediates cell death. They now describe a novel protein, Iduna, which is neuroprotective and acts by selectively impairing PAR-linked cell death … associated with its binding directly to PAR.” Finally, Snyder nominated a paper by Zwilling et al. (29) that describes a potential approach to treating neurodegenerative disorders by altering the abundance of tryptophan metabolites in the brain. The kynurenine pathway represents a major route of tryptophan degradation. Whereas the kynurenine pathway metabolite quinolinic acid, which acts as an NMDA receptor agonist, has been postulated to contribute to the pathophysiology of Huntington’s disease, kynurenic acid, which is produced through a side arm of the pathway, is neuroprotective in models of ischemia. Kynurenic acid inhibits quinolinic acid–mediated neurodegeneration, reduces extracellular glutamate concentrations, and blocks the glycine coagonist site of the NMDA receptor (Fig. 3). In making his nomination, Snyder noted, “Robert Schwarcz and colleagues have long advocated the tryptophan metabolites quinolinic acid and kynurenine, respectively, as endogenous neurotoxic and neuroprotective substances. They now report a pro-drug of kynurenine, JM6, which inhibits kynurenine monooxygenase, leading to accumulation of kynurenine and decreased quinolinic acid.” The drug, which does not cross the blood-brain barrier effectively, inhibited kynurenine monooxygenase in blood cells, leading to kynurenine transport into the brain, increased brain kynurenic acid, and decreased extracellular glutamate. JM6 had therapeutic benefits in mouse models of Alzheimer’s disease and Huntington’s disease.

Fig. 3

Kynurenic acid is neuroprotective.


Moving from neuropathology to the healthy brain, Mikoshiba nominated an article by Panatier et al. (30) showing that astrocytes detect and modulate basal synaptic transmission—the release of neurotransmitter at an individual synapse in response to a single action potential. In making this nomination, Mikoshiba noted not only the conceptual advance to our understanding of synaptic communication but also the authors’ technical achievement: “Ca2+ imaging in neuronal spines has been around for a considerable amount of time and is now a standard technique … but has been notably absent in the astrocyte field. The authors have demonstrated that a similar level of resolution can be obtained in astrocytes and capitalized on this to address some key conceptual issues surrounding the role of astrocytes in synaptic computation.… this technique will be quickly emulated in other leading labs and lead to further advancement in brain science.” Mikoshiba also nominated another paper for technological achievements likely to open up new research directions in calcium signaling.

Fluorescence indicators that measure changes in intracellular calcium have provided numerous insights into signaling mediated by this ubiquitous second messenger. These have included both calcium-sensitive dyes and engineered fluorescent proteins. As Mikoshiba pointed out, “Genetically encoded Ca2+ indicators [have provided] a powerful tool to monitor … cellular activity, even in vivo, however, the color [has been] limited to green….” Thus, our last signaling breakthrough of 2011 is for work by Zhao et al. (31) that promises to open the door to “a colorful new era of Ca2+ imaging” by providing genetically encoded Ca2+ indicators in multiple colors that can be targeted to distinct subcellular compartments, allowing simultaneous imaging of Ca2+ in different colors and different compartments of the same cell (Fig. 4).

Fig. 4

HeLa cells transfected with Ca2+ indicators that fluoresce in different colors and are targeted to distinct cellular compartments.


Related Resources

Editorial Guides

  • E. M. Adler, 2010: Signaling breakthroughs of the year. Sci. Signal. 4, eg1 (2011). [Abstract] [Full Text] [PDF]

  • N. R. Gough, Focus Issue: Cracking the G protein–coupled receptor code. Sci. Signal. 4, eg7 (2011). [Abstract] [Full Text] [PDF]

  • W. Wong, Focus Issue: Signals for gene expression. Sci. Signal. 3, eg10 (2010). [Abstract] [Full Text] [PDF]

Editors’ Choice

  • S. M. Hurtley, Directing quality control. Sci. Signal. 4, ec278 (2011). [Summary]

  • J. F. Foley, Magnesium required? Sci. Signal. 4, ec212 (2011). [Summary]

  • E. M. Adler, Building a better barrier with broccoli? Sci. Signal. 4, ec304 (2011). [Summary]

  • J. F. Foley, Enhancing basal transmission. Sci. Signal. 4, ec252 (2011). [Summary]

  • V. K. Vinson, Calcium in color. Sci. Signal. 4, ec279 (2011). [Summary]


  • R. Treisman, N. Q. McDonald, S. Mouilleron, A. M. VanHook, Science Signaling Podcast: 14 June 2011. Sci. Signal. 4, pc11 (2011). [Abstract] [Full Text]

Research Articles

  • L. Poliseno, L. Salmena, L. Riccardi, A. Fornari, M. S. Song, R. M. Hobbs, P. Sportoletti, S. Varmeh, A. Egia, G. Fedele, L. Rameh, M. Loda, P. P. Pandolfi, Identification of the miR-106b~25 microRNA cluster as a proto-oncogenic PTEN-targeting intron that cooperates with its host gene MCM7 in transformation. Sci. Signal. 3, ra29 (2010). [Summary] [Abstract] [Full Text] [PDF]

  • Y. Wang, N. S. Kim, J.-F. Haince, H. C. Kang, K. K. David, S. A. Andrabi, G. G. Poirier, V. L. Dawson, T. M. Dawson, Poly(ADP-ribose) (PAR) binding to apoptosis-inducing factor is critical for PAR polymerase-1–dependent cell death (parthanatos). Sci. Signal. 4, ra20 (2011). [Summary] [Abstract] [Full Text] [PDF]


Teaching Resources

  • A. M. Preininger, H. E. Hamm, Heterotrimeric G protein cycle. Sci. STKE 2004, tr1 (2004). [Abstract] [Full Text]

  • R. Iyengar, Structure of G protein–coupled receptors and G proteins. Sci. STKE 2005, tr10 (2005). [Abstract] [Full Text] [PDF]

Virtual Journal

  • K. S. Ramamurthi, mRNA delivers the goods. Science 331, 1021–1022 (2011). [Summary] [Full Text] [PDF]

  • S. Kawaguchi, D. T. W. Ng, Sensing ER stress. Science 333, 1830–1831 (2011). [Summary] [Full Text] [PDF]


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