bluuebunny/crossref_metadata_2025 huggingface dataset:
The Emergence of Pattern in Embryogenesis: Regulation of β-Catenin Localization During Early Sea Urchin Development
Authors: Ettensohn Charles A.
Published: December 2006

The accumulation of β-catenin in the nuclei of blastomeres at one pole of the early embryo is a highly conserved and essential feature of animal development. In the sea urchin, β-catenin accumulates in the nuclei of vegetal blastomeres during early cleavage and activates gene regulatory networks that drive mesoderm and endoderm formation. Measurements of β-catenin half-life in vivo have demonstrated a gradient in stability along the animal-vegetal axis. Dishevelled (Dsh), a protein that regulates β-catenin turnover, is localized in the vegetal cortex, where it has an essential role in stabilizing β-catenin and activating endomesodermal gene networks. Two motifs of Dsh are required for targeting to the vegetal cortex. Overexpression of Dsh in animal blastomeres does not alter their fate, which suggests that a localized activator of Dsh may be missing in these cells. Wnt signaling may be localized in the early sea urchin embryo, as it is in
Xenopus
, but findings point to possible differences in the initial polarizing signal in amphibians and echinoderms. Further studies will be required to determine the extent to which mechanisms that control β-catenin nuclearization in early embryogenesis have been conserved during animal evolution.
Why Spider Bites Hurt
Authors: Gough Nancy R.
Published: December 2006

Peptide toxins produced by venomous creatures contain potent inhibitors of channel activity, and these inhibitors contribute to the shock, paralysis, and death that can accompany bites from one of these organisms. Siemens
et al
. show that, in addition to these potent channel inhibitors, spider venom has peptides of the inhibitor cysteine knot (ICK) family that activate transient receptor potential (TRPs) channels associated with pain perception. Venom from 22 spiders and scorpions was applied to human embryonic kidney (HEK) 293 cells transfected with TRPV1, TRPA1, or TRPM8 (all TRP channels found in primary afferent neurons, the activation of which is associated with pain and inflammation). Venom from one species of tarantula stimulated an increase in calcium signaling when applied to the TRPV1-expressing cells but not the TRPA1- or TRPM8-expressing cells. The active peptides were isolated and sequenced and named vanillotoxins 1, 2, and 3 (VaTx1, VaTx2, and VaTx3). VaTx1 and VaTx2 were most similar to an ICK that inhibits Kv2-type voltage-gated potassium channels, whereas VaTx3 resembles a toxin (huwentoxin 5) from another spider that has no known target. Huwentoxin 5 also triggered a calcium signal in TRPV1-expressing cells. VaTx1 and VaTx2 inhibited Kv2.1 activity, although VaTx2 was more potent at activating the TRPV1 channel than at inhibiting the Kv2.1 channel. VaTx3 did not inhibit Kv2.1 channels. Dose-response analysis showed that VaTx3 was most potent, followed by VaTx2, then VaTx1, and the abundance of these toxins in the venom was inversely correlated with their potency. To confirm the relevance of these results in pain transmission, the authors demonstrated that dissociated sensory neurons from mouse trigeminal ganglia responded to VaTx2 or VaTx3 with a robust calcium signal and that this response was abolished in neurons from mice deficient in TRPV1. Injection of VaTx3 into the paws of mice caused pain-related behaviors and swelling; these responses were absent in the TRPV1-deficient mice. These results provide mechanistic insight into the pain associated with bites from venomous animals and also new tools for studying TRP channel function.

J. Siemens, S. Zhou, R. Piskorowski, T. Nikai, E. A. Lumpkin, A. I. Basbaum, D. King, D. Julius, Spider toxins activate the capsaicin receptor to produce inflammatory pain.
Nature
444
, 208-212 (2006).
[PubMed]
Choosing Channel Selectivity
Authors: Kelner Katrina L.
Published: December 2006

Ion channel proteins form pores in the membranes of cells and are regulated by voltage or small messenger molecules to control information flow to and from cells. The K
+
channel, important for the excitability of nerve cells, conducts only K
+
ions while completely excluding a smaller ion, Na
+
. Valiyaveetil
et al
. show that this selectivity is accomplished in two ways: In the presence of K
+
, the pore remains open and conductive but collapses when K
+
concentrations are low, excluding Na
+
. In addition, in the conductive state, the pore is lined with multiple binding sites that are specific for K
+
.

F. I. Valiyaveetil, M. Leonetti, T. W. Muir, R. MacKinnon, Ion selectivity in a semisynthetic K
+
channel locked in the conductive conformation.
Science
314
, 1004-1007 (2006).
[Abstract]
[Full Text]
Converging on the Promoter
Authors: Adler Elizabeth M.
Published: December 2006

Steroid hormones modulate gene transcription through interactions of their receptors with hormone-responsive elements on target genes. Noting that steroid receptors also activate the extracellular signal-regulated kinase (ERK) signaling pathway, Vicent
et al
. used the T47D-MTVL breast cancer cell line--which carries a chromosomally integrated copy of the luciferase gene under the control of the MMTV-LTR promoter--to investigate the role of ERK signaling in progestin action. Treatment with the progesterone receptor (PR) agonist R5020 led to rapid phosphorylation of ERK1/2, the progesterone receptor-B isoform (PR
B
), and the ERK target MSK1 (mitogen- and stress-activated protein kinase 1) as well as to transcriptional activation of the MMTV reporter. Hormone-dependent phosphorylation of PR and MSK1 required ERK activation, as did the hormone-dependent induction of MMTV (which also required MSK1 activation) and other progesterone target genes. R5020 stimulated recruitment to the MMTV promoter of PR and a complex containing phosphorylated PR
B
, phosphorylated ERK, and phosphorylated MSK1. Furthermore, R5020 elicited a MSK1-dependent increase in phosphorylation on serine 10 of histone H3 of the MMTV promoter, associated with the MSK1-dependent loss of HP1γ (heterochromatin protein 1γ) and recruitment of chromatin-remodeling factors and RNA polymerase II. Thus, activation of the ERK signaling pathway appears to play a critical role in progestin-dependent gene transcription that involves MSK1-dependent phosphorylation of histone H3, enabling the loss of repressive complexes from the promoters of target genes and the recruitment of chromatin-remodeling factors.

G. P. Vicent, C. Ballaré, A. S. Nacht, J. Clausell, A. Subtil-Rodríguez, I. Quiles, A. Jordan, M. Beato, Induction of progesterone target genes requires activation of Erk and Msk kinases and phosphorylation of histone H3.
Mol. Cell.
24
, 367-381 (2006).
[PubMed]
Hippo Pathway Gains Fat
Authors: Ray L. Bryan
Published: December 2006

Three papers this week connect the atypical cadherin Fat to the Hippo signaling pathway (Hippo is a serine-threonine kinase that resembles the yeast Sterile-20 protein and acts as a tumor suppressor in
Drosophila
), which is implicated in the control of tissue or organ size. Fat is also a tumor suppressor in flies, and
fat
mutant flies showed overgrown imaginal discs similar to those of flies with mutations in the Hippo pathway. Cells lacking Fat grew and proliferated more quickly than did control cells and had increased amounts of Cyclin E and of the antiapoptotic protein Diap1. In the planar-cell polarity pathway, Fat interacts with another atypical cadherin, and the two are thought to function as receptor and ligand, respectively. In the control of organ size analyzed here, Fat appeared to interact with the cytoskeletal adaptor protein known as Expanded, which is the most upstream protein previously shown to function in the Hippo pathway. Fat was required for stability of the Expanded protein and its normal localization at the plasma membrane at apical junctions. The results indicate that Fat may serve as a cell-surface scaffold or receptor that leads to activation of the Hippo pathway through a mechanism that remains to be fully understood. The components of the Hippo pathway are conserved in vertebrates, and some have been implicated in tumorigenesis, but their roles in a pathway controlling cell proliferation or organ size remain to be investigated.

M. Willecke, F. Hamaratoglu, M. Kango-Singh, R. Udan, C.-L. Chen, C. Tao, X. Zhang, G. Halder, The Fat cadherin acts through the Hippo tumor-suppressor pathway to regulate tissue size.
Curr. Biol.
16
, 2090-2100 (2006).
[PubMed]

F. C. Bennett, K. F. Harvey, Fat cadherin modulates organ size in
Drosophila
via the Salvador/Warts/Hippo signaling pathway.
Curr. Biol.
16
, 2101-2110 (2006).
[PubMed]

E. Silva, Y. Tsatskis, L. Gardano, N. Tapon, H. McNeill, The tumor-suppressor gene
fat
controls tissue growth upstream of Expanded in the Hippo signaling pathway.
Curr. Biol.
16
, 2081-2089 (2006).
[PubMed]
The Bald Truth About Lipids
Authors: Kiberstis Paula A.
Published: December 2006

Hair loss can be traumatic, whether it is linked to illness or simply part of the natural aging process, and there is considerable interest in dissecting its underlying mechanisms. Kazantseva
et al
. identify a culprit gene in a group of Russian families who show an inherited deficiency in hair growth but are otherwise healthy. The mutant gene,
LIPH
, encodes lipase H, a phospholipase thought to regulate the production of lipid signaling molecules. This discovery will likely stimulate investigations aimed at understanding the precise role of lipase H in hair follicle biology and whether the
LIPH
gene also contributes to the more common forms of baldness in the general population.

A. Kazantseva, A. Goltsov, R. Zinchenko, A. P. Grigorenko, A. V. Abrukova, Y. K. Moliaka, A. G. Kirillov, Z. Guo, S. Lyle, E. K. Ginter, E. I. Rogaev, Human hair growth deficiency is linked to a genetic defect in the phospholipase gene
LIPH
.
Science
314
, 982-985 (2006).
[Abstract]
[Full Text]
Spotting Invaders
Authors: Riddihough Guy
Published: December 2006

The cell’s ability to distinguish invading RNA or DNA from the plethora of its own nucleic acid sequences plays a critical role in protecting the genome from potentially harmful damage, and a number of systems have evolved to sniff out unwanted alien genes and trigger cellular responses. Retinoic acid-inducible protein I (RIG-I), part of the cellular alarm system in the cytoplasm, specifically recognizes a number of RNA viruses, but what is RIG-I actually sensing? Hornung
et al
. and Pichlmair
et al
. show that RIG-I detects and binds to an unusual feature of the 5′ end of the viral RNA, specifically, a 5′-phosphate group.

V. Hornung, J. Ellegast, S. Kim, K. Brzózka, A. Jung, H. Kato, H. Poeck, S. Akira, K.-K. Conzelmann, M. Schlee, S. Endres, G. Hartmann, 5′-Triphosphate RNA is the ligand for RIG-I.
Science
314
, 994-997 (2006).
[Abstract]
[Full Text]

A. Pichlmair, O. Schulz, C. P. Tan, T. I. Näslund, P. Liljeström, F. Weber, C. Reis e Sousa, RIG-I-mediated antiviral responses to single-stranded RNA bearing 5′-phosphates.
Science
314
, 997-1001 (2006).
[Abstract]
[Full Text]

T. Fujita, Sensing viral RNA amid your own.
Science
314
, 935-936 (2006).
[Summary]
[Full Text]
PTEN Regulation, a Novel Function for the p85 Subunit of Phosphoinositide 3-Kinase
Authors: Barber Domingo F. , Alvarado-Kristensson Maria , González-García Ana , Pulido Rafael , Carrera Ana C.
Published: December 2006

Timely regulation of phosphatidylinositol-3,4-bisphosphate [PI(3,4)P
2
] and phosphatidylinositol-3,4,5-trisphosphate [PI(3,4,5)P
3
] abundance in cells is essential for the control of cellular homeostasis. The concentrations of these lipids are low in quiescent cells but rapidly and transiently increase following growth factor receptor (GFR) stimulation, which triggers cellular metabolic changes, proliferation, survival, and motility. Class I
A
phosphatidylinositol 3-kinase (PI3K), which is composed of a p85 (regulatory) and p110 (catalytic) subunits, is the enzyme generating PI(3,4)P
2
and PI(3,4,5)P
3
following GFR stimulation. Although the steps in GFR-induced activation of PI3K , are relatively well known, the mechanisms for subsequent 3-polyphospho-PI down-regulation are less understood. Examination of frequent genetic alterations in human cancer showed that PTEN (phosphatase with tensin homology on chromosome 10) is the major enzyme that decreases PI(3,4)P
2
and PI(3,4,5)P
3
cell content. Nonetheless, interpretation of the complexity of PTEN regulation remains a matter of debate. The recent description of diminished PTEN activity in liver-conditional knockout mice lacking the p85α PI3K regulatory subunit reveals a previously unknown p85α-dependent negative-feedback pathway that controls PI(3,4)P
2
and PI(3,4,5)P
3
half-life by regulating PTEN.
Ubiquitin and NEDD8: Brothers in Arms
Authors: Schmidt Mirko H. H. , Dikic Ivan
Published: December 2006

Ubiquitin (Ub) and ubiquitin-like (Ubl) proteins are small signaling molecules that are involved in many aspects of cell function. It has been assumed that Ub and Ubl have functionally distinct roles because they use different conjugation machineries and bind to different effector proteins. This paradigm, however, must be revisited after recent findings that signaling cascades mediated by Ub and the Ubl NEDD8 (Neural precursor cell–Expressed Developmentally Down-regulated 8) in the regulation of epidermal growth factor receptor (EGFR) endocytosis are redundant. In this context, Ub and NEDD8 share the same E3 ligase, Cbl, and are recognized by identical components of the endocytic sorting machinery. This unexpected redundancy introduces additional complexity to the current view of Ub signaling pathways.
Activating Gene Expression
Authors: Adler Elizabeth M.
Published: December 2006

Small noncoding double-stranded RNAs (dsRNA) have been implicated in RNA interference (RNAi) and thereby the silencing of gene expression. Li
et al
. transfected human prostate cancer cell lines with 21-nucleotide dsRNAs that targeted regions of the E-cadherin promoter and saw an increase in the abundance of E-cadherin mRNA and protein. The increase in E-cadherin mRNA abundance, which occurred within 48 hours and was apparent at dsRNA concentrations as low as 1 nM, was apparent for days and appeared to depend on target location on the promoter. Similar increases in target gene expression were seen in various human cell lines transfected with dsRNA targeting the promoters of the genes encoding vascular endothelial growth factor and p21
WAF1/CIP1
. Truncation and extension of the 21-nucleotide dsRNAs that stimulated E-cadherin expression suggested that neither 16-nucleotide nor 26-nucleotide dsRNAs were effective in stimulating gene expression. Further, mutational analysis of dsRNAs targeted against E-cadherin and p21 indicated that the 5′ region of the antisense strand was critical for dsRNA-induced gene activation (RNAa). Experiments using siRNA directed against Argonaute proteins indicated that Argonaute 2 (which is required for RNAi) was also necessary for RNAa. Chromatin immunoprecipitation analysis indicated that RNAa was associated with a loss of histone 3 methylation at lysine-9 at dsRNA target sites; however, bisulfite genomic sequencing indicated that changes in DNA methylation status were not involved. Thus, small noncoding RNAs appear to play a role in activating--as well as inhibiting--the expression of target genes.

L. C. Li, S. T. Okino, H. Zhao, D. Pookot, R. F. Place, S. Urakami, H. Enokida, R. Dahiya, Small dsRNAs induce transcriptional activation in human cells.
Proc. Natl. Acad. Sci. U.S.A.
103
, 17337-17342 (2006).
[Abstract]
[Full Text]
Fat But Healthy
Authors: Gough Nancy R.
Published: December 2006

Resveratrol is a polyphenolic compound produced by plants and found in red wine. It has been reported to extend life span in various model organisms, presumably through its ability to stimulate the deacetylase activity of sirtuins (there are seven isoforms in mammals, SIRT1 through 7). Baur
et al
. report that in mice, the addition of resveratrol to a high-calorie, high-fat diet (HCR) prevented much of the aging and disease associated with obesity without affecting body weight. Mice fed the HCR diet showed increased life span compared with high-calorie, high-fat diet (HC)-fed mice, and longevity was similar to that of mice on a standard diet. HCR mice exhibited greater insulin sensitivity and decreased circulating concentrations of glucose, insulin, and insulin-like growth factor 1 (IGF-1). The activity of adenosine monophosphate-activated protein kinase (AMPK), which is a crucial regulator of metabolism, was increased to a greater extent in the livers of the HCR-fed mice than in the livers of the HC-fed mice. Histology and assessment of various markers for the function of liver, pancreas, and heart indicated that the HCR diet prevented the damage associated with obesity. Acetylation of PGC-1α (peroxisome proliferator-activated receptor γ coactivator 1α) was decreased in the livers of the HCR-fed mice. PGC-1α is a substrate for SIRT1, and its acetylation status is used as a measure of SIRT activity. Parametric analysis of gene set enrichment (PAGE), a computational method for analyzing microarray data, suggested that resveratrol affected 127 biochemical and signaling pathways. Notable were the down-regulation of genes associated with insulin signaling and metabolism and the up-regulation of genes associated with STAT3 (signal transducer and activator of transcription 3) signaling. STAT3 signaling declines with age and may contribute to liver regeneration. Although it would obviously be best to limit caloric intake and exercise, this study suggests that there may be pharmacological interventions that can prevent some of the diseases associated with obesity (see Kaeberlein and Rabinovitch).

M. Kaeberlein, P. S. Rabinovitch, Grapes versus gluttony.
Nature
444
, 280-281 (2006).
[PubMed]

J. A. Baur, K. J. Pearson, N. L. Price, H. A. Jamieson, C. Lerin, A. Kalra, V. V. Prabhu, J. S. Allard, G. Lopez-Lluch, K. Lewis, P. J. Pistell, S. Poosala, K. G. Becker, O. Boss, D. Gwinn, M. Wang, S. Ramaswamy, K. W. Fishbein, R. G. Spencer, E. G. Lakatta, D. Le Couteur, R. J. Shaw, P. Navas, P. Puigserver, D. K. Ingram, R. de Cabo, D. A. Sinclair, Resveratrol improves health and survival of mice on a high-calorie diet.
Nature
444
, 337-342 (2006).
[PubMed]
Shedding Light on Immunosuppression
Authors: Adler Elizabeth M.
Published: December 2006

Ultraviolet (UV) radiation from sunlight has been implicated in causing skin cancer and, perhaps not coincidentally, suppresses the immune response. UV-dependent immune suppression depends on the absorption of its electromagnetic energy by an epidermal photoreceptor.
Trans
-urocanic acid (UCA) isomerizes to
cis
-UCA in response to UV exposure, and epidermal UCA has long been known to act as a UV photoreceptor that can mediate immune suppression. The mechanism whereby
cis
-UCA affects the immune response, however, has been unclear.
Cis
-UCA forms a ringlike structure in solution, and Walterscheid
et al
.--who serendipitously observed that the serotonin [5-hydroxytryptamine (5-HT)] receptor antagonist ketanserin blocked UV- and
cis
-UCA-mediated immune suppression--used competitive binding assays to show that radiolabeled
cis
-UCA bound to human serotonin receptors. Immunoprecipitation analysis with antibodies directed against
cis
-UCA or serotonin confirmed the structural similarity of the two compounds, and saturation binding studies indicated that
cis
-UCA bound to the human 5-HT
2A
receptor with a K
d
of 4.6 nM.
Cis
-UCA stimulated calcium mobilization in L-NCG-5-HT
2A
cells but not in untransfected controls [LM(TK
–
) cells], and this calcium mobilization was blocked by ketanserin. UV- or
cis
-UCA-induced immune suppression in mice was blocked by antibodies directed against serotonin (as well as by antibodies directed against
cis
-UCA) and by 5-HT
2A
receptor antagonists. Thus, the authors propose that the ability of
cis
-UCA to suppress the immune response--and that of UV radiation--is mediated through the 5-HT
2A
receptor.

J. P. Walterscheid, D. X. Nghiem, N. Kazimi, L. K. Nutt, D. J. McConkey, M. Norval, S. E. Ullrich,
Cis
-urocanic acid, a sunlight-induced immunosuppressive factor, activates immune suppression via the 5-HT
2A
receptor.
Proc. Natl. Acad. Sci. U.S.A.
103
, 17420-17425 (2006).
[Abstract]
[Full Text]
Hsp90 Controls GSK-3β Kinase Specificity
Authors: Ray L. Bryan
Published: December 2006

Glycogen synthase kinase 3 (GSK3) has long been known as a signaling component in insulin regulation of metabolism and, more recently, as a key part of the Wnt signaling pathway regulating cell proliferation, cell fate, and other processes during development. Unlike most other kinases, GSK3 is constitutively active and is regulated by inhibition. Full expression of this constitutive activity in the mammalian enzyme appears to require phosphorylation of a tyrosine residue in the activation loop of GSK3, which the enzyme accomplishes by intramolecular autophosphorylation, even though the kinase phosphorylates strictly serine and threonine residues on its exogenous substrates. Lochhead
et al
. explored the mechanism by which this switch in residue specificity is possible. Tagged GSK-3β synthesized in a rabbit reticulocyte lysate translation system showed rapid autophosphorylation that was inhibited by inhibitors of the molecular chaperone protein Hsp90. This chaperone-assisted tyrosine kinase activity was specific for tyrosine, as substitution of serine or threonine for the tyrosine in the activation loop reduced the extent of autophosphorylation. The tyrosine kinase activity was also insensitive to inhibitors or GSK-3β’s serine-threonine kinase activity toward its substrates. Attention is focused on the potential therapeutic value of inhibition of GSK-3β activity in a number of disease states, and the authors note that the auto-activation mechanism provides a possible target, with distinct specificity for inhibition from the serine-threonine kinase enzymatic activity of the mature enzyme.

P. A. Lochhead, R. Kinstrie, G. Sibbet, T. Rawjee, N. Morrice, V. Cleghon, A chaperone-dependent GSK3β transitional intermediate mediates activation-loop autophosphorylation.
Mol. Cell
24
, 627-633 (2006).
[Online Journal]
The Long and the Short of Relaxin Signaling
Authors: Ray L. Bryan
Published: December 2006

The hormone relaxin functions in the reproductive system and derived its name from its role in relaxation of the pubic symphysis during parturition. Relaxin and the related hormone insulin-like peptide 3 (INSL3) act through heterotrimeric guanine nucleotide­-binding protein (G protein)-coupled receptors (GPCRs). Scott
et al
. report studies of human splice variants of these proteins that reveal an unusual mode of signaling by these receptors. The receptors for relaxin and INSL3, called LGR7 (leucine-rich repeat-containing GPCR 7) and LGR8, respectively [or, in an alternative nomenclature, relaxin family peptide receptors 1 and 2 (RXFP1 and RXFP2)] differ from other GPCRs in that they contain N-terminal domains with similarity to the ligand-binding domains of low-density lipoprotein class A (LDLa). Splice variants exist in which this LDLa module is missing or in which a secreted protein mainly encoding just the LDLa module is made. The authors examined the signaling properties of natural or artificial variant receptors in transfected cells. Although they bound relaxin normally, LGR7 variants without the LDLa module failed to produce their normal G protein-coupled signaling effects on accumulation of cyclic AMP. The truncated excreted form inhibited signaling from the normal receptor. It is not yet clear precisely how the LDLa modules influence signaling. In LDL receptors, these modules are binding sites for ligands or for protein-protein interactions. The truncated, excreted form of LDL7 was detected in human uterus and brain and was most abundant in uteri of pregnant mice. Thus, the authors propose that LGR7 and LGR8 have an unusual mechanism of GPCR signaling and that the alternative splicing of the receptors may produce an inhibitory factor that provides an additional regulatory mechanism for controlling relaxin action during reproduction.

D. J. Scott, S. Layfield, Y. Yan, S. Sudo, A. J. W. Hsueh, G. W. Tregear, R. A. D. Bathgate, Characterization of novel splice variants of LGR7 and LGR8 reveals that receptor signaling is mediated by their unique low density lipoprotein class A modules.
J. Biol. Chem.
281
, 34942-34954 (2006).
[Abstract]
[Full Text]
Directing the Mucosal Immune Response
Authors: Simpson Stephen
Published: December 2006

The mucosal lining of the intestine is stuffed with antibody-secreting B cells, which produce vast quantities of immunoglobulin A (IgA), a specialized form of antibody equipped specifically for secretion across the gut wall, where it protects against enteric pathogens. The cues that make a mucosal B cell produce IgA, rather than any of the other forms of antibody, are unclear. Mora
et al
. now show that another immune cell, the dendritic cell, imparts this information within lymphoid tissue associated with the gut. Once activated by the gut dendritic cells, B cells become "imprinted" to enter the circulation and then home back to the mucosal lining to begin IgA production. Induction depended on the vitamin A metabolite retinoic acid, which may explain why vitamin A deficiency exacerbates childhood diarrheal disease in the developing world.

J. R. Mora, M. Iwata, B. Eksteen, S.-Y. Song, T. Junt, B. Senman, K. L. Otipoby, A. Yokota, H. Takeuchi, P. Ricciardi-Castagnoli, K. Rajewsky, D. H. Adams, U. H. von Andrian, Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells.
Science
314
, 1157-1160 (2006).
[Abstract]
[Full Text]
Sorting, Signaling, and Sara
Authors: Hurtley Stella M.
Published: December 2006

Morphogenic gradients of signaling molecules are key to tissue patterning during development. Endocytic compartments have been shown to play a role in the generation and maintenance of such gradients. Bökel
et al
. (see the Perspective by Knoblich) now provide evidence that the apical signaling endosome, characterized by the presence of the protein Sara (Smad anchor for receptor activation), uses the mitotic spindle to distribute developmentally important signaling molecules across division. This process ensures that the two daughter cells retain information contained in the morphogen gradient.

C. Bökel, A. Schwabedissen, E. Entchev, O. Renaud, M. González-Gaitán, Sara endosomes and the maintenance of Dpp signaling levels across mitosis.
Science
314
, 1135-1139 (2006).
[Abstract]
[Full Text]

J. A. Knoblich, Sara splits the signal.
Science
314
, 1094-1096 (2006).
[Summary]
[Full Text]
Pannexin-1: A P2X
7
ATP Receptor-Activated Pore
Authors: Gough Nancy R.
Published: December 2006

Activation of the inflammasome, a complex that processes interleukin-1β (IL-1β), occurs in response to activation of the adenosine triphosphate receptor P2X
7
on macrophages. Activation of P2X
7
also triggers the opening of a nonselective, large pore in the plasma membrane. Pelegrin and Surprenant found that pannexin-1 (panx1), a protein that produces hemichannel currents when ectopically expressed in oocytes, was present in monocytes, macrophages, astrocytes, and various cell lines. Panx1, when expressed in transfected HEK cells, coimmunoprecipitated with the P2X
7
receptor and colocalized with the P2X
7
receptors in ATP-stimulated cells. Using either an siRNA to knock down panx1 or a peptide inhibitor to block the pore function of panx1, the authors showed that dye uptake (a measure of pore opening) in response to P2X
7
required panx1. When overexpressed in cells that lack P2X
7
receptors, panx1 caused constitutive dye uptake, and when overexpressed in cells that contain P2X
7
receptors, panx1 increased the rate of dye uptake in response to ATP but did not cause constitutive dye uptake. Inhibition of panx1 function in macrophages or a monocyte cell line prevented P2X
7
-mediated stimulation of caspase 1 activation and IL-1β release. However, inhibition of panx1 function did not prevent intracellular K
+
depletion, which has been proposed as an activator of the inflammasome. The authors propose that opening of the pannexin1 channel in response to P2X
7
activation may allow extracellular ATP to enter the cell and the increased intracellular ATP concentration may contribute to the activation of caspase 1.

P. Pelegrin, A. Surprenant, Pannexin-1 mediates large pore formation and interleukin-1β release by the ATP-gated P2X
7
receptor.
EMBO J.
25
, 5071-5082 (2006).
[PubMed]
The Inositol 1,4,5-Trisphosphate Receptor (IP
3
R) and Its Regulators: Sometimes Good and Sometimes Bad Teamwork
Authors: Choe Chi-un , Ehrlich Barbara E.
Published: December 2006

In both nonexcitable and excitable cells, the inositol 1,4,5-trisphosphate receptor (IP
3
R) is the primary cytosolic target responsible for the initiation of intracellular calcium (Ca
2+
) signaling. To fulfill this function, the IP
3
R depends on interaction with accessory subunits and regulatory proteins. These include proteins that reside in the lumen of the endoplasmic reticulum (ER), such as chromogranin A and B and ERp44, and cytosolic proteins, such as neuronal Ca
2+
sensor 1, huntingtin, cytochrome c, IP
3
R-binding protein released with inositol 1,4,5-trisphosphate, Homer, and 4.1N. Specific interactions between these modulatory proteins and the IP
3
R have been described, making it clear that the controlled modulation of the IP
3
R by its binding partners is necessary for physiological cell regulation. The functional coupling of these modulators with the IP
3
R can control apoptosis, intracellular pH, the initiation and regulation of neuronal Ca
2+
signaling, exocytosis, and gene expression. The pathophysiological relevance of IP
3
R modulation is apparent when the functional interaction of these proteins is enhanced or abolished by mutation or overexpression. The subsequent deregulation of the IP
3
R leads to pathological changes in Ca
2+
signaling, signal initiation, the amplitude and frequency of Ca
2+
signals, and the duration of the Ca
2+
elevation. Consequences of this deregulation include abnormal growth and apoptosis. Complex regulation of Ca
2+
signaling is required for the cell to live and function, and this difficult task can only be managed when the IP
3
R teams up and acts properly with its numerous binding partners.
Males Afraid, Females Brave
Authors: Gough Nancy R.
Published: December 2006

There are different kinds of memories. In mice, differences have been noted in contextual fear memory formation and spatial memory formation, although both forms of memory appear to involve a calcium signal and the activation of calcium/calmodulin-dependent kinases (CaMKs). In mice, there are two isoforms of CaMK that have been implicated in memory formation (CaMKI and CaMKIV) and two upstream kinases that phosphorylate CaMK (CaM kinase kinases: CaMKKα and CaMKKβ). CaMKKβ has been implicated in spatial memory formation, and CaMKIV has been implicated in long-term potentiation and fear conditioning. Two groups, Blaeser
et al
. and Mizuno
et al
., created mice deficient in CaMKKα function and found that the mice showed normal spatial memory, normal motor activity, and normal sensory perception; however, male mice were impaired in the formation of contextual fear memories. Synaptic transmission was not impaired in the CamKKα-deficient mice, nor was formation of hippocampal long-term potentiation. Blaeser
et al
. showed that, compared with wild-type mice, the CamKKα-deficient male mice exhibited decreased phosphorylation of CaMKIV and the transcriptional regulator CREB (a substrate of CaMKIV) in response to fear conditioning. Phosphorylation of CREB under basal conditions was increased in the mutant mice in certain brain regions; however, the fear-induced increases in phosphorylation were absent. Mizuno
et al
. investigated memory formation in both male and female mice deficient for CaMKKα and noted that females did not show impairment of contextual fear conditioning. (It was known that female mice tend to exhibit contextual fear conditioning to a lesser extent than do male mice.) In wild-type mice, contextual fear conditioning promoted an increase in brain-derived neurotrophic factor (BDNF) in males only and a decrease in BDNF in females (transcript abundance was measured by real-time polymerase chain reaction). In the CaMKKα-deficient mice, the increase in BDNF in males was compromised, but the decrease in females was unaffected. The gene encoding BDNF is a CREB target; however, expression of another gene regulated by CREB, the gene encoding nerve growth factor-inducible gene B (NGF-1B), was increased in response to fear conditioning in both males and females and was not affected by lack of CaMKKα. Thus, in addition to specific forms of memory requiring specific signaling cascades, there is an additional gender-specific layer of regulation.

F. Blaeser, M. J. Sanders, N. Truong, S. Ko, L. J. Wu, D. F. Wozniak. M. S. Fanselow, M. Zhuo, T. A. Chatila, Long-term memory deficits in Pavlovian fear conditioning in Ca
2+
/calmodulin kinase kinase α-deficient mice.
Mol. Cell. Biol.
26
, 9105-9115 (2006).
[Abstract]
[Full Text]

K. Mizuno, L. Ris, A. Sánchez-Capelo, E. Godaux, K. P. Giese, Ca
2+
/calmodulin kinase kinase α is dispensable for brain development but is required for distinct memories in male, though not in female, mice.
Mol. Cell. Biol.
26
, 9094-9104 (2006).
[Abstract]
[Full Text]
Of Arsenic and NF-κB
Authors: Adler Elizabeth M.
Published: December 2006

Arsenic (used in the therapy of some cancers) is carcinogenic at low doses but can be cytotoxic at higher concentrations. Song
et al
. investigated the mechanisms underlying arsenite cytotoxicity, focusing on the role of nuclear factor-κB (NF-κB), a family of proteins sequestered in the cytoplasm that translocates to the nucleus to regulate the transcription of target genes when activated by means of IκB kinase (IKK). Although NF-κB generally mediates antiapoptotic signals--in part through inhibition of c-Jun N-terminal kinase (JNK) signaling--under some conditions, NF-κB signaling is proapoptotic. Wild-type mouse embryo fibroblasts (MEFs) were more sensitive to the cytotoxic effects of arsenite than were MEFs lacking IKKβ or expressing an IKKβ dominant-negative. IKKβ
–/–
MEFs failed to show arsenite-dependent JNK phosphorylation, and inhibition of JNK signaling attenuated arsenite-mediated cell death. Arsenite stimulated NF-κB-dependent phosphorylation of MKK4, a kinase upstream of JNK that dominant-negative experiments implicated in arsenite-mediated JNK activation and cell death. Arsenite acted through IKKβ-NF-κB to increase the abundance of GADD45α (growth arrest and DNA damage-inducible gene); experiments with GADD45α overexpression and silencing indicated that GADD45α up-regulation was required for arsenite-induced phosphorylation of MKK4 and JNK. Analysis of MEFs from knockout mice implicated the NF-κB1 subunit (p50), which lacks a transactivation domain, in arsenite’s cytotoxic effects. Indeed, a combination of pharmacological analysis and immunoprecipitation in wild-type, IKKβ
–/–
, and p50
–/–
MEFs suggested that GADD45α up-regulation depended on p50-dependent inhibition of ubiquitination and proteasomal degradation. Thus, arsenite-mediated cytotoxicity appears to involve IKKβ-NF-κB-dependent activation of JNK signaling through a mechanism that depends on accumulation of GADD45α rather than the transcriptional activation of target genes.

L. Song, J. Li, D. Zhang, Z.-g. Liu, J. Ye, Q. Zhan, H.-M. Shen, M. Whiteman, C. Huang, IKKβ programs to turn on the GADD45-MKK4-JNK apoptotic cascade specifically via p50 NF-κB in arsenite response.
J. Cell Biol.
175
, 607-617 (2006).
[Abstract]
[Full Text]
Brain Versus Brawn
Authors: Kiberstis Paula A.
Published: December 2006

The clock genes that control circadian rhythms in mammals also contribute to other aspects of physiology, behavior, and health. One such clock gene,
Bmal1
, encodes a transcription factor whose inactivation in mice causes disturbances in circadian rhythms and alterations in activity level, body weight, and other physiological functions. By re-expressing the
Bmal1
gene in selective tissues in
Bmal1
-deficient mice, McDearmon
et al
. show that the transcription factor exerts distinct tissue-specific functions. Circadian rhythmicity in the mutant mice was normalized only when
Bmal1
was expressed in the brain, whereas normalization of the animals’ activity level and body weight required
Bmal1
expression in muscle.

E. L. McDearmon, K. N. Patel, C. H. Ko, J. A. Walisser, A. C. Schook, J. L. Chong, L. D. Wilsbacher, E. J. Song, H.-K. Hong, C. A. Bradfield, J. S. Takahashi, Dissecting the functions of the mammalian clock protein BMAL1 by tissue-specific rescue in mice.
Science
314
, 1304-1308 (2006).
[Abstract]
[Full Text]
Brassinosteroid Signaling Pathway
Authors: Belkhadir Youssef , Wang Xuelu , Chory Joanne
Published: December 2006

Plant growth is regulated by an intricate network of hormonal signaling pathways. These small-molecule hormones cause changes in gene expression that are associated with cell expansion and division and changes in development. Paradoxically, six of these hormones appear to have largely overlapping functions, yet the loss of response to any one hormone cannot be compensated by the action of another plant hormone. Among these hormones are the brassinosteroids (BRs), the polyhydroxylated steroid hormones of plants. The emerging picture of BR signal transduction diverges radically from the paradigms of animal steroid signaling, which generally involve the action of members of the nuclear receptor superfamily. BRs bind the extracellular domain of a small family of leucine-rich-repeat receptor kinases to activate intracellular signal transduction cascades that regulate the expression of hundreds of genes. The signaling pathway involves a cell surface receptor complex, a glycogen synthase kinase 3, a kelch-containing serine/threonine phosphatase, and a novel family of basic helix-loop-helix and Myc-like plant specific transcription factors. The receptor and each of the signaling components were identified in
Arabidopsis thaliana,
and knowledge of their sequences allowed identification of orthologs in rice, tomato, barley, and pea.
Arabidopsis
Brassinosteroid Signaling Pathway
Authors: Belkhadir Youssef , Wang Xuelu , Chory Joanne
Published: December 2006

Plants control their size through the action of several phytohormones. One class of growth-promoting hormones is the brassinosteroids (BRs), the polyhydroxylated steroid hormones of plants. Here, we present the
Arabidopsis-
specific proteins that are the founding members of key BR signaling pathway components found in all plants. The genetic studies that identified these components are unique to
Arabidopsis
owing to its rapid generation time, sophisticated genetics, and facile transformation protocols, thereby highlighting the importance of a reference plant for understanding fundamental processes in all land plants.
Pheromone Signaling Pathways in Yeast
Authors: Dohlman Henrik G. , Slessareva Janna E.
Published: December 2006

The actions of many extracellular stimuli are elicited by complexes of cell surface receptors, heterotrimeric guanine nucleotide–binding proteins (G proteins), and mitogen-activated protein kinase (MAPK) complexes. Analysis of haploid yeast cells and their response to peptide mating pheromones has produced important advances in the understanding of G protein and MAPK signaling mechanisms. Many of the components, their interrelationships, and their regulators were first identified in yeast. Examples include definitive demonstration of a positive signaling role for G protein βγ subunits, the discovery of a three-tiered structure of the MAPK module, development of the concept of a kinase-scaffold protein, and the discovery of the first regulator of G protein signaling protein. New and powerful genomic, proteomic, and computational approaches available in yeast are beginning to uncover new pathway components and interactions and have revealed their presence in unexpected locations within the cell. This updated Connections Map in the Database of Cell Signaling includes several major revisions to this prototypical signal response pathway.
Notch Signaling Pathway
Authors: Ehebauer Matthias , Hayward Penelope , Martinez-Arias Alfonso
Published: December 2006

Notch is a receptor that mediates intercellular signaling through a pathway conserved across the metazoa. It is involved in cell fate assignation and pattern formation during development. The receptor acts as a membrane-tethered transcription factor and is activated by members of the Delta, Serrate, Lag-2 family of Notch ligands, which trigger two successive proteolytic cleavages of the receptor. The second cleavage releases the intracellular domain of Notch, which translocates to the nucleus, where it interacts with the CSL family of transcriptional regulators and forms part of a Notch target gene–activating complex. In the absence of signaling, CSL [CBF1, Su(H), Lag-1] regulators repress Notch target genes through interactions with several transcriptional co-repressors that recruit histone deacetylases and other chromatin-modifying enzymes. After forming, the transcription-activating binary Notch intracellular domain–CSL complex recruits several proteins that facilitate transcription, among them the coactivator MAM and histone acetylases. Transcription of target genes is terminated when the Notch intracellular domain is degraded in a proteasome-dependent manner.
Signal Reception and Transmission
Authors: Gough Nancy R.
Published: December 2006

From plants to yeast to animals, new pathways and updates to the Database of Cell Signaling highlight how signals received at the surface are transmitted into the cell to mediate complex cellular responses.
Stimulating Phagocytosis
Authors: Adler Elizabeth M.
Published: December 2006

Phagocytes engulf microbes by enveloping them in a patch of membrane and internalizing them in phagosomes, which fuse with endosomes and lysosomes to form the phagolysosomes in which the internalized pathogens are destroyed. Trivedi
et al
. exposed mouse macrophages to latex beads to investigate mechanisms through which immunoglobulin G (IgG) class antibodies, which stimulate phagocytosis, might promote the latter part of this process. When macrophages incubated with beads coated with either bovine serum albumin or IgG at 15
o
C (allowing bead engulfment but not fusion of phagosomes with lysosomes) were warmed to 37
o
C, the association of IgG-coated beads with fluorescently labeled phagolysosomes was faster than that of the albumin-coated beads. A cytosol-dependent cell-free scintillation proximity assay, in which phagosomes containing scintillant beads were incubated with tritium-labeled lysosomes, revealed that cytosol from phagocytes incubated with IgG beads was more effective at promoting phagosome-lysosome interactions than cytosol from cells that had not been incubated with IgG beads. Similarly, cytosol from CHO cells transfected with human Fcγ receptor IIa (making them phagocytic) and incubated with IgG beads promoted phagosome-lysosome interactions more effectively than that from cells unexposed to IgG beads, an effect enhanced by transfection of the cells with protein kinase C (PKC)-α. Moreover, inhibition of PKC abolished the stimulatory effect of IgG in the in vitro assay and blocked IgG-dependent stimulation of phagosome maturation in cells. Further pharmacological analysis indicated that IgG stimulated the actin-dependent tethering or docking (or both) of phagosomes and lysosomes. Thus, facilitation of phagosome-lysosome attachment by way of PKC appears to be one mechanism whereby IgG signaling stimulates phagocytosis.

V. Trivedi, S. C. Zhang, A. B. Castoreno, W. Stockinger, E. C. Shieh, J. M. Vyas, E.-M. Frickel, A. Nohturfft, Immunoglobulin G signaling activates lysosome/phagosome docking.
Proc. Natl. Acad. Sci. U.S.A.
103
, 18226-18231 (2006).
[Abstract]
[Full Text]
A Painful Endogenous Opioid
Authors: Gough Nancy R.
Published: December 2006

Dynorphin A
1-17
is derived from proteolytic processing of prodynorphin and has high affinity for μ, δ, and κ opioid receptors. However, increased amounts of dynorphin A are found in models of chronic pain, and antibodies against dynorphin A alleviate, rather than potentiate, pain. Lai
et al
. show that a fragment of dynorphin A that has low affinity for the opioid receptors (dynorphin A
2-13
) stimulated a transient increase in intracellular calcium concentration in cultured embryonic dorsal root ganglion (DRG) cells and in F-11 cells, a neuroblastoma-DRG hybridoma. The increase in intracellular calcium was blocked by selective inhibition of L-type or P/Q-type voltage-sensitive calcium channels. A bradykinin B2 antagonist blocked the dynorphin-induced increase in intracellular calcium, and transfection of either the bradykinin B2 or B1 receptor reconstituted dynorphin A
2-13
responsiveness in cells that had spontaneously lost the ability to respond to dynorphin A. Dynorphin A
2-13
or dynorphin A
1-17
competed for binding to B1 or B2 receptors, suggesting that dynorphin is acting as an agonist at the bradykinin receptors. In rats, intrathecal injection of dynorphin A
2-13
caused enhanced sensitivity to touch and heat, and these effects were reversed by injection of a B2 receptor antagonist. Furthermore, knockout mice lacking B2 receptors did not show hypersensitive responses in response to dynorphin A
2-13
injection. Finally, in a rat model of neuropathic pain, B2 receptor and prodynorphin transcript abundance were increased in the DRG of rats as early as day 2 after nerve injury, and treatment with a B2 antagonist after nerve injury prevented hypersensitivity responses. As discussed by Altier and Zamponi, it appears that under conditions of chronic pain, enhanced production of dynorphin in the spinal cord produces a hyperalgesia response instead of an analgesic response through the ability of dynorphin to activate spinal bradykinin receptors.

J. Lai, M.-C. Luo, Q. Chen, S. Ma, L. R. Gardell, M. H. Ossipov, F. Porreca, Dynorphin A activates bradykinin receptors to maintain neuropathic pain.
Nat. Neurosci.
9
, 1534-1540 (2006).
[PubMed]

C. Altier, G. W. Zamponi, Opioid, cheating on its receptors, exacerbates pain.
Nat. Neurosci.
9
, 1465-1467 (2006).
[PubMed]