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Article
| Open AccessAsparagine promotes cancer cell proliferation through use as an amino acid exchange factor
Cancer cells have been shown to be dependent upon glutamine for growth. Here, the authors show that intracellular asparagine, a glutamine-derived metabolite, is critical to cancer cell growth and can compensate glutamine deficiency by acting as an amino acid exchange factor.
- Abigail S. Krall
- , Shili Xu
- & Heather R. Christofk
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Article
| Open AccessExpression of a functional oxygen-labile nitrogenase component in the mitochondrial matrix of aerobically grown yeast
The sensitivity of nitrogenase to oxygen is a major barrier to engineer biological nitrogen fixation into cereal crops by direct nif gene transfer. Here the authors use yeast to show that targeting nitrogenase Fe protein to the mitochondrial matrix overcomes the O2sensitivity impediment.
- Gema López-Torrejón
- , Emilio Jiménez-Vicente
- & Luis M. Rubio
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Article
| Open AccessMyoscape controls cardiac calcium cycling and contractility via regulation of L-type calcium channel surface expression
Heart failure is a major public health issue but due to our poor disease understanding the current therapies are symptomatic. Here the authors identify Myoscape as a novel cardiac protein regulating membrane localization of the L-type calcium channel and heart's contractile force, thus promising new therapeutic avenues for heart failure.
- Matthias Eden
- , Benjamin Meder
- & Norbert Frey
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Article
| Open AccessAn essential malaria protein defines the architecture of blood-stage and transmission-stage parasites
Blood-stage malaria parasites replicate through a specialised type of cell division known as schizogony. Here, Absalon et al. identify a parasite protein that is essential during schizogony for cytokinesis and formation of the inner membrane complex, the structural scaffold of daughter parasites.
- Sabrina Absalon
- , Jonathan A. Robbins
- & Jeffrey D. Dvorin
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Article
| Open AccessEpigenetic profiles signify cell fate plasticity in unipotent spermatogonial stem and progenitor cells
Spermatogonial stem cells (SSCs) spontaneously convert to multipotent adult spermatogonial-derived stem cells (MASCs). Here, the authors reveal the dynamics of bivalent histone H3-lysine4 and -lysine27 methylation signatures at somatic gene promoters in SSCs and ESC-like promoter chromatin states in MASCs.
- Ying Liu
- , Eugenia G. Giannopoulou
- & Marco Seandel
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Article
| Open AccessA cell cycle kinase with tandem sensory PAS domains integrates cell fate cues
The membrane-bound kinase CckA controls the activity of the Caulobacter crescentusmaster regulator CtrA, which in turn coordinates asymmetric cell division. Here, the authors show that CckA contains two sensory domains that have distinct sensitivities to fluctuations in cyclic-di-GMP concentration and subcellular niche.
- Thomas H. Mann
- , W. Seth Childers
- & Lucy Shapiro
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Article
| Open AccessHomotypic cell competition regulates proliferation and tiling of zebrafish pigment cells during colour pattern formation
Melanophores, iridophores and xanthophores are pigment-cell types that interact to form the stripes in zebrafish. Here, the authors study the interaction between cells of the same kind and show that each pigment-cell type covers the skin by contact based competition.
- Brigitte Walderich
- , Ajeet Pratap Singh
- & Christiane Nüsslein-Volhard
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Article
| Open AccessNMDA receptors are selectively partitioned into complexes and supercomplexes during synapse maturation
NMDARs and MAGUK proteins are capable of forming higher-order protein assemblies, however their organisation in the intact brain is unclear. Here, Frank et al. identify mouse and human supercomplexes and discover their mechanism of assembly using genetic tagging and affinity purification.
- René A. W. Frank
- , Noboru H. Komiyama
- & Seth G. N. Grant
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Article
| Open AccessmiR-22 has a potent anti-tumour role with therapeutic potential in acute myeloid leukaemia
Mir-22 has been shown to be an oncogenic microRNA in breast cancer and myelodysplastic syndrome. Here, the authors show that mir-22 functions as a tumour suppressor in de novoacute myeloid leukaemia by inhibiting the expression of several oncogenes and that restoring mir-22 expression suppresses AML progression.
- Xi Jiang
- , Chao Hu
- & Jianjun Chen
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Article
| Open AccessMechanical cell competition kills cells via induction of lethal p53 levels
Cell competition is a quality control mechanism to eliminate unfit cells. Here the authors show that physical compaction of less fit cells surrounded by healthy neighbours leads to increased expression of tumour suppressor p53 in the compacted cells, causing cell death.
- Laura Wagstaff
- , Maja Goschorska
- & Eugenia Piddini
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Article
| Open AccessPhosphotransferase-dependent accumulation of (p)ppGpp in response to glutamine deprivation in Caulobacter crescentus
The small molecule (p)ppGpp is commonly produced by bacteria as a signal of nutrient starvation. Here, Ronneau et al. show that (p)ppGpp accumulation in the model bacterium Caulobacter crescentusis modulated by a nitrogen-related phosphotransferase system in response to glutamine deprivation.
- Séverin Ronneau
- , Kenny Petit
- & Régis Hallez
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Article
| Open AccessFoldamer-mediated manipulation of a pre-amyloid toxin
Intrinsically disordered proteins that form amyloid fibrils are hard to target with traditional therapeutic approaches. Here, the authors report on an oligoquinoline derivative that binds the human islet amyloid polypeptide, stabilising an alpha-helical structure that reduces its cellular toxicity.
- Sunil Kumar
- , Melissa Birol
- & Andrew D. Miranker
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Article
| Open AccessComparative analysis of ear-hole closure identifies epimorphic regeneration as a discrete trait in mammals
The extent to which mammals and other vertebrates share similar mechanisms of tissue regeneration is unclear. Here, the authors use an ear punch assay in spiny mice, which regenerate fully, to show blastema formation and mesenchymal cell proliferation as cell cycle regulators p21 and p27 remain cytoplasmic.
- Thomas R. Gawriluk
- , Jennifer Simkin
- & Ashley W. Seifert
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Article
| Open AccessSingle-cell RNA-seq reveals cell type-specific transcriptional signatures at the maternal–foetal interface during pregnancy
The zinc finger transcriptional repressor Prdm1/Blimp1 is essential for remodelling maternal blood vessels in a subset of trophoblast cells. Here, the authors perform single-cell RNA-seq analysis on this Blimp1+ lineage, identifying functionally distinct cell types present at the maternal–foetal interface.
- Andrew C. Nelson
- , Arne W. Mould
- & Elizabeth J. Robertson
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Article
| Open AccessThe obesity-induced transcriptional regulator TRIP-Br2 mediates visceral fat endoplasmic reticulum stress-induced inflammation
Visceral and subcutaneous fat are associated with different metabolic risk, but mediators of such depot specific effects are not very well known. Here the authors identify the transcriptional regulator, TRIP-Br2, as a regulator of endoplasmic reticulum (ER) stress-induced inflammatory responses specifically in visceral fat.
- Guifen Qiang
- , Hyerim Whang Kong
- & Chong Wee Liew
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Article
| Open AccessDysregulation of miRNAs-COUP-TFII-FOXM1-CENPF axis contributes to the metastasis of prostate cancer
The orphan nuclear receptor COUP-TFII is highly expressed in metastatic prostate cancers and its overexpression accelerates prostate tumour progression in mouse models. Here, the author show that that loss of miR-101 and miR-27a in prostate cancer cells can lead to COUP-TFII expression which in turn directly regulates FOXM1 and CENPFfavouring prostate cancer metastasis.
- Shih-Chieh Lin
- , Chung-Yang Kao
- & Ming-Jer Tsai
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Article
| Open AccessThe HSP70 co-chaperone DNAJC14 targets misfolded pendrin for unconventional protein secretion
Mutations in pendrin, a plasma membrane transporter, lead to Pendred syndrome, which is associated with hearing loss. Here, Jung et al. show that cell-surface expression of a mutated form of pendrin can be restored by blocking ER-to-Golgi traffic and triggering a DNAJC14 dependent unconventional secretion pathway.
- Jinsei Jung
- , Jiyoon Kim
- & Min Goo Lee
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Article
| Open AccessThiol reductive stress induces cellulose-anchored biofilm formation in Mycobacterium tuberculosis
When grown in the lab, Mycobacterium tuberculosis can form pellicle biofilms. Here, Trivedi et al. show that thiol reductive stress (induced by dithiothreitol) triggers rapid formation of thicker biofilms containing cellulose as well as antibiotic-tolerant, metabolically active bacteria.
- Abhishek Trivedi
- , Parminder Singh Mavi
- & Ashwani Kumar
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Article
| Open AccessThe molecular basis of the genesis of basal tone in internal anal sphincter
The molecular basis of the basal tone generated by internal anal sphincters (IAS) is largely unknown. Here, the authors show that the tone arises from a global rise in intracellular Ca2+ in smooth muscle cells via a Ryanodine receptor-TMEM16A-L-type Ca2+channel-MLC kinase pathway, suggesting a potential therapy for IAS motility disorders.
- Cheng-Hai Zhang
- , Pei Wang
- & Min-Sheng Zhu
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Article
| Open AccessEssential role for a novel population of binucleated mammary epithelial cells in lactation
The main function of the mammary gland is to produce milk to sustain offspring. Here, the authors show that secretory alveolar cells in the lactating gland in several species are binucleated, which increases milk production, and that binucleation is regulated by Aurora kinase-A and Polo-like kinase-1.
- Anne C. Rios
- , Nai Yang Fu
- & Jane E. Visvader
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Article
| Open AccessThe Gonium pectorale genome demonstrates co-option of cell cycle regulation during the evolution of multicellularity
The undifferentiated Gonium pectorale represents the initial transition to multicellularity. Here, Bradley Olson, Erik Hanschen and colleagues describe the genome of Gonium pectorale, demonstrating that co-option of the retinoblastoma cell cycle regulatory pathway was a key genetic change in the evolution of multicellularity.
- Erik R. Hanschen
- , Tara N. Marriage
- & Bradley J. S. C. Olson
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Article
| Open AccessAdipose tissue mTORC2 regulates ChREBP-driven de novo lipogenesis and hepatic glucose metabolism
The kinase mTOR controls anabolic metabolism. Here, the authors create fat-specific mTORC2 knockout mice using the Adiponectin-Cre driver and show mTORC2 signalling is important for systemic metabolic homeostasis by controlling adipocyte de novolipogenesis and glucose uptake.
- Yuefeng Tang
- , Martina Wallace
- & David A. Guertin
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Article
| Open AccessCRL4Wdr70 regulates H2B monoubiquitination and facilitates Exo1-dependent resection
The repair of double-strand DNA breaks by homologous recombination requires resection of the DNA ends. Here the authors show that in Schizosaccharomyces pombe and human cells, Wdr70 is recruited as part of the CRL4 complex to promote ubiquitination of H2B and allow Exo1-mediated resection.
- Ming Zeng
- , Laifeng Ren
- & Cong Liu
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Article
| Open AccessLocation-dependent synaptic plasticity rules by dendritic spine cooperativity
Inputs to functionally related synapses have been suggested to show cooperative summation, although the rules governing these interactions are unclear. Here, Weber et al. uncover non-linear interactions dependent on NMDAR signalling that vary across the proximal-distal axis of individual dendrites.
- Jens P. Weber
- , Bertalan K. Andrásfalvy
- & Judit K. Makara
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Article
| Open AccessReal-time quantification of protein expression at the single-cell level via dynamic protein synthesis translocation reporters
Single cells can display large heterogeneity in gene induction. Here, Aymoz et al. present an expression reporter based on protein translocation that can accurately measure both the levels and dynamics of protein synthesis in live single cells with a temporal resolution of less than one minute.
- Delphine Aymoz
- , Victoria Wosika
- & Serge Pelet
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Article
| Open AccessEpidermal Notch1 recruits RORγ+ group 3 innate lymphoid cells to orchestrate normal skin repair
In normal skin, Notch directs keratinocytes to terminally differentiate. Here the authors show that Notch1 has a wider role in skin repair; Notch1 is activated in keratinocytes after damage and drives transcription of TNFα and inflammatory chemokines, which in turn recruit ILC3s and macrophages that promote repair.
- Zhi Li
- , Tom Hodgkinson
- & Carrie A. Ambler
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Article
| Open AccessMolecular requirements for the inter-subunit interaction and kinetochore recruitment of SKAP and Astrin
SKAP and Astrin form a heterodimer that localizes to spindle microtubules and to mature microtubule-kinetochore attachments during mitosis. Here, the authors identify molecular requirements for the inter-subunit interaction of SKAP and Astrin and kinetochore recruitment.
- Alexandra Friese
- , Alex C. Faesen
- & Andrea Musacchio
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Article
| Open AccessWhi5 phosphorylation embedded in the G1/S network dynamically controls critical cell size and cell fate
In budding yeast the G1/S transition requires the attainment of a critical cell size. Here the authors unravel its basic control mechanism by integrating simulations of a mathematical model of multisite phosphorylation of Whi5 by Cln3–Cdk1, with molecular analyses of a Whi5 phospho-mimetic mutant.
- Pasquale Palumbo
- , Marco Vanoni
- & Lilia Alberghina
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Article
| Open AccessCell-cycle-independent transitions in temporal identity of mammalian neural progenitor cells
The molecular mechanisms determining the temporal identity patterns of self-renewing progenitors during cerebral development are largely unclear. Here, using single cell transcriptome analyses, the authors find progenitor temporal identity arises independent of cell-cycle progression and Notch activation.
- Mayumi Okamoto
- , Takaki Miyata
- & Ayano Kawaguchi
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Article
| Open AccessHypoxia regulates global membrane protein endocytosis through caveolin-1 in cancer cells
Hypoxia promotes tumour aggressiveness and resistance of cancers to oncological treatment. Here, the authors show that caveolin-1 can down-regulate global membrane protein endocytosis in hypoxic cells with potential implications for targeting the hypoxic 3microenvironment of aggressive tumours.
- E. Bourseau-Guilmain
- , J. A. Menard
- & M. Belting
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Article
| Open AccessmiR-3188 regulates nasopharyngeal carcinoma proliferation and chemosensitivity through a FOXO1-modulated positive feedback loop with mTOR–p-PI3K/AKT-c-JUN
Although miR-related mechanisms have been implicated in nasopharyngeal carcinoma (NPC), a precise role for miR-3188 has not been reported in this context. Here, Zhao et al. show that FOXO1-induced miR-3188 acts as a tumour suppressor in NPC by regulating the axis mTOR/PI3K/Akt/c-Jun.
- Mengyang Zhao
- , Rongcheng Luo
- & Weiyi Fang
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Article
| Open AccessIdentification of pyrazolopyridazinones as PDEδ inhibitors
PDEδ is a widely expressed factor that sustains the spatial organization and signalling of Ras family proteins. Here the authors describe the activity of Deltazinone 1, a new highly selective PDEδ inhibitor of KRAS-dependent cancer cell growth with low cytotoxic side effects.
- Björn Papke
- , Sandip Murarka
- & Philippe I.H. Bastiaens
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Article
| Open AccessTum/RacGAP functions as a switch activating the Pav/kinesin-6 motor
Centralspindlin consists of dimeric kinesin-6 and dimeric RacGAP, and is involved in the organization of anaphase midzone microtubules. Here, the authors show that the RacGAP is needed for motor activity at the plus-end of microtubules, but not for the bundling activity associated with kinesin-6.
- Li Tao
- , Barbara Fasulo
- & William Sullivan
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Article
| Open AccessSuper-complexes of adhesion GPCRs and neural guidance receptors
FLRT proteins are known to interact with Lphns and Unc5s, mediating cell adhesion and repulsion respectively. Here the authors use crystallography, native mass spectrometry, molecular dynamics simulations and cell-based assays to show that these three proteins form large super-complexes with functions distinct from their smaller subcomplexes.
- Verity A. Jackson
- , Shahid Mehmood
- & Elena Seiradake
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Article
| Open AccessAurora A drives early signalling and vesicle dynamics during T-cell activation
Aurora A is a protein kinase that contributes to the progression of mitosis by stimulating microtubule nucleation. Here the authors show that Aurora A also functions during T cell activation by maintaining TCR signaling through Lck activation.
- Noelia Blas-Rus
- , Eugenio Bustos-Morán
- & Francisco Sánchez-Madrid
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Article
| Open AccessRepulsive cues combined with physical barriers and cell–cell adhesion determine progenitor cell positioning during organogenesis
The precise positioning of organ progenitor cells is essential for organ development and function. Here the authors use live imaging and mathematical modelling to show that the confinement of a motile progenitor cell population results from coupled physical barriers and cell-cell interactions.
- Azadeh Paksa
- , Jan Bandemer
- & Erez Raz
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Article
| Open AccessMincle-mediated translational regulation is required for strong nitric oxide production and inflammation resolution
Resolution of granulomas in mycobacterial infection requires macrophages to switch from cytokine to nitric oxide (NO) production. Here the authors show that Mincle stimulates translation of the key NO synthesis genes by a mechanism dependent on p38-mediated hypusination of eiF5A.
- Wook-Bin Lee
- , Ji-Seon Kang
- & Young-Joon Kim
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Article
| Open AccessProstacyclin-producing human mesenchymal cells target H19 lncRNA to augment endogenous progenitor function in hindlimb ischaemia
Human mesenchymal stem cells (hMSC) expressing paracrine factors may enhance therapeutic benefits when transplanted. Here, the authors show that hMSCs stably expressing prostacyclin enhance host regeneration and muscle mass gain in a mouse hindlimb ischaemia model, mediated by the long noncoding RNA H19.
- Yuxiao Deng
- , Zhongwei Yang
- & Qi Liu
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Article
| Open AccessSignalling couples hair follicle stem cell quiescence with reduced histone H3 K4/K9/K27me3 for proper tissue homeostasis
Changes in global histone trimethylation have been linked to embryonic but not adult stem cell plasticity. Here, Lee et al. find H3 K4/K9/K27me3 levels actively reduced in adult mouse skin and hair follicle stem cells during quiescence (catagen) and link this to active bone morphogen protein signalling.
- Jayhun Lee
- , Sangjo Kang
- & Tudorita Tumbar
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Article
| Open AccessA vacuole-like compartment concentrates a disordered calcium phase in a key coccolithophorid alga
Coccolithophores are unicellular marine algae that produce calcitic particles inside their cells. Here the authors study cells of the dominant coccolithophore Emiliania huxleyiand identify an intracellular compartment that is filled with high concentrations of a disordered form of calcium.
- Sanja Sviben
- , Assaf Gal
- & André Scheffel
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Article
| Open AccessSteroid binding to Autotaxin links bile salts and lysophosphatidic acid signalling
Autotaxin generates the bioactive lipid lysophosphatidic acid to regulate diverse biological processes. Here, the authors identify a role for bile salts as direct allosteric inhibitors of autotaxin activity, suggesting that steroids may function as regulators of lysophosphatidic acid signalling.
- Willem-Jan Keune
- , Jens Hausmann
- & Anastassis Perrakis
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Article
| Open AccessRAS signalling through PI3-Kinase controls cell migration via modulation of Reelin expression
Ras signalling through PI3K kinase has an important role in tumour initiation and progression. Here, the authors show that the interaction of Ras with PI3-Kinase p110α and the subsequent activation of Rac-GTPase impairs cell -cell interaction by blocking the downstream Reelin/E-cadherin, thus resulting in cell migration.
- Esther Castellano
- , Miriam Molina-Arcas
- & Julian Downward
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Article
| Open AccessThe cell adhesion molecule Fasciclin2 regulates brush border length and organization in Drosophila renal tubules
In Drosophila, Fasciclin 2 (Fas2) has been mainly studied in the nervous system, yet this adhesion protein is more abundant in the adult renal tubule. Here the authors show that Fas2 is essential for brush border maintenance in renal tubules through regulation of microvilli length and organization.
- Kenneth A. Halberg
- , Stephanie M. Rainey
- & Julian A. T. Dow
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Article
| Open AccessDazl is a target RNA suppressed by mammalian NANOS2 in sexually differentiating male germ cells
The Nanos family protein, NANOS2, is required for sexual differentiation of male germ cells in mice, however, the molecular RNA targets are unknown. Here, Kato et al. identify Dazl, a germ cell-specific gene, as being a target of NANOS, with stabilized DazlmRNA causing abnormal resumption of the cell cycle.
- Yuzuru Kato
- , Takeo Katsuki
- & Yumiko Saga
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Article
| Open AccessFimbrin phosphorylation by metaphase Cdk1 regulates actin cable dynamics in budding yeast
Metaphase cells preferentially promote actin cable assembly through cyclin-dependent kinase 1 (Cdk1) activity. Here the authors identify fimbrin as one of the main metaphase Cdk1 targets for cell cycle regulation of actin cable assembly in budding yeast.
- Yansong Miao
- , Xuemei Han
- & David G. Drubin
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Article
| Open AccessMicrotubule-dependent balanced cell contraction and luminal-matrix modification accelerate epithelial tube fusion
During tracheal tube fusion in Drosophila, a pair of tip cells form an adherens junction and then fuse their plasma membranes. Here the authors show that a balanced pulling force mediated by myosin and microtubules, as well as localized deposition of matrix, promotes plasma membrane fusion.
- Kagayaki Kato
- , Bo Dong
- & Shigeo Hayashi
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Article
| Open AccessAlternative splicing of MALT1 controls signalling and activation of CD4+ T cells
MALT1 regulates NFκB signalling both as a scaffolding protein and as a protease. Here the authors show that during T cell activation the expression of MALT1 gene switches to an alternatively spliced variant, which increases TCR signal transduction due to enhanced TRAF6 binding.
- Isabel Meininger
- , Richard A. Griesbach
- & Daniel Krappmann
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Article
| Open AccessParathyroid hormone receptor signalling in osterix-expressing mesenchymal progenitors is essential for tooth root formation
How the parathyroid hormone-related protein receptor (PPR) and its ligand act in root formation and tooth eruption is unclear. Here, the authors identify osterix-expressing dental mesenchymal cells as progenitors for root formation and that PPR signalling mediates their differentiation and tooth eruption.
- Wanida Ono
- , Naoko Sakagami
- & Henry M. Kronenberg
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Article
| Open AccessPathological lymphangiogenesis is modulated by galectin-8-dependent crosstalk between podoplanin and integrin-associated VEGFR-3
Pathological lymphangiogenesis is associated with various eye diseases. Here the authors show that a carbohydrate-binding protein, galectin-8, promotes pathological lymphangiogenesis in the eye by regulating the crosstalk among VEGF-C, podoplanin and integrin pathways, and thus may represent a useful therapeutic target.
- Wei-Sheng Chen
- , Zhiyi Cao
- & Noorjahan Panjwani
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