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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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| 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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| 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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| 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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| 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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| 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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| 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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| 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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Ubiquitination and degradation of the FADD adaptor protein regulate death receptor-mediated apoptosis and necroptosis
Fas-associated protein with death domain (FADD) is part of a signalling complex that controls some forms of programmed cell death. Lee and colleagues demonstrate that FADD ubiquitination by the E3 ubiquitin ligase MKRN1 regulates FADD protein stability and thereby cell death.
- Eun-Woo Lee
- , Jung-Hoon Kim
- & Jaewhan Song
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| Open AccessUnfolded protein response, activated by OASIS family transcription factors, promotes astrocyte differentiation
The protein OASIS belongs to the CREB/ATF transcription factor family and is involved in endoplasmic reticulum stress responses. Saito and colleagues show that these stress responses temporally activate OASIS in neural precursor cells, resulting in their differentiation into astrocytes.
- Atsushi Saito
- , Soshi Kanemoto
- & Kazunori Imaizumi
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| Open AccessThe role of heterodimerization between VEGFR-1 and VEGFR-2 in the regulation of endothelial cell homeostasis
Vascular endothelial growth factor receptors (VEGFRs) assemble in dimers, the composition of which is thought to influence their function. Here, Cudmoreet al. create a synthetic ligand that specifically activates VEGFR-1:VEGFR-2 heterodimers and explore their role in regulating endothelial cell function.
- Melissa J. Cudmore
- , Peter W. Hewett
- & Asif Ahmed
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| Open AccessDiscordant timing between antennae disrupts sun compass orientation in migratory monarch butterflies
Monarch Butterflies (Danaus plexippus) use their antennae for orientation during their autumnal migration. Guerra and colleagues differentially disrupt clock gene expression in each antenna and find that the individual outputs are integrated and processed to allow precise control of orientation behaviour.
- Patrick A. Guerra
- , Christine Merlin
- & Steven M. Reppert
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| Open AccessSwitching of myosin-V motion between the lever-arm swing and Brownian search-and-catch
The motor protein myosin-V transports cargo along actin filaments, but the biophysical mechanisms by which myosin-V generates force are unclear. Here, optical tweezers and a DNA handle are used to study the forces generated by myosin-V: the mechanism of force generation is found to depend on the load applied.
- Keisuke Fujita
- , Mitsuhiro Iwaki
- & Toshio Yanagida
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Reprogramming of tRNA modifications controls the oxidative stress response by codon-biased translation of proteins
In response to stress, yeast cells selectively translate proteins that can enhance cell survival. In this study, the authors find that tRNALEU(CAA)in yeast cells is modified in response to oxidative stress by a methyltransferase and this results in the selective translation of the mRNA for these genes.
- Clement T.Y. Chan
- , Yan Ling Joy Pang
- & Peter C. Dedon
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Chloroplast-mediated activation of plant immune signalling in Arabidopsis
Mediators of plant immunity, such as salicylic acid, are produced in the chloroplasts, but the molecular link between chloroplasts and the immune system is unclear. This work finds that pathogen-associated molecular pattern signals are relayed to chloroplasts and evoke Ca2+signatures in the stroma.
- Hironari Nomura
- , Teiko Komori
- & Takashi Shiina
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SUMO1 modification of PTEN regulates tumorigenesis by controlling its association with the plasma membrane
PTEN is a tumour suppressor that inhibits activation of the phosphatidylinositol 3-kinase pathway. These authors show that PTEN is SUMOylated on two lysine residues and that this modification is required for binding to acidic phospholipids and blocking tumour formation in mice.
- Jian Huang
- , Jie Yan
- & Jianxiu Yu
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| Open AccessFcp1-dependent dephosphorylation is required for M-phase-promoting factor inactivation at mitosis exit
Cyclin B-dependent kinase 1, the M-phase-promoting factor, is precisely activated and inactivated to control mitosis. In this study, Fcp1—the RNA polymerase II-carboxy-terminal domain phosphatase—is identified as a phosphatase required to inactivate the M-phase-promoting factor and promote mitosis exit.
- Roberta Visconti
- , Luca Palazzo
- & Domenico Grieco
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Impaired thermogenesis and adipose tissue development in mice with fat-specific disruption of insulin and IGF-1 signalling
Insulin and insulin-like growth factor 1 signalling pathways have overlapping effects on adipose tissue and glucose homeostasis. Boucheret al.created fat-specific double knockouts of these pathways and demonstrated their crucial role for adipocyte development, metabolism and thermogenesis in mice.
- Jeremie Boucher
- , Marcelo A. Mori
- & C. Ronald Kahn
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Alternative splicing of CD44 mRNA by ESRP1 enhances lung colonization of metastatic cancer cell
CD44 is a cell surface protein that is a marker for stem cell-like cancer cells and has a role in invasion and metastasis. Here, epithelial splicing regulatory protein 1 is shown to generate a CD44 variant protein that enhances metastasis in a mouse model and protects cells from oxidative stress.
- Toshifumi Yae
- , Kenji Tsuchihashi
- & Osamu Nagano
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O-glycosylation modulates integrin and FGF signalling by influencing the secretion of basement membrane components
Altered O-glycosylation of proteins is implicated in various human diseases. In this study, Tian and co-workers study mice that are deficient in the O-glycosylation enzyme Galnt1, and find reduced cell proliferation and organogenesis as well as increased endoplasmic reticulum stress.
- E. Tian
- , Matthew P. Hoffman
- & Kelly G. Ten Hagen
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Assembly kinetics determine the architecture of α-actinin crosslinked F-actin networks
Processes that regulate the mechanical and dynamic properties of actin cytoskeleton are important for multiple eukaryotic cell functions. In this study, using reconstituted crosslinked actin networks, organization is found to be determined by the competing kinetics of actin gelation and bundle formation.
- Tobias T. Falzone
- , Martin Lenz
- & Margaret L. Gardel
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| Open AccessThe Dishevelled-associating protein Daple controls the non-canonical Wnt/Rac pathway and cell motility
The non-canonical Wnt signalling pathway mediates cell migration via the GTPase Rac but the detailed mechanism is unclear. In this study, the Daple protein is shown to regulate Wnt5a mediated activation of Rac, resulting in the formation of lamellipodia and cell migration.
- Maki Ishida-Takagishi
- , Atsushi Enomoto
- & Masahide Takahashi
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Microtubule and cortical forces determine platelet size during vascular platelet production
Platelets are formed from megakaryocytes but the exact mechanisms are unknown. Thonet al.describe circular preplatelets and barbell shaped proplatelets in human blood and demonstrate, with the aid of a mathematical model, a role for microtubule-based forces in regulating final platelet size.
- Jonathan N Thon
- , Hannah Macleod
- & Joseph E. Italiano Jr
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Article
| Open AccessActivin induces cortical interneuron identity and differentiation in embryonic stem cell-derived telencephalic neural precursors
Signalling inputs to neural progenitors regulate the differentiation of the stem cell pool. By analysing the mechanisms occuring during neurogenesis, Cambrayet al. report that activin is the pivotal factor regulating the differentiation of telencephalic neural precursors towards a cortical interneuron fate.
- Serafí Cambray
- , Charles Arber
- & Tristan A. Rodríguez
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A crucial role for bone morphogenetic protein-Smad1 signalling in the DNA damage response
The bone morphogenetic protein (BMP) and Smad1 signalling pathway is required for embryogenesis. In this study, Smad1 is shown to be phosphorylated by Atm in response to DNA damage and this results in elevated Smad1 signalling, thus uncovering a new role for this pathway in the DNA damage response.
- Jenny Fung Ling Chau
- , Deyong Jia
- & Baojie Li
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Polyploid cells rewire DNA damage response networks to overcome replication stress-induced barriers for tumour progression
Tumour cells are subject to replication stress but how cells overcome damage without inducing senescence and apoptotic pathways is unclear. Here, the authors study polyploidy in cancer cells and show that this blocks apoptotic and senescent pathways, resulting in the induction of proteins involved in DNA repair.
- Li Zheng
- , Huifang Dai
- & Binghui Shen
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Article
| Open AccessThe Eutherian Armcx genes regulate mitochondrial trafficking in neurons and interact with Miro and Trak2
Mitochondrial dynamics and trafficking are important for providing energy for neuron function. In this study, the Armadillo repeat containing proteins clustered on the X chromosome are shown to be highly expressed in the nervous system and have a role in mitochondrial dynamics.
- Guillermo López-Doménech
- , Román Serrat
- & Eduardo Soriano
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Article
| Open AccessJAK/STAT3 signalling is sufficient and dominant over antagonistic cues for the establishment of naive pluripotency
Culture conditions are critical for the successful induction of pluripotent stem cells and define whether cells are primed or naïve. Here, activation of JAK/STAT3 signalling is shown to be sufficient and dominant over antagonistic cues to enable the induction of a naïve pluripotent state in stem cells.
- Anouk L. van Oosten
- , Yael Costa
- & José C.R. Silva
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Involvement of urinary bladder Connexin43 and the circadian clock in coordination of diurnal micturition rhythm
Humans and rodents normally store more urine in the bladder when fast asleep than when awake. In this study, the production of the gap junction protein connexin43, a regulator of bladder capacity, is shown to oscillate in mouse urinary bladder muscle in synchrony with the circadian clock.
- Hiromitsu Negoro
- , Akihiro Kanematsu
- & Osamu Ogawa
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Stiffening hydrogels to probe short- and long-term cellular responses to dynamic mechanics
Studying the effects of extracellular matrix stiffening has been impeded because mostin vitromodels are static. Here, dynamic hydrogels are developed that stiffen in the presence of cells and are used to investigate the short-term (minutes-to-hours) and long-term (days-to-weeks) cellular responses to dynamic stiffening.
- Murat Guvendiren
- & Jason A. Burdick
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miR-484 regulates mitochondrial network through targeting Fis1
Abnormal mitochondrial fission leads to apoptosis and disease. Li and colleagues reveal the mechanism with which the transcription factor Foxo3a suppresses Fis1-mediated mitochondrial fission and apoptosis in cardiomyocytes and adrenocortical cancer cells, which involves miR-484 inhibition of Fis1 translation.
- Kun Wang
- , Bo Long
- & Pei-Feng Li
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Article
| Open AccessCYLD negatively regulates transforming growth factor-β-signalling via deubiquitinating Akt
Lung injury initiates a series of wound-healing responses, which if unregulated, can lead to fibrosis. Liet al. show that the deubquitinase CYLD has a key role in the prevention of fibrosis by inhibiting transforming growth factor β-signalling through the direct deubiquitination of the protein kinase Akt.
- Jae Hyang Lim
- , Hirofumi Jono
- & Jian-Dong Li
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Drosophila follicle stem cells are regulated by proliferation and niche adhesion as well as mitochondria and ROS
Stem cells are thought to be tethered in their niche via adhesion molecules and the inhibition of cell differentiation. Here, the authors screened for genes required for maintainingDrosophilaovarian follicle stem cells and found their function to depend on cell proliferation, mitochondrial function and niche adhesion.
- Zhu A. Wang
- , Jianhua Huang
- & Daniel Kalderon
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Annexin A2 binds to endosomes following organelle destabilization by particulate wear debris
Endosomes contain hydrolytic enzymes, and recent reports have suggested that the endosomal membrane can be damaged by wear particles, resulting in the release of their contents and an inflammatory response. In this study, a role for annexin II in the repair of the damaged endosome membrane is reported.
- Brian Scharf
- , Cristina C. Clement
- & Laura Santambrogio
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