bluuebunny/crossref_metadata_2025 huggingface dataset:
Location, Location, Location
Authors: Ray L. Bryan
Published: September 2007

Despite substantial effort, it has remained relatively mysterious how the protein known as Hedgehog (Hh) activates signaling pathways that regulate various biological processes, including stem cell function, development, and cancer. Rohatgi
et al
. (see the Perspective by Christensen and Ott) show that mammalian cells use their primary cilium as an antenna that samples the surrounding environment for the presence of Hh. When Hh bound to its receptor Patched 1 (Ptc1), the receptor left the cilia, where (in the absence of stimulation) it acts to restrain Hh signaling by preventing accumulation of the signaling protein Smoothened (Smo). Accumulation of Smo in the cilia of stimulated cells corresponded to activation of Hh signaling. Further understanding the molecular mechanisms that influence cellular localization of Ptc1 and Smo will improve understanding of the signaling pathway and may lead to new therapeutic targets.

R. Rohatgi, L. Milenkovic, M. P. Scott, Patched1 regulates Hedgehog signaling at the primary cilium.
Science
317
, 372-376 (2007).
[Abstract]
[Full Text]

S. T. Christensen, C. M. Ott, A ciliary signaling switch.
Science
317
, 330-331 (2007).
[Summary]
[Full Text]
Minimal Exposure
Authors: Simpson Stephen J.
Published: September 2007

The recent discovery that certain viruses express microRNAs (miRNAs) raises the question as to whether these pathogens might use miRNA to evade their hosts. Stern-Ginossar
et al
. (see the Perspective by Cullen) find that for human cytomegalovirus, this indeed appears to be the case. One of the virus’s miRNAs was predicted to target the 3′ untranslated regions of two immune-related genes, which become activated in response to viral infections. Expression of one of these proteins was indeed dampened by the viral miRNA, which reduced recognition by antiviral natural killer cells. It remains to be seen if miRNA will turn out to be a widespread method exploited by viruses to evade host immunity.

N. Stern-Ginossar, N. Elefant, A. Zimmermann, D. G. Wolf, N. Saleh, M. Biton, E. Horwitz, Z. Prokocimer, M. Prichard, G. Hahn, D. Goldman-Wohl, C. Greenfield, S. Yagel, H. Hengel, Y. Altuvia, H. Margalit, O. Mandelboim, Host immune system gene targeting by a viral miRNA.
Science
317
, 376-381 (2007)
[Abstract]
[Full Text]

B. R. Cullen, Outwitted by viral RNAs.
Science
317
, 329-330 (2007).
[Summary]
[Full Text]
Molecular Scaffolds Regulate Bidirectional Crosstalk Between Wnt and Classical Seven-Transmembrane Domain Receptor Signaling Pathways
Authors: Force Thomas , Woulfe Kathleen , Koch Walter J. , Kerkelä Risto
Published: September 2007

Signaling downstream of classical seven-transmembrane domain receptors (7TMRs) had generally been thought to recruit factors that are in large part separate from those recruited by atypical 7TMRs, such as Frizzleds (Fzs), receptors for the Wnt family of glycoproteins. Classical 7TMRs are also known as G protein–coupled receptors (GPCRs) and are mediated by signaling factors such as heterotrimeric guanine nucleotide–binding proteins (G proteins), GPCR kinases (GRKs), and β-arrestins. Over the past few years, it has become increasingly apparent that classical and atypical 7TMRs share these factors, which are often associated with mediating classical 7TMR signaling, as well as the scaffolding proteins that were initially thought to be involved in transmitting atypical 7TMR signals. This sharing of signaling components by agonists that bind classical 7TMRs and those binding to atypical 7TMRs establishes the possibility of extensive crosstalk between these receptor classes. We discuss the evidence for, and against, crosstalk, and examine mechanisms by which this can occur.
An Arrestin Immune Response
Authors: Adler Elizabeth M.
Published: September 2007

Our survival depends on the elimination of pathogens by the immune system. If not kept in check, however, the immune system can become self-destructive, and dysregulation of the adaptive immune response—for instance, failure to eliminate effector T cells after a pathogen has been cleared—is associated with the development of autoimmune disorders (see Frederick and Miller). Shi
et al
. found that mice lacking
Arrb1
, which encodes β-arrestin-1 (a scaffolding protein identified in terms of its cytoplasmic role in G protein-coupled receptor signaling but since discovered to act in the nucleus as well), had fewer peripheral CD4
+
T cells than did wild-type mice. Naive and activated CD4
+
T cells from

Arrb1
–/–

mice were more likely to undergo apoptosis than those from wild-type mice, whereas activated CD4
+
T cells from
Arrb1
-transgenic mice (
Arrb1
tg mice) were less likely to do so. Several days after an immunological challenge,

Arrb1
–/–

mice had a smaller population of responding CD4
+
T cells than did wild-type mice, whereas
Arrb1
tg mice had a larger population.
Arrb1
knockdown led to a decrease in transcription of the gene encoding the antiapoptotic protein Bcl-2. After CD4
+
T cell activation,
Bcl-2
expression tracked that of
Arrb1
; such dynamic changes in
Bcl-2
expression were absent in

Arrb1
–/–

cells. Further analysis indicated that β-arrestin-1 stimulated
Bcl-2
expression through acetylation of histone H4 at the
Bcl-2
promoter. Intriguingly,

Arrb1
–/–

mice were less susceptible to experimental autoimmune encephalomyelitis than were wild-type mice, whereas
Arrb1
tg mice were more susceptible, and CD4
+
T cells from people with multiple sclerosis showed increased expression of
ARRB1
and
BCL2
. Moreover, β-arrestin-1 knockdown in CD4
+
T cells directed against myelin basic protein led to a decrease in Bcl-2 and an increased susceptibility to apoptosis. Thus, the authors conclude that β-arrestin-1 plays a key role in CD4
+
T cell homeostasis by regulating the expression of
Bcl-2
.

Y. Shi, Y. Feng, J. Kang, C. Liu, Z. Li, D. Li, W. Cao, J. Qiu, Z. Guo, E. Bi, L. Zang, C. Lu, J. Z. Zhang, G. Pei, Critical regulation of CD4
+
T cell survival and autoimmunity by β-arrestin 1.
Nat. Immunol.
8
, 817-824 (2007).
[PubMed]

T. J. Frederick, S. D. Miller, Arresting autoimmunity by blocking β-arrestin 1.
Nat. Immunol.
8
, 791-792 (2007).
[PubMed]
BAK1 for Pathogen Response
Authors: Gough Nancy R.
Published: September 2007

BAK1 (brassinosteroid insensitive 1-associated receptor kinase 1) is best known and is named for its role as a leucine-rich repeat receptor-like kinase (LRR-RLK) involved in brassinosteroid signaling in
Arabidopsis thaliana
. Chinchilla
et al
. report that BAK1 also contributes to the response to pathogen-associated molecular patterns (PAMPs), such as those triggered by bacterial flagellin or elongation factor Tu (EF-Tu). Heese
et al
. identified BAK1 as a coimmunoprecipitation partner for
Arabipdosis
FLS2. Chinchilla
et al
. identified plants with insertions in the
bak1
gene in a screen for genes that encode LRR-RLKs that produce plants with decreased sensitivity to the PAMP flagellin peptide flg22 (the growth of seedlings was not inhibited by flg22). The insertional mutant plants also showed decreased responsiveness to brassinosteroids; however, the defect in brassinosteroid signaling was not the cause of the defective PAMP response. Even when brassinosteroid signaling was restored by high concentrations of exogenous brassinolide, the
bak1
mutant seedlings failed to exhibit growth inhibition in response to flg22. Both groups reported that stimulation of mitogen-activated protein kinase activity and the oxidative burst that are characteristic of the wild-type response to flg22 were diminished in
bak1
mutant plants. Both groups also determined that BAK1 was not specific to the flagellin PAMP but appeared to play a role in triggering responses to various PAMPs. Heese
et al
. identified the
Nicotiana benthamiana
homolog of BAK1 and found that knockdown of the protein in this plant allowed enhanced growth of bacteria on the plants. Thus, BAK1 appears to be a promiscuous LRR-RLK, partnering with various ligand-binding receptors to trigger ligand-specific responses.

D. Chinchilla, C. Zipfel, S. Robatzek, B. Kemmerling, T. Nürnberger, J. D. G. Jones, G. Felix, T. Boller, A flagellin-induced complex of the receptor FLS2 and BAK1 initiates plant defence.
Nature
448
, 497-500 (2007).
[PubMed]

A. Heese, D. R. Hann, S. Gimenez-Ibanez, A. M. E. Jones, K. He, J. Li, J. I. Schroeder, S. C. Peck, J. P. Rathjen, The receptor-like kinase SERK3/BAK1 is a central regulator of innate immunity in plants.
Proc. Natl. Acad. Sci. U.S.A.
104
, 12217-12222 (2007).
[Abstract]
[Full Text]
Essence of Alpha Male
Authors: Gough Nancy R.
Published: September 2007

Pheromones are chemicals involved in mating and reproduction. In rodents, these chemicals are detected by the vomeronasal organ, which humans lack, and by the olfactory system. Mate-specific pheromone memories play an important role in female rodent reproduction. Two parts of the brain that undergo neurogenesis in the adult are the olfactory bulb (the new neurons originate in the subventricular zone) and the dentate gyrus of the hippocampus. In rodents, neurogenesis in the olfactory bulb is stimulated by mating or pregnancy. Neurogenesis in the hippocampus is stimulated by running, enriched environments, or learning. Mak
et al
. found that pheromones in the urine of dominant, but not subordinate or castrated, male mice stimulated the neurogenesis of both the olfactory bulb and the dentate gyrus in female mice. Furthermore, females exposed to dominant-male pheromones and then presented with both a dominant and a subordinate male spent more time sniffing the dominant male's compartment, indicating preference for the dominant male. This pheromone-induced male preference was lost if the female mice were deficient in the prolactin receptor (PRLR) or if neurogenesis was blocked by injection of cytosine arabinoside. It is known that male pheromones trigger surges in luteinizing hormone (LH) and prolactin (PRL) in the female mice. Mak
et al
. detected PRLR in the subventricular zone (the source of the new olfactory bulb neurons) and detected the LH receptor in both the subventricular zone and the dentate gyrus. Injection of low doses of LH stimulated neurogenesis in the dentate gyrus, whereas injection of PRL stimulated neurogenesis in the subventricular zone. Male pheromones failed to stimulate subventricular zone neurogenesis in the female mice deficient for the PRL receptor, and neurogenesis in the dentate gyrus was absent in the mice deficient for the LH receptor. These results raise the question of whether male pheromones contribute to human mate selection, and undoubtedly the perfume industry will be keenly interested in whether they can create the "dominant-male fragrance" (see commentary by DiRocco and Xia).

G. K. Mak, E. K. Enwere, C. Gregg, T. Pakarainen, M. Poutanen, I. Huhtaniemi, S. Weiss, Male pheromone-stimulated neurogenesis in the adult female brain: Possible role in mating behavior.
Nat. Neurosci.
10
, 1003-1011 (2007).
[PubMed]

D. P. DiRocco, Z. Xia, Alpha males win again.
Nat. Neurosci.
10
, 938-940 (2007).
[PubMed]
Sensor Evolution in Action
Authors: Ray L. Bryan
Published: September 2007

The photosynthetic bacterium
Rhodopseudomonas palustris
is an extremely adaptable bug that can survive by producing energy through photosynthesis, aerobic respiration, anaerobic respiration, or fermentation. Now studies of bacteriophytochrome photoreceptor proteins (BphPs) by Vuillet
et al
. appear to show an example of evolution in action in which different strains of
Rps. palustris
use a nearly identical protein for either light or redox sensing. The BphPs get their light-sensing ability from a chromophore that is covalently linked to the protein through a Cys residue. Indeed, the product of the
Rp
BphP4 protein can sense light and activates histidine kinase activity of the protein, which is coupled to a two-component regulatory system. However, most strains of
Rps. palustris
express a
Rp
BphP4 protein that lacks the critical Cys where the chromophore would be linked. Instead, the authors show that the achromo-
Rp
BphP4 protein is sensitive to changes in redox state. The strains that express achromo-
Rp
BphP4 can respond to low oxygen tension, through the two-component system, to regulate synthesis of a set of light-harvesting complexes. This is the same response produced when specific wavelengths of light are detected in strains expressing the chromo-
Rp
BphP4 protein. Thus, the authors propose that the system appears to display an example of evolution of the nature of signal perception by a histidine kinase sensor protein that may enhance the adaptability of the species to rapid changes in its environment.

L. Vuillet, M. Kojadinovic, S. Zappa, M. Jaubert, J.-M. Adriano, J. Fardoux, L. Hannibal, D. Pignol, A. Verméglio, E. Giraud, Evolution of a bacteriophytochrome from light to redox sensor.
EMBO J.
26
, 3322-3331 (2007).
[PubMed]
Ethylene Controls Root Meristem Production
Authors: Kelner Katrina L.
Published: September 2007

In plants, undifferentiated meristem tissue provides stem cells to produce roots and shoots. The root meristem contains a few of these stem cells in a region called the quiescent center. Ortega-Martínez
et al
. studied
Arabidopsis
plants with a defect in a gene that controls ethylene biosynthesis and found that it produced more of the gaseous hormone ethylene. The quiescent center cells in these mutants went through more cell divisions than normal, resulting in extra stem cells in the root meristem. Adding exogenous ethylene also increased quiescent cell division, and blocking its synthesis in the mutants prevented extra divisions.

O. Ortega-Martínez, M. Pernas, R. J. Carol, L. Dolan, Ethylene modulates stem cell division in the
Arabidopsis thaliana
root.
Science
317
, 507-510 (2007).
[Abstract]
[Full Text]
Leukotriene Synthesis Inhibitors in a FLAP
Authors: Vinson Valda J.
Published: September 2007

Leukotrienes are bioactive lipid metabolites involved in respiratory and cardiovascular diseases. They are synthesized from arachidonic acid by the enzyme 5-lipoxygenase, and the integral membrane protein 5-lipoxygenase–activating protein (FLAP) plays an essential role in their biosynthesis. Ferguson
et al
. describe the crystal structure of human FLAP in complex with two different leukotriene biosynthesis inhibitors. The structures suggest how the inhibitors prevent arachidonic acid from binding to FLAP, from which it is likely transferred to 5-lipoxygenase. The structural data provide a basis for the development of drugs targeted against FLAP that would inhibit leukotriene biosynthesis.

A. D. Ferguson, B. M. McKeever, S. Xu, D. Wisniewski, D. K. Miller, T.-T. Yamin, R. H. Spencer, L. Chu, F. Ujjainwalla, B. R. Cunningham, J. F. Evans, J. W. Becker, Crystal structure of inhibitor-bound human 5-lipoxygenase-activating protein.
Science
317
, 510-512 (2007).
[Abstract]
[Full Text]
Noise, Gene Expression, and Competence
Authors: Purnell Beverly A.
Published: September 2007

The soil bacterium
Bacillus subtilis
can become "competent"--it can take up genetic material from its surroundings. Competence is regulated by the protein ComK, which controls the genes responsible for DNA uptake. However, cells can only transition to competence in a random fashion during a limited period of time at the beginning of the stationary phase of growth. Maamar
et al
. (see the Perspective by Mettetal and van Oudenaarden) now find that temporal regulation of
comK
transcription defines the "window of opportunity" during which cells can become competent, and intrinsic noise in gene expression controls the rate at which stochastic transitions to the competent state occur.

H. Maamar, A. Raj, D. Dubnau, Noise in gene expression determines cell fate in
Bacillus subtilis
.
Science
317
, 526-529 (2007).
[Abstract]
[Full Text]

J. T. Mettetal, A. van Oudenaarden, Necessary noise.
Science
317
, 463-464 (2007).
[Summary]
[Full Text]
Correcting Cocaine-Induced Plasticity
Authors: Stern Peter
Published: September 2007

It has been proposed that metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD) can reverse cocaine-evoked synaptic plasticity in the ventral tegmental area (VTA). Mameli
et al
. have now unraveled the expression mechanism of mGluR-LTD in the VTA of mice exposed to a single dose of cocaine. LTD in this system is not due to the simple removal of AMPA receptors (AMPARs) from the synapse. Instead, AMPARs are replaced by new ones that contain newly synthesized GluR2 subunits. The synapse thus expresses LTD not because there are fewer receptors but because the conductance of the new GluR2-containing AMPARs is reduced.

M. Mameli, B. Balland, R. Luján, C. Lüscher, Rapid synthesis and synaptic insertion of GluR2 for mGluR-LTD in the ventral tegmental area.
Science
317
, 530-533 (2007).
[Abstract]
[Full Text]
NFAT in Lymphocytes: A Factor for All Events?
Authors: Serfling Edgar , Berberich-Siebelt Friederike , Avots Andris
Published: September 2007

A typical immune response to infection by a microbe results in rapid amplification and subsequent differentiation of a few antigen-specific naïve lymphocytes into many effector lymphocytes. Upon antigen exposure, these effector T or B cells rapidly secrete large amounts of either lymphokines (cytokines produced by lymphocytes) or soluble antibodies, respectively. Although the vast majority of these effector cells die after antigen clearance, some cells survive as memory cells and give lifelong protection to the host against a second infection by the same microbe. It has been appreciated for years that memory cells respond more rapidly than do naïve lymphocytes; however, the molecular mechanisms controlling memory cells remain largely unknown. A study now shows that abundance of the transcription factors nuclear factor of activated T cells c1 and c2 (NFATc1 and NFATc2) is much higher in memory (and effector) T cells than in naïve T cells. This suggests that NFATs have an important function in memory T cells but leaves open the questions of which transcription factors control interleukin-2 (IL-2) synthesis in naïve T cells and which mechanisms generate the high abundance of NFAT in memory T cells.
A Role for the Cytoplasmic Adaptor Protein Act1 in Mediating IL-17 Signaling
Authors: Lindén Anders
Published: September 2007

Interleukin (IL)–17 (also known as IL-17A) plays an important role in host defense and inflammatory disorders, in part by linking the activation of a subset of T lymphocytes to the mobilization of neutrophils and macrophages. IL-17 exerts its effects both directly and indirectly; the latter by stimulating the production of various chemokines, IL-6, and growth factors from resident cells in the affected tissue. As a result, IL-17 coordinates the innate immune response to extracellular bacteria, which is interesting because IL-17 is produced by several types of T cells that are traditionally regarded as key players in adaptive immunity. Studies have uncovered the function and relevance of a unique subset of CD4
+
T helper (Th) cells that produce IL-17 (Th17 cells), but our understanding of the function of IL-17 receptors (IL-17Rs) and their downstream signaling pathways remains poor. This Review discusses studies that suggest that the cytoplasmic adaptor protein Act1 [nuclear factor-κB (NF-κB) activator 1] is essential for linking stimulation of IL-17Rs to downstream signaling pathways, and, therefore, that Act1 might play a role in local inflammatory responses. Act1 mediates activation of NF-κB and the subsequent production of IL-6 and chemokines that are chemotactic for neutrophils and macrophages. These findings have increased our understanding of host defense against bacteria and indicated a role for Act1 in mediating in chronic inflammatory disease. Future studies on Act1 and IL-17 signaling should contribute to the identification and improved understanding of the mechanisms behind aberrant innate immune responses in chronic inflammatory disease.
Sleepy Time with TNF-α
Authors: Foley John F.
Published: September 2007

Why is it that soon after being exposed to an infectious agent we suffer from fatigue as well as fever? Part of the innate immune response to microbial infections is the production of proinflammatory cytokines such as interleukin (IL)-1β and tumor necrosis factor-α (TNF-α). Previous studies have implicated TNF-α as a causative agent of fatigue in humans and mice; however, the mechanism is not known. Sleep is regulated by circadian mechanisms that include a negative feedback system involving the Per transcriptional repressors, the abundance of which is controlled by the transcription factors BMAL1 and CLOCK, whose expression is in turn controlled by the Per repressors. Cavadini
et al
. treated synchronized NIH 3T3 fibroblasts with TNF-α and observed a dose-dependent decrease in the expression of the transcriptional repressor genes
Per1
,
Per2
, and
Per3
compared with untreated cells, as assessed by real-time reverse transcription polymerase chain reaction (RT-PCR) analyses. The effect of TNF-α on
Per
gene expression was shared by IL-1β but not by interferon-α (IFN-α) or IL-6, two other proinflammatory cytokines that are produced upon microbial infection.
Clock
gene expression was unaffected by TNF-α treatment. Using fibroblasts transfected with luciferase reporter genes, the authors demonstrated that TNF-α treatment inhibited expression of circadian genes under the control of promoters that contained an E-box motif--a helix-loop-helix transcription factor-binding site.
Per
genes, which were inhibited by TNF-α, contain E-box motifs, whereas
Bmal1
and
Clock
genes, which were not affected by TNF-α, do not. Mice were treated with TNF-α every day for 7 days, and RT-PCR analysis of the liver showed decreased expression of
Per3
and other genes regulated by circadian processes, such as
Dbp
, which encodes the transcription factor Dbp that contributes to circadian control of locomotor activity. TNF-α treatment of mice also decreased
Dbp
expression in the hypothalamus. By monitoring running-wheel activity, Cavadini
et al
. showed that administration of TNF-α to mice reduced their movements and increased the amount of time that the mice spent resting. Together, these data suggest that TNF-α, produced during the initial stages of microbial infections and associated with autoimmune disorders such as rheumatoid arthritis, alters circadian signaling and induces fatigue. Clinical intervention to prevent this may help patients overcome the disruptive effects of TNF-α on their sleep patterns.

G. Cavadini, S. Petrzilka, P. Kohler, C. Jud, I. Tobler, T. Birchler, A. Fontana, TNF-α suppresses the expression of clock genes by interfering with E-box-mediated transcription.
Proc. Natl. Acad. Sci. U.S.A.
104
, 12843-12848 (2007).
[Abstract]
[Full Text]
Slit Has Complex Effects
Authors: Adler Elizabeth M.
Published: September 2007

Developing axons interact with cells and substrate encountered en route to their target through adhesion molecules such as N-cadherin. The repulsive guidance cue Slit acts through the Robo receptor to inhibit N-cadherin-mediated adhesion--and thereby neurite outgrowth--through the phosphorylation-dependent dissociation of β-catenin from N-cadherin. This occurs in conjunction with the formation of a multimeric complex that includes not only Robo and N-cadherin but also the Abl tyrosine kinase. Rhee
et al.
found that, after treatment with Slit, Abl and Robo immunoprecipitated from chick neural retina cells together with the adaptor protein Cables (for Cdk5 and Abl enzyme substrate). As the name implies, Cables is also a substrate for Cdk5, and Slit stimulated an increase in the amount of Cdk5 that immunoprecipitated with Abl and with cadherin, whereas it elicited a decrease in cadherin association with the Cdk5 regulatory subunit p35. p35 interacts with β-catenin, and disruption of the Cdk5-Cables interaction inhibited the Slit-induced loss of β-catenin and p35 from the N-cadherin complex, as well as inhibiting association of β-catenin with Cables. In vitro binding assays indicated that Cables bound to β-catenin and Abl, but not to N-cadherin. Further, Cables and p35 competed with each other for binding to β-catenin, and Cables knockdown led to an increase in the association of N-cadherin and β-catenin and a "flattened" phenotype in cells expressing a constitutively active form of Robo. Mutational analysis indicated that Abl phosphorylated β-catenin on tyrosine 489 (Y489), inhibiting the β-catenin-N-cadherin interaction. Y489-phosphorylated β-catenin translocated to the nucleus, where it interacted with the transcription factor Tcf and activated the transcription of a target gene reporter. Thus, Cables appears to play a key role in the formation of the Robo-N-cadherin complex, and release of β-catenin from N-cadherin allows Slit not only to coordinate axonal guidance and adhesion but also to mediate changes in gene transcription.

J. Rhee, T. Buchan, L. Zukerberg, J. Lilien, J. Balsamo, Cables links Robo-bound Abl kinase to N-cadherin-bound β-catenin to mediate Slit-induced modulation of adhesion and transcription.
Nat. Cell Biol.
9
, 883-892 (2007).
[PubMed]
Insulin Signaling Up Close and Personal
Authors: Ray L. Bryan
Published: September 2007

Novel quantitative methods are allowing the analysis of gene and protein expression in unprecedented detail. Dong
et al
. (see the Perspective by Kim) profiled protein abundance changes in response to perturbations of insulin and insulin-like growth factor-1 (IGF-1) signaling in
Caenorhabditis elegans
and identified 86 targets. More than half of the targets identified by this quantitative proteomics approach were not previously identified and may provide new insights into the mechanisms of diabetes and aging.

M.-Q. Dong, J. D. Venable, N. Au, T. Xu, S. K. Park, D. Cociorva, J. R. Johnson, A. Dillin, J. R. Yates III, Quantitative mass spectrometry identifies insulin signaling targets in
C. elegans
.
Science
317
, 660-663 (2007).
[Abstract]
[Full Text]

S. K. Kim, Proteins that promote long life.
Science
317
, 603-604 (2007).
[Summary]
[Full Text]
Leukocytes on Border Patrol
Authors: Simpson Stephen J.
Published: September 2007

Immune cells move between the circulation system and tissues in response to infection. Upon detection of inflammation, leukocytes initiate a highly orchestrated sequence of events, whereby they attach and roll along on the surface of the endothelium before squeezing through to the underlying tissue. Auffray
et al
. reveal a quite distinct type of behavior displayed by a population of monocytes that remain attached to the endothelium in the absence of inflammation. The resident cells appeared to survey the surface of postcapillary venules, veins, and arteries, depending on specific chemokine and integrin signals. Upon detection of inflammatory cues, the cells move into infected sites, where they undergo differentiation into macrophages. Mueller
et al
. reveal how the down-regulation of chemokines in the lymph node prevents T lymphocytes from entering during an ongoing immune response. This delay may help to optimize the lymph node environment to produce the most effective immune response.

C. Auffray, D. Fogg, M. Garfa, G. Elain, O. Join-Lambert, S. Kayal, S. Sarnacki, A. Cumano, G. Lauvau, F. Geissmann, Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior.
Science
317
, 666-670 (2007).
[Abstract]
[Full Text]

S. N. Mueller, K. A. Hosiawa-Meagher, B. T. Konieczny, B. M. Sullivan, M. F. Bachmann, R. M. Locksley, R. Ahmed, M. Matloubian, Regulation of homeostatic chemokine expression and cell trafficking during immune responses.
Science
317
, 670-674 (2007).
[Abstract]
[Full Text]
Keeping Tabs on a TLR Response
Authors: Simpson Stephen J.
Published: September 2007

Toll-like receptors (TLRs) exert powerful proinflammatory responses to microbial pathogens, and TLR responses are stringently regulated during infection so that the chronic exposure of cells to microbial products can ultimately lead to a state of hyporesponsiveness. Carmody
et al
. identify an essential role for the proto-oncogene protein B cell leukemia (Bcl)-3 in negatively regulating TLR signaling in this context. Bcl-3 blocks ubiquitination of the nuclear factor κB subunit p50, which prevents its degradation and allows it to maintain its inhibition of gene transcription in response to TLR signals. This pathway offers a means by which microbial signals can be prevented from overpowering the immune response.

R. J. Carmody, Q. Ruan, S. Palmer, B. Hilliard, Y. H. Chen, Negative regulation of Toll-like receptor signaling by NF-κB p50 ubiquitination blockade.
Science
317
, 675-678 (2007).
[Abstract]
[Full Text]
Monitoring Cellular Mechanical Stress
Authors: Vinson Valda J.
Published: September 2007

Cells exert and respond to mechanical forces, but investigating how these signals are transduced is a challenge. By measuring differential labeling of cysteines in stressed and relaxed cells, Johnson
et al
. identify proteins that change their structure in response to stress. Using mass spectroscopy, they determined the specific Cys residues that experience structural changes. In red blood cells, spectrin unfolds as cells are stressed, and in mesenchymal stem cells, both myosin IIA and vimentin show differential labeling in tensed versus drug-relaxed cells.

C. P. Johnson, H.-Y. Tang, C. Carag, D. W. Speicher, D. E. Discher, Forced unfolding of proteins within cells.
Science
317
, 663-666 (2007).
[Abstract]
[Full Text]
High-Salt Survival Tactics
Authors: Vinson Valda J.
Published: September 2007

The Na
+
/H
+
antiporter NhaA is an inner-membrane protein in
Escherichia coli
that is required for survival in high salt or under alkaline stress. NhaA uses energy from proton transport down an electrochemical gradient into the cell to excrete Na
+
, but not K
+
, from the cytoplasm. Starting from a recently determined structure of NhaA, Arkin
et al
. performed molecular dynamics simulations to examine the mechanism of ion transport, pH regulation, and cation selectivity. The simulations, together with existing experimental data and mutagenesis experiments, indicate that three aspartates are essential to NhaA function: Asp
164
is the Na
+
binding site, Asp
163
controls alternating cytoplasmic or periplasmic access to the binding site, and Asp
133
is involved in pH regulation.

I. T. Arkin, H. Xu, M. Ø. Jensen, E. Arbely, E. R. Bennett, K. J. Bowers, E. Chow, R. O. Dror, M. P. Eastwood, R. Flitman-Tene, B. A. Gregersen, J. L. Klepeis, I. Kolossváry, Y. Shan, D. E. Shaw, Mechanism of Na
+
/H
+
antiporting.
Science
317
, 799-803 (2007).
[Abstract]
[Full Text]
Signals on the Move: Chemokine Receptors and Organogenesis in Zebrafish
Authors: Perlin Julie R. , Talbot William S.
Published: September 2007

The chemokine SDF1 (stromal cell–derived factor 1) directs cell migration in many different contexts, ranging from embryogenesis to inflammation. SDF1a is the guidance cue for the zebrafish lateral line primordium, a tissue that moves along the flank of the embryo and deposits cells that form mechanosensory organs. The SDF1a receptor CXCR4b acts in cells at the leading edge of the primordium to direct its migration. Two new studies show that a second SDF1 receptor, CXCR7, is required only in the trailing cells of the primordium, and they explore how these two receptors orchestrate migration of the primordium. CXCR4b and CXCR7 are expressed in complementary domains, possibly through mutual repression in which each receptor inhibits expression of the other. These studies illustrate how the entire primordium can respond to a single signal, yet generate cell type–specific responses by using different receptors.
Methods for Pseudopodia Purification and Proteomic Analysis
Authors: Wang Yingchun , Ding Shi-Jian , Wang Wei , Yang Feng , Jacobs Jon M. , Camp David , Smith Richard D. , Klemke Richard L.
Published: September 2007

Directional cell migration requires the formation of a dominant pseudopodium in the direction toward which the cell migrates. When a migratory cell is stimulated with a chemoattractant or extracellular matrix (ECM) gradient, it responds with localized amplification of signals on the side facing the gradient. The signals mediate reorganization of the actin-myosin cytoskeleton, leading to morphological polarization of the cell and pseudopodium extension. To identify these signals, we developed an approach to biochemically isolate the pseudopodium from the cell body using 3.0-micrometer porous filters for large-scale quantitative proteomic and phosphoproteomic analysis. Here, we detail the methodology for pseudopodium purification and proteomic analysis. This model system should be widely applicable for the analysis of the pseudopodium proteome from various migratory cell lines, including primary and cancer cell lines stimulated with a diverse array of chemoattractants, ECM proteins, or both.
Notch Sees Clearly
Authors: Foley John F.
Published: September 2007

To maintain the clarity required for light to reach the retina, the upper epidermal cells of the cornea are not keratinized and the lower stroma has no vasculature. Aberrant development of an opaque cornea after injury or disease is one of the leading causes of blindness. Vauclair
et al
. showed that mice with a skin-specific deficiency in Notch1, a receptor important for embryonic and postnatal development, developed corneal hyperplasia. Histopathological analysis showed that the corneal epithelia of Notch1-deficient mice became keratinized and thickened in comparison with those of wild-type mice. Corneal epithelial cells of Notch1-deficient mice were hyperproliferative as assessed by immunohistochemical detection of Ki67 (an antigen associated with actively growing cells), and the stroma of Notch1-deficient mice became vascularized. Notch1 deficiency also resulted in a loss of functional meibomian glands, which secrete a lipid layer that protects the eye from irritants. This led the authors to examine the role of wounding in initiating keratinization of the corneal epithelium. Whereas wounding of wild-type animals resulted in recovery of the epithelium, wounding of Notch1-deficient animals resulted in occlusion of the cornea and the expression of skin-specific keratins. DNA microarray analysis identified cellular retinol-binding protein (CRBP1), a protein important in the metabolism of vitamin A, as a downstream target of Notch1. Wounding of the corneal epithelium of CRBP1-deficient mice resulted in a phenotype similar to that observed in Notch1-deficient animals. These data show the importance of Notch1 in cell fate determination during wound repair and link Notch1 with vitamin A metabolism, which is important for maintaining a healthy cornea.

S. Vauclair, F. Majo, A.-D. Durham, N. B. Ghyselinck, Y. Barrandon, F. Radtke, Corneal epithelial cell fate is maintained during repair by Notch1 signaling via the regulation of vitamin A metabolism.
Dev. Cell
13
, 242-253 (2007).
[PubMed]
XRab40 Participates in a Ubiquitin Ligase Complex
Authors: Adler Elizabeth M.
Published: September 2007

Noting that some Rab GTPases (guanosine triphosphatases) have been implicated in embryogenesis, Lee
et al
. injected mRNA encoding Rab proteins into developing
Xenopus
embryos and found that the protein encoded by one of them inhibited gastrulation. This protein, XRab40, contained not only a GTPase domain but also a SOCS (suppressors of cytokine signaling) box domain. SOCS-box proteins associate with Elongin B and Elongin C as part of Cullin-based ubiquitin ligase complexes, and a combination of mass spectrometry analysis, yeast two-hybrid assays, and pull-down assays revealed that XRab40 interacted with the
Xenopus
homologs of Elongins B and C and Cullin5, and with the XRap2 GTPase. The SOCs box was required for XRab40 binding to XElonginB, XElonginC, and XCul5, whereas the GTPase domain was required for interaction with XRap2. XRab40 localized to the Golgi, and this localization depended on the SOCs box. Although wild-type XRab40 rescued gastrulation defects produced by antisense morpholino oligonucleotides directed against XRab40 (XRab40 Mo), mutants that did not localize to the Golgi failed to do so. Moreover, morpholinos directed against XCul5 (XCul5 Mo), which inhibited localization of XRab40 to the Golgi, elicited a phenotype similar to that of XRab40 Mo, as did a Cul5 dominant-negative mutant. XRab40 knockdown or mislocalization led to XRap2 mislocalization and a decrease in XRap2 ubiquitination (but not its stability). XRap2 bound to XMINK (Misshapen/Nck-interacting kinase) and morpholinos directed against XMINK also elicited gastrulation defects. Analyses of the ability to rescue morpholino-induced phenotypes indicated that XMINK acted downstream of XRab40 and XRap2. XMINK bound to Dishevelled (Dsh), translocation of which to the plasma membrane has been implicated in noncanonical Wnt signaling. Morpholinos directed against XRab40, XCul5, and XMINK inhibited Dsh localization to the plasma membrane when the Wnt pathway was activated. Thus, the authors conclude that XRab40 participates in a Cullin-based ubiquitin ligase complex, which regulates noncanonical Wnt signaling by way of XRap2 and XMINK and plays a critical role in
Xenopus
gastrulation.

R. H. K. Lee, H. Iioka, M. Ohashi, S.-i. Iemura, T. Natsume, N. Kinoshita, XRab40 and XCullin5 form a ubiquitin ligase complex essential for the noncanonical Wnt pathway.
EMBO J.
26
, 3592-3606 (2007).
[PubMed]
Fleeting Memories
Authors: Stern Peter
Published: September 2007

How persistent is our memory, how is it maintained, and how can it be disrupted? It has recently been shown that PKMζ, a protein kinase C isoform, is critical for maintaining hippocampus-dependent spatial memory and long-term potentiation. Using a conditioning taste aversion paradigm, Shema
et al
. (see the news story by Miller) found that long-term memory could be erased by infusion of a PKMζ inhibitor, ZIP, into the insular cortex. The activity of PKMζ was specifically involved in the storage of memories but not in their acquisition.

R. Shema, T. C. Sacktor, Y. Dudai, Rapid erasure of long-term memory associations in the cortex by an inhibitor of PKMζ.
Science
317
, 951-953 (2007).
[Abstract]
[Full Text]

G. Miller, Enzyme keeps old memories alive.
Science
317
, 883 (2007).
[Summary]
[Full Text]
Smell the CO
2
Authors: Ray L. Bryan
Published: September 2007

Although invertebrates are known to sense and show behavioral responses to concentrations of CO
2
similar to those in Earth's atmosphere, it has been unclear whether the mammalian olfactory system also can sense such amounts of CO
2
. Hu
et al
. describe a set of olfactory neurons that appear to allow detection of concentrations of CO
2
about 70% greater than those in air. The neurons express carbonic anhydrase II, which catabolizes CO
2
and appears to be required as part of the sensing mechanism.

J. Hu, C. Zhong, C. Ding, Q. Chi, A. Walz, P. Mombaerts, H. Matsunami, M. Luo, Detection of near-atmospheric concentrations of CO
2
by an olfactory subsystem in the mouse.
Science
317
, 953-957 (2007).
[Abstract]
[Full Text]
Toll-like Receptor 2 and Type 1 Diabetes
Authors: Foley John F.
Published: September 2007

Clearance of apoptotic cells by phagocytosis helps prevent the leakage of cellular contents that may stimulate inflammation or autoimmunity. Nonobese diabetic (NOD) mice develop type I diabetes (T1D) because of the impaired phagocytosis of apoptotic pancreatic β cells by macrophages; however the mechanism involved is unclear. Kim
et al
. (see commentary by Filippi and von Herrath) examined the responses of mouse macrophages [which enter the pancreas at the onset of T1D and later act as antigen-presenting cells (APCs) for T cells] to exposure to MIN6N8 insulinoma cells in various stages of radiation-induced cell death. Whereas incubation of macrophages with apoptotic MIN6N8 cells did not stimulate production of the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α), as measured by enzyme-linked immunosorbant assay (ELISA), secondary necrotic (SN) cells resulted in substantial TNF-α production. SN cells are late-stage, intact apoptotic cells that can be distinguished from apoptotic cells by flow cytometry on the basis of cell size and staining for markers of cell death and are characteristic of apoptotic cells that escaped phagocytosis. Gel-shift experiments showed that incubation of macrophages with SN MIN6N8 cells resulted in activation of the transcription factor nuclear factor-κB (NF-κB). Exposure of macrophages from
Tlr2
–/–
mice to SN cells resulted in a lower amount of TNF-α production than did exposure of wild-type macrophages to the cells.
Tlr2
–/–
mice were more resistant to T1D induced by pharmacological killing of β cells than were wild-type mice (as assessed by histological analysis of islets). Coculture and adoptive transfer experiments in mice showed that TLR2 was necessary for the maturation of APCs and the subsequent activation and proliferation of T cells that mediate T1D. These results link the accumulation of apoptotic cells with TLR2-dependent initiation of autoimmunity, raising the possibility of targeting TLR2 signaling in apoptosis-related diseases and autoimmune disorders.

H. S. Kim, M. S. Han, K. W. Chung, S. Kim, E. Kim, M. J. Kim, E. Jang, H. A. Lee, J. Youn, S. Akira, M.-S. Lee, Toll-like receptor 2 senses β-cell death and contributes to the initiation of autoimmune diabetes.
Immunity
27
, 321-333 (2007).
[PubMed]

C. M. Filippi, M. G. von Herrath, Islet β-cell death: Fuel to sustain autoimmunity?
Immunity
27
, 183-185 (2007).
[Online Journal]
A Silent Partner
Authors: Adler Elizabeth M.
Published: September 2007

Like the vertebrate retinoid X receptors (RXR) that it structurally and functionally resembles, the arthropod Ultraspiracle (USP) heterodimerizes with other nuclear receptors to transcriptionally activate target genes. Although various substances activate RXR and have been postulated to serve as endogenous ligands--and the USP binding partner EcR (ecdysone receptor) is known to be activated by ecdysone--the ligand for USP has remained unknown. Noting the similarity between the ligand-binding domain of USP in arthropods that are not Mecopterida (a group of insects) to that of the RXR, Iwema
et al
. cloned the USP of the beetle
Tribolium castaneum
(TcUSP) as a representative non-Mecopterida USP. RXR ligands failed to activate a protein containing the TcUSP D/E domains (containing regions important for ligand binding and heterodimerization) fused to the GAL4 DNA-binding domain (GAL4-TcUSP, which acted as a functional partner for EcR) when transiently expressed in cultured human or
Drosophila
cells. Similarly, RXR ligands failed to activate a GAL4-TcUSP transgene in organ cultures from transgenic
Drosophila
. Electrospray ionization mass spectrometric analysis indicated that TcUSP failed to bind RXR ligands in vitro, as did surface plasmon resonance (SPR) and limited proteolysis. Analysis of the crystal structure of the TcUSP ligand-binding domain in the context of the functional TcUSP-EcR heterodimer indicated that TcUSP exhibited a stable apo structure in an inactive "antagonist" conformation, which did not have a conventional ligand-binding pocket; moreover, SPR revealed that it failed to bind coactivator peptides. Phylogenetic analysis emphasized the evolutionary plasticity of the RXR-USP family ligand-binding domain, and indicated a lower evolutionary rate for the ligand-binding region of the vertebrate RXR than for that of the non-Mecopterida USP, suggesting that, even though non-Mercopterida USP do not, RXR do indeed bind endogenous ligands.

T. Iwema, I. M. Billas, Y. Beck, F. Bonneton, H. Nierengarten, A. Chaumot, G. Richards, V. Laudet, D. Moras, Structural and functional characterization of a novel type of ligand-independent RXR-USP receptor.
EMBO J.
26
, 3770-3782 (2007).
[PubMed]
Toll-Like Receptors in Brain Development and Homeostasis
Authors: Larsen Peter H. , Holm Thomas H. , Owens Trevor
Published: September 2007

Toll-like receptors (TLRs) are best known as initiators of the innate immune response to pathogens. Recent reports now reveal intriguing roles for TLRs in the central nervous system (CNS). These include the regulation of neuroinflammation and of neurite outgrowth. The archetypal Toll protein in
Drosophila melanogaster
was implicated in the development of the nervous system. Now similar functions have been uncovered for the mammalian orthologs, the TLRs. TLRs expressed on CNS glia and neurons may recognize endogenous ligands and participate both in development and in responses associated with CNS injury.
Knitting a Ravelled Sleave
Authors: Adler Elizabeth M.
Published: September 2007

For an activity in which we spend about a third of our lifetime, much about sleep remains enigmatic. Foltenyi
et al
. investigated the role of epidermal growth factor receptor (EGFR) signaling in regulating sleep in
Drosophila melanogaster
. Activation of fly EGFR ligands like Spitz depends on the transmembrane protein Star and on Rhomboid family (Rho) proteases. Using flies in which Rho and Star expression could be conditionally induced, the authors showed that their overexpression led to a dose-dependent increase in sleep. There was a transient increase in both the duration and number of sleep episodes, which was followed by a decrease and then a return to normal. Overexpression of a soluble form of Spitz, which does not require Rho processing, had similar effects. Overexpression of Rho and Star led to an increase in phosphorylation of extracellular signal-regulated kinase (ERK, a target of EGFR signaling) in the head that paralleled the temporal pattern of increased sleep, an increase that was blocked by coexpression of a dominant-negative EGFR mutant. Immunohistochemical analysis indicated that the increase in ERK phosphorylation was greatest in the tritocerebrum. Moreover, several lines of flies in which Rho activity in neurons projecting from the pars intercerebralis (PI, a region analogous to the vertebrate hypothalamus) to the tritocerebrum was inhibited with RNAi showed decreased sleep. This decrease involved brief sleep episodes in conjunction with an increase in the number of times that sleep was attempted--a pattern that could constitute a fly model of insomnia. The authors propose that the production of EGFR ligand by PI neurons leads to ERK activation in tritocerebrum neurons, thereby promoting sleep. Colwell provides thoughtful commentary.

K. Foltenyi, R. J. Greenspan, J. W. Newport, Activation of EGFR and ERK by rhomboid signaling regulates the consolidation and maintenance of sleep in
Drosophila
.
Nat. Neurosci
.
10
, 1160-1167 (2007).
[PubMed]

C. S. Colwell, Soporific signaling: How flies sleep through the night.
Nat. Neurosci
.
10
, 1079-1080 (2007).
[PubMed]