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| Open AccessRab9 and retromer regulate retrograde trafficking of luminal protein required for epithelial tube length control
The development of biological tubes is regulated by mutual interactions between cells and luminal extracellular matrix. Donget al. show that retrograde recycling of luminal chitin deacetylase regulates Drosophila tracheal tubule geometry by restricting length independently of diameter.
- Bo Dong
- , Ken Kakihara
- & Shigeo Hayashi
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Article
| Open AccessThe bipolar assembly domain of the mitotic motor kinesin-5
During mitosis, kinesin-5 motors are thought to crosslink microtubules in a muscle-like sliding filament mechanism. By combining electron microscopy with other structural tools, the authors reveal how four kinesin-5 polypeptides are organized into bipolar minifilaments.
- Seyda Acar
- , David B. Carlson
- & Jonathan M. Scholey
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Splicing factor SRSF3 is crucial for hepatocyte differentiation and metabolic function
Splicing factors, such as the protein SRSF3, regulate mRNA metabolism but are hard to study in vivobecause genetic kockouts are usually lethal. Here, Sen and colleagues create mice with a hepatocyte-specific knockout of Srsf3 and demonstrate its role in hepatocyte differentiation and liver function.
- Supriya Sen
- , Hassan Jumaa
- & Nicholas J. G. Webster
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Activity of the mitochondrial calcium uniporter varies greatly between tissues
The flow of calcium into the mitochondrial matrix is mediated by the mitochondrial calcium uniporter. Fieniet al. apply patch-clamp techniques to mitoplasts isolated from different mouse and Drosophilatissues and find that the mitochondrial calcium uniporter activity varies depending on the tissue studied.
- Francesca Fieni
- , Sung Bae Lee
- & Yuriy Kirichok
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| Open AccessExtracellular Ca2+ is a danger signal activating the NLRP3 inflammasome through G protein-coupled calcium sensing receptors
Levels of extracellular calcium can increase at sites of infection and inflammation; however, the physiological significance of this has been unclear. This work shows that extracellular calcium acts as a danger signal, triggering the NLRP3 inflammasome via two G protein-coupled receptors.
- Manuela Rossol
- , Matthias Pierer
- & Ulf Wagner
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Phospho-dependent ubiquitination and degradation of PAR-1 regulates synaptic morphology and tau-mediated Aβ toxicity in Drosophila
PAR-1 inDrosophilahas been identified as a key physiological tau kinase. Lee and colleagues perform genetic screens for regulators of PAR-1 and find that it is targeted for ubiquitination and degradation by the ubiquitin ligase complex SCF(Slimb), and that this pathway modulates synaptic morphology.
- Seongsoo Lee
- , Ji-Wu Wang
- & Bingwei Lu
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PPARγ is an E3 ligase that induces the degradation of NFκB/p65
NFκB/p65 and PPARγ are both transcription factors that perform distinct but overlapping roles in cellular regulation. Hou et al. report that PPARγ acts as an E3 ubiquitin ligase and promotes Lys48-linked ubiquitination and degradation of p65, terminating NFκB-mediated inflammation and tumorigenesis.
- Yongzhong Hou
- , France Moreau
- & Kris Chadee
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Article
| Open AccessTransmembrane insertion of twin-arginine signal peptides is driven by TatC and regulated by TatB
TatA, B and C act together to translocate folded proteins across bacterial and chloroplast membranes, however the precise mechanism remains unclear. Fröbel and colleagues discover that TatC has unforeseen membrane insertase activity, while TatB prevents premature cleavage before translocation.
- Julia Fröbel
- , Patrick Rose
- & Matthias Müller
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The developmental basis of bat wing muscle
Phylogenetic bat studies suggest that powered flight is evolutionarily conserved. Tokita et al.find that bat wing muscles are derived from multiple myogenic sources with different embryonic origins, and that spatiotemporal correlations exist between outgrowth of wing membranes and expansion of wing muscles.
- Masayoshi Tokita
- , Takaaki Abe
- & Kazuo Suzuki
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A role for calpain-dependent cleavage of TDP-43 in amyotrophic lateral sclerosis pathology
The mislocalization and downregulation of the proteins TDP-43 and ADAR2, respectively, are implicated in amyotrophic lateral sclerosis pathology. Yamashita et al. find that downregulation of ADAR2 results in calcium-permeable AMPA receptor-mediated calpain activation and subsequent aberrant cleavage of TDP-43.
- Takenari Yamashita
- , Takuto Hideyama
- & Shin Kwak
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DJ-1 promotes angiogenesis and osteogenesis by activating FGF receptor-1 signaling
Osteoblasts and endothelial cells have important roles in bone regeneration. Kim and colleagues identify the protein DJ-1 as an angiogenic and osteogenic signalling molecule involved in the cross-talk between these cells and show that DJ-1 promotes bone regeneration and fracture healing in mice.
- Jung-Min Kim
- , Hong-In Shin
- & Pann-Ghill Suh
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ASK3 responds to osmotic stress and regulates blood pressure by suppressing WNK1-SPAK/OSR1 signaling in the kidney
Cells must be able to sense and respond to changes in osmotic pressure, which can be lethal. Here, Naguro and colleagues reveal a role for the protein kinase ASK3 in sensing osmotic stress in the mouse kidney and show that ASK3 contributes to the regulation of blood pressure.
- Isao Naguro
- , Tsuyoshi Umeda
- & Hidenori Ichijo
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Preotic neural crest cells contribute to coronary artery smooth muscle involving endothelin signalling
Endothelin-1 regulates cardiovascular development by acting on neural crest cells. Here endothelin-1-deficient mice are studied, revealing that preotic neural crest cells differentiate into coronary artery smooth muscle cells through endothelin-1-dependent mechanisms.
- Yuichiro Arima
- , Sachiko Miyagawa-Tomita
- & Hiroki Kurihara
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Article
| Open AccessMPIase is a glycolipozyme essential for membrane protein integration
Proteins are integrated into cellular membranes either co-translationally through Sec/SRP or post-translationally by chaperones. These authors show that an integration-dedicated chaperone inE. coli, MPIase, is a glycolipid and facilitates protein insertion into the inner membrane of the bacterium.
- Ken-ichi Nishiyama
- , Masahide Maeda
- & Keiko Shimamoto
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Receptor tyrosine kinase ErbB2 translocates into mitochondria and regulates cellular metabolism
ErbB2 is a receptor tyrosine kinase that localizes to the plasma membrane. Dinget al. now show that ErbB2 also localizes to mitochondria, where it regulates mitochondrial respiratory function and resistance to cancer chemotherapy.
- Yan Ding
- , Zixing Liu
- & Ming Tan
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Cooperation between different RNA virus genomes produces a new phenotype
RNA viruses are known to rapidly evolve new features through errors in replication and reshuffling of genomic segments. These authors report another strategy used by the measles virus to improve infectivity; the cooperation between wild-type and mutant fusion proteins in the same viral particle.
- Yuta Shirogane
- , Shumpei Watanabe
- & Yusuke Yanagi
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Molecular determinants of selective clearance of protein inclusions by autophagy
Dysfunctional or aggregated proteins in cells are degraded by autophagy. Wong et al.study aggregates of the protein synphilin-1 and show that ubiquitination alters their dynamic properties, which determines whether the aggregates are degraded via basal or inducible forms of autophagy.
- Esther Wong
- , Eloy Bejarano
- & Ana Maria Cuervo
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The RB family is required for the self-renewal and survival of human embryonic stem cells
While human embryonic stem cells (ESC) hold great therapeutic promise, many aspects of their basic biology remain poorly understood. Conklin et al.show that too much or too little activation of RB family proteins is detrimental to human ESC populations and identify unique cell cycle regulatory networks in these cells.
- Jamie F. Conklin
- , Julie Baker
- & Julien Sage
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Cholesterol modulates cell signaling and protein networking by specifically interacting with PDZ domain-containing scaffold proteins
Cholesterol indirectly regulates intracellular signalling by modulating the physical properties of lipid membranes. Sheng et al.now show that many PDZ domains contain a functional cholesterol-binding motif, revealing that cholesterol can also control the localization and function of signalling proteins directly.
- Ren Sheng
- , Yong Chen
- & Wonhwa Cho
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Article
| Open AccessIdentification and characterization of a human mitochondrial NAD kinase
Despite the central importance of NADP+ in mitochondrial energy metabolism, no NAD kinase has been found in human mitochondria to synthesize NADP+. These authors show C5orf33, a protein specific to animals and protists, to be the missing NAD kinase and demonstrate its mitochondrial localization and activity.
- Kazuto Ohashi
- , Shigeyuki Kawai
- & Kousaku Murata
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| Open AccessLaminin E8 fragments support efficient adhesion and expansion of dissociated human pluripotent stem cells
The use of animal products as culture substrates for human embryonic stem cell and induced pluripotent stem cell culture raises numerous safety concerns in a therapeutic setting. Miyazaki et al.. show that minimal fragments of human laminins provide a more effective support for the culture of these cell types.
- Takamichi Miyazaki
- , Sugiko Futaki
- & Eihachiro Kawase
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Involvement of PGC-1α in the formation and maintenance of neuronal dendritic spines
PGC-1α regulates mitochondrial biogenesis and adaptive thermogenesis. Cheng and colleagues alter the expression of PGC-1α in primary neuronal cultures and in the adult mouse brain, and find that it regulates dendritic spine formation and maintenance by mediating the synaptogenic actions of BDNF and CREB.
- Aiwu Cheng
- , Ruiqian Wan
- & Mark P. Mattson
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Article
| Open AccessPhosphorylation of VE-cadherin is modulated by haemodynamic forces and contributes to the regulation of vascular permeability in vivo
Vascular endothelial-cadherin is a junctional protein implicated in the control of vascular permeability. Orsenigo et al.find that vascular endothelial-cadherin is phosphorylated in veins but not in arteries of mice, and that this sensitizes vessels to rapid changes in permeability in response to inflammatory mediators.
- Fabrizio Orsenigo
- , Costanza Giampietro
- & Elisabetta Dejana
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Article
| Open AccessThe Hedgehog signalling pathway regulates autophagy
Autophagy is a cellular process that controls protein and organelle turnover. Jimenez-Sanchez and colleagues demonstrate in cultured mammalian cells and in fruit fly larvae that autophagy is regulated by Hedgehoc signalling, a pathway that is important for early embryonic development.
- Maria Jimenez-Sanchez
- , Fiona M. Menzies
- & David C. Rubinsztein
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A monomeric red fluorescent protein with low cytotoxicity
Fluorescent proteins are widely used to image cellular structures. Here, Shemiakina and colleagues develop an enhanced version of a red fluorescent protein that is monomeric and less cytotoxic, thereby improving the quality of images that can be obtained in the red part of the visible spectrum.
- I.I. Shemiakina
- , G.V. Ermakova
- & D. Shcherbo
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A peptide derived from laminin-γ3 reversibly impairs spermatogenesis in rats
The temporal opening and closing of cell–cell junctions at the blood–testis barrier allows the passage of immature germ cells during spermatogenesis. Su and colleagues identify a peptide fragment of the laminin-γ3 chain that disrupts the blood–testis barrier and reversibly impairs spermatogenesis in rats.
- Linlin Su
- , Dolores D. Mruk
- & C. Yan Cheng
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Sos-mediated cross-activation of wild-type Ras by oncogenic Ras is essential for tumorigenesis
The ras family of oncogenes consists of H-ras, K-ras and N-ras, and usually only one of these genes is mutated in a given tumour type. In this study, K-ras is found to promote the activation of wild-type H-ras and N-ras in a manner dependent on the Ras guanine nucleotide exchange factor Son of sevenless.
- Hao-Hsuan Jeng
- , Laura J Taylor
- & Dafna Bar-Sagi
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Tyrosine sulfation in a Gram-negative bacterium
The sulfation of protein tyrosine residues is a common post-translational modification in eukaryotes. Here, Han et al.show that the protein RaxST, produced by a plant bacterium, has tyrosine sulfotransferase activity, demonstrating for the first time tyrosine sulfation in prokaryotes.
- Sang-Wook Han
- , Sang-Won Lee
- & Pamela C. Ronald
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Lfng regulates the synchronized oscillation of the mouse segmentation clock via trans-repression of Notch signalling
The mouse segmentation clock regulates the periodicity of somite formation. Okubo and colleagues investigate the mechanisms underlying the synchronization of the clock in embryonic chimaeras and find that the synchronization is regulated by the protein Lfng, which represses Notch signalling in neighbouring cells.
- Yusuke Okubo
- , Takeshi Sugawara
- & Yumiko Saga
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| Open AccessEndocannabinoid-Goα signalling inhibits axon regeneration in Caenorhabditis elegans by antagonizing Gqα-PKC-JNK signalling
Axon regeneration inC. elegansis positively regulated by the JNK/MAP kinase pathway. Pastuhov and colleagues identify the endocannabinoid anandamide as a negative regulator of this pathway and show that anandamide inhibits axon regeneration in mature neurons after axotomy.
- Strahil Iv. Pastuhov
- , Kota Fujiki
- & Naoki Hisamoto
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A combinatorial extracellular matrix platform identifies cell-extracellular matrix interactions that correlate with metastasis
Interactions of cells with extracellular matrix are important in normal physiology and cancer metastasis. Here, an extracellular matrix molecule array is developed and used to show that conserved changes in adhesive properties are associated with metastasis, including binding to fibronectin in combination with galectin-3, galectin-8 or laminin.
- Nathan E. Reticker-Flynn
- , David F. Braga Malta
- & Sangeeta N. Bhatia
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Mst1 regulates integrin-dependent thymocyte trafficking and antigen recognition in the thymus
Autoreactive T cells are eliminated as they encounter self-antigens during transit through the thymus. Uedaet al. reveal that mice lacking the Hippo homologue Mst1 develop autoimmunity as a result of impaired integrin-dependent T cell migration through this negatively selective niche.
- Yoshihiro Ueda
- , Koko Katagiri
- & Tatsuo Kinashi
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Cadherin selectivity filter regulates endothelial sieving properties
Endothelial cells provide a vital barrier system to the passage of water and ions but not large plasma proteins. Using fluorescently labelled dextrans, the authors show that regions of high or low adherens junction density differentially restrict the passage of molecules up to 70 kDa in size.
- Sadiqa K. Quadri
- , Li Sun
- & Jahar Bhattacharya
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Article
| Open AccessDirect visualization of cell division using high-resolution imaging of M-phase of the cell cycle
Current methods for detecting proliferation in live cells cannot distinguish between dividing cells and cells that are progressing through the cell cycle. Here, a method is described that detects anillin in the contractile ring and in the midbody of cells during M-phase, providing a more accurate detection of dividing cells.
- Michael Hesse
- , Alexandra Raulf
- & Bernd K. Fleischmann
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The nuclear hormone receptor PPARγ counteracts vascular calcification by inhibiting Wnt5a signalling in vascular smooth muscle cells
Vascular calcification is commonly associated with advanced stages of atherosclerosis. Woldtet al. show that the nuclear hormone receptor PPARγ in vascular smooth muscle cells protects mice from vascular calcification by inhibiting Wnt5a signalling triggered by activation of the cell-surface receptor LRP1.
- Estelle Woldt
- , Jérome Terrand
- & Philippe Boucher
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Article
| Open AccessThe miRNA-212/132 family regulates both cardiac hypertrophy and cardiomyocyte autophagy
Heart failure is often a consequence of pathological growth of cardiomyocytes or cardiac hypertrophy. Here Ucar and colleagues report that the microRNAs miR-132 and miR-212 promote cardiac hypertrophy and inhibit autophagy in cardiomyocytes by downregulating the transcription factor FoxO3.
- Ahmet Ucar
- , Shashi K. Gupta
- & Thomas Thum
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Delivery of endosomes to lysosomes via microautophagy in the visceral endoderm of mouse embryos
Nutrients and growth factors initiate endocytotic processes in the embryonic endoderm that control embryonic patterning. Here, Kawamuraet al.show that the small GTP-binding protein rab7 controls a unique microautophagy-like process that is involved in endocytosis in the endoderm of mouse embryos.
- Nobuyuki Kawamura
- , Ge-Hong Sun-Wada
- & Yoh Wada
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p47 negatively regulates IKK activation by inducing the lysosomal degradation of polyubiquitinated NEMO
The IKK complex activates the NF-κB pathway and can culminate in inflammation, which needs to be tightly controlled. NEMO is part of the IKK complex and, in this study, is shown to associate with the golgi-reassembly protein p47, resulting in the lysosomal degradation of NEMO and inhibition of NF-κB activation.
- Yuri Shibata
- , Masaaki Oyama
- & Jun-ichiro Inoue
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Article
| Open AccessEndogenous Wnt signalling in human embryonic stem cells generates an equilibrium of distinct lineage-specified progenitors
Human embryonic stem cell cultures are morphologically heterogeneous. Here, differences in Wnt signalling are shown to contribute to this heterogeneity, cells containing high levels of Wnt form endodermal and cardiac cells, whereas cells with low Wnt form neuroectodermal cells, when differentiation is induced.
- Timothy A. Blauwkamp
- , Shelly Nigam
- & Roel Nusse
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Article
| Open AccessGreatwall kinase and cyclin B-Cdk1 are both critical constituents of M-phase-promoting factor
Cyclin B–Cdk1 is thought to be synonymous with the promoting factor that drives entry into M-phase of the cell cycle. Here, Greatwall kinase is shown to be required for the breakdown of the nuclear envelope and the assembly of the spindle on entry into M-phase, suggesting that it too is a part of the M-phase-promoting factor.
- Masatoshi Hara
- , Yusuke Abe
- & Takeo Kishimoto
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TGFβ induces the formation of tumour-initiating cells in claudinlow breast cancer
TGF-β signalling suppresses tumorigenesis in breast cancer cells but its effects on breast cancer initiating cells have not been reported. Using cells in culture, Brunaet al. show that TGF-β increases breast cancer initiating cell numbers in cells that have low levels of the tight junction protein claudin.
- Alejandra Bruna
- , Wendy Greenwood
- & Carlos Caldas
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Article
| Open AccessThe allosteric vestibule of a seven transmembrane helical receptor controls G-protein coupling
Class A seven transmembrane helical receptors harbour vestibules at the entrance to the ligand-binding domain. Here, Bocket al. use probes to monitor the conformation of the M2 muscarinic receptor and show that the vestibule alters the extent of receptor movement.
- Andreas Bock
- , Nicole Merten
- & Klaus Mohr
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Identification of the functional binding pocket for compounds targeting small-conductance Ca2+-activated potassium channels
Small- and intermediate-conductance K+channels are activated by calcium-bound calmodulin and modulated by small molecules. In this study, a functional binding pocket for the 1-EBIO class of modulators is described and is located at the calmodulin-channel interface.
- Miao Zhang
- , John M. Pascal
- & Ji-Fang Zhang
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The critical size is set at a single-cell level by growth rate to attain homeostasis and adaptation
It is assumed that budding yeast need to reach a certain size before entering the cell cycle. Here, using imaging and a mathematical model, Ferrezueloet al.show that there is variability in the size of cells entering the cell cycle and this is controlled by growth rate in G1.
- Francisco Ferrezuelo
- , Neus Colomina
- & Martí Aldea
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Organellar mechanosensitive channels in fission yeast regulate the hypo-osmotic shock response
Mechanosensitive channels are required to sense cell swelling in response to osmotic shock. Nakayamaet al.report that Msy1 and Msy2 are the fission yeast homologues of the bacterial mechanosensitive channel MscS, and are required for regulating intracellular calcium in response to cell swelling.
- Yoshitaka Nakayama
- , Kenjiro Yoshimura
- & Hidetoshi Iida
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Article
| Open AccessPINK1 autophosphorylation upon membrane potential dissipation is essential for Parkin recruitment to damaged mitochondria
The kinase PINK1 is mutated in Parkinson's disease and accumulates in defective mitochondria, where it recruits Parkin. Here, PINK1 is shown to be autophosphorylated and this is required for the localization of PINK1 to mitochondria with a reduced membrane potential, and for the recruitment of Parkin.
- Kei Okatsu
- , Toshihiko Oka
- & Noriyuki Matsuda
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FOXO3 signalling links ATM to the p53 apoptotic pathway following DNA damage
The protein ataxia-telangiectasia mutated (ATM) detects DNA damage and can trigger cellular apoptosis, but how this process is regulated at the molecular level is unclear. Here, Chunget al. show that the transcription factor FOXO3 controls the formation of ATM-containing signalling complexes at sites of DNA damage that trigger apoptosis.
- Young Min Chung
- , See-Hyoung Park
- & Mickey C.-T. Hu
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Evidence for activity-regulated hormone-binding cooperativity across glycoprotein hormone receptor homomers
Glycoprotein hormone receptors show negative cooperativity following a single molecule of agonist binding to each receptor dimer. Here, constitutively active receptors are shown to display less cooperative allosteric regulation, suggesting a direct relationship between conformational changes in the transmembrane domain and allosteric behaviour of the receptor dimers.
- Maxime Zoenen
- , Eneko Urizar
- & Sabine Costagliola
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Article
| Open AccessProteomic screen reveals Fbw7 as a modulator of the NF-κB pathway
Fbw7 is a ubiquitin-ligase, which targets several oncoproteins for proteolysis, and is therefore important for the control and prevention of tumorigenesis. In this study, Arabi and colleagues carry out a proteomic screen of the targets of Fbw7, and identify Nuclear Factor of κ-B2 as a substrate.
- Azadeh Arabi
- , Karim Ullah
- & Olle Sangfelt
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