Featured
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Letter |
Control of cortical GABA circuitry development by Nrg1 and ErbB4 signalling
Although several synaptic adhesion proteins have been identified as genetic risk factors in schizophrenia, it is unclear as to what role they play in disease progression. Here, it is shown that two such proteins — neuregulin 1 and its receptor ErbB4 — function to regulate the connectivity of specific cortical circuits. The study not only implicates these proteins in the wiring of inhibitory synapses, about which little is known, but also provides a new perspective on their involvement in schizophrenia.
- Pietro Fazzari
- , Ana V. Paternain
- & Beatriz Rico
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Article |
Adiponectin and AdipoR1 regulate PGC-1α and mitochondria by Ca2+ and AMPK/SIRT1
Adiponectin is a protein with anti-diabetic properties; its levels are decreased in obesity, insulin resistance and type 2 diabetes. It is shown here that mice with a muscle-specific disruption of adiponectin receptor 1 (AdipoR1) are insulin resistant and less able to endure exercise. The pathway downstream of receptor activation is delineated; the findings suggest that the decreased levels of adiponectin and AdipoR1 seen in obesity may have causal roles in the mitochondrial dysfunction and insulin resistance seen in diabetes.
- Masato Iwabu
- , Toshimasa Yamauchi
- & Takashi Kadowaki
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Letter |
NINJA connects the co-repressor TOPLESS to jasmonate signalling
In plants, the hormone jasmonoyl-isoleucine (JA-Ile) regulates growth, development and defence against pathogens. Proteins of the JAZ family repress JA-Ile-dependent gene expression, but the mechanism has been unclear. Here, an adaptor protein, NINJA, has been identified, which recruits co-repressor proteins that are known to mediate auxin-responsive gene expression as well. Hence these co-repressors are part of general repression complexes that are recruited to several different signalling pathways.
- Laurens Pauwels
- , Gemma Fernández Barbero
- & Alain Goossens
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Letter |
Phosphorylation of histone H3T6 by PKCβI controls demethylation at histone H3K4
The amino-terminal tails of histone proteins are subject to a variety of post-translational modifications; addition or removal of these 'marks' facilitates gene activation or silencing. Here, a mechanism is defined that modulates the activity of the dual-specificity histone demethylase LSD1 during androgen-dependent transcription. Androgen-dependent signalling through protein kinase C beta I leads to phosphorylation of a histone amino acid, which prevents demethylation of an adjacent amino acid by LSD1.
- Eric Metzger
- , Axel Imhof
- & Roland Schüle
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Research Highlights |
Neuroscience: Nerve cell talk
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Research Highlights |
Cancer biology: Arsenic activation
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Letter |
Spatial control of EGF receptor activation by reversible dimerization on living cells
Signalling through the epidermal growth factor receptor (EGFR) is preceded by its dimerization, which has typically been thought to occur through a ligand-induced conformational change. Here, the dimerization dynamics of individual EGFR molecules have been determined in living cells in real time, using a quantum-dot-based approach. Unliganded EGFR molecules undergo spontaneous and reversible dimerization; these pre-formed dimers are primed for ligand binding and signalling and are enriched at the cell periphery.
- Inhee Chung
- , Robert Akita
- & Ira Mellman
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Article |
Systems survey of endocytosis by multiparametric image analysis
A new strategy is presented to accurately profile the activity of human genes in endocytosis by combining genome-wide RNAi, automated high-resolution confocal microscopy and quantitative multi-parametric image analysis. Several novel components of endocytosis and endosome trafficking were uncovered; a systems analysis further revealed that the cell regulates the number, size and concentration of cargo within endosomes.
- Claudio Collinet
- , Martin Stöter
- & Marino Zerial
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Letter |
An intrinsic vasopressin system in the olfactory bulb is involved in social recognition
Peptide hormones such as oxytocin and vasopressin influence social behaviour in several mammalian species. Here it is shown that a population of interneurons in the rat olfactory bulb releases vasopressin, and that vasopressin signalling is required in the olfactory system for proper social recognition in rats. Although vasopressin may not work in exactly the same way in humans, social recognition mediated by experience-dependent vasopressin release may be common.
- Vicky A. Tobin
- , Hirofumi Hashimoto
- & Mike Ludwig
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Letter |
RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF
The RAS–RAF signalling pathway is an attractive target for drug development in oncology, and several RAF inhibitors are being tested in clinical trials. Here and in an accompanying paper, RAF inhibitors are shown to have opposing roles, functioning as either inhibitors or activators of RAF depending on the cellular context and mutational status of RAF. The mechanistic basis for these opposing roles is dissected. The results have implications for the clinical use of these inhibitors and for the design of kinase inhibitors.
- Poulikos I. Poulikakos
- , Chao Zhang
- & Neal Rosen
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Letter |
Rere controls retinoic acid signalling and somite bilateral symmetry
The vertebrate body plan shows marked bilateral symmetry, although this can be disrupted in conditions such as scoliosis. Here, a mutation in Rere is found that leads to the formation of asymmetrical somites in mouse embryos; furthermore, Rere is shown to control retinoic acid signalling, which is required to maintain somite symmetry by interacting with Fgf8. The results provide insight into how bilateral symmetry is maintained.
- Gonçalo C. Vilhais-Neto
- , Mitsuji Maruhashi
- & Olivier Pourquié
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Letter |
Differential innate immune signalling via Ca2+ sensor protein kinases
Plants and animals sense intruding pathogens by using proteins that recognize diverse microbe-associated molecular patterns (MAMPs) and initiate innate immune responses. Early signalling responses in the host include calcium influx, an oxidative burst and transcriptional reprogramming. Here, four calcium-dependent protein kinases are described that function as calcium sensors, act as convergence points for various MAMPs, and are crucial for transcriptional reprogramming and oxidative burst in plants.
- Marie Boudsocq
- , Matthew R. Willmann
- & Jen Sheen
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Letter |
Mical links semaphorins to F-actin disassembly
Semaphorins and their receptors, plexins, relay guidance information to neurons during development and regulate actin dynamics through an unknown mechanism. Recently, proteins of the Mical family of enzymes have been found to associate with plexins; here, Mical is reported to directly link semaphorins and their plexin receptors to the precise control of actin filament dynamics.
- Ruei-Jiun Hung
- , Umar Yazdani
- & Jonathan R. Terman
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Letter |
Enzyme-inhibitor-like tuning of Ca2+ channel connectivity with calmodulin
Ca2+ channels and calmodulin (CaM) are two prominent hubs of biological signalling networks, affecting functions such as cardiac excitability and gene transcription. The prevailing view has been that the ultrastrong affinity of channels for the Ca2+-free form of calmodulin (apoCaM) ensures their saturation with CaM and yields a form of concentration independence between Ca2+ channels and CaM. Here, however, significant exceptions to this autonomy are shown to exist.
- Xiaodong Liu
- , Philemon S. Yang
- & David T. Yue
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Letter |
TGF-β–FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia
Chronic myeloid leukaemia is caused by a BCR-ABL fusion, a constitutively active tyrosine kinase that, it is believed, leads to suppression of the forkhead O transcription factors (FOXO). Although the use of the tyrosine kinase inhibitor imatinib is a breakthrough for CML therapy, imatinib does not deplete the leukaemia-initiating cells (LICs) that drive the recurrence of CML. Foxo3a is now shown to have an essential role in the maintenance of CML LICs in a mouse model.
- Kazuhito Naka
- , Takayuki Hoshii
- & Atsushi Hirao
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Letter |
RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth
The RAS–RAF signalling pathway is an attractive target for drug development in oncology, and several RAF inhibitors are being tested in clinical trials. Here and in an accompanying paper, RAF inhibitors are shown to have opposing roles, functioning as either inhibitors or activators of RAF depending on the cellular context and mutational status of RAF. The mechanistic basis for these opposing roles is dissected. The results have implications for the clinical use of these inhibitors and for the design of kinase inhibitors.
- Georgia Hatzivassiliou
- , Kyung Song
- & Shiva Malek
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Research Highlights |
Cancer biology: Kicking out cancer cells
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Research Highlights |
Neuroscience: Dark migraine relief
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Letter |
The Dbf4–Cdc7 kinase promotes S phase by alleviating an inhibitory activity in Mcm4
Kinase regulatory pathways are used in eukaryotic DNA replication to facilitate coordination with other processes during cell division cycles and response to environmental cues. The Dbf4–Cdc7 kinase (DDK) is one of at least two cell-cycle-regulated protein kinase systems essential for initiation of DNA replication. DDK is now shown to relieve the inhibitory activity of the amino-terminal domain of the replicative helicase Mcm4, thus promoting S phase.
- Yi-Jun Sheu
- & Bruce Stillman