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| Open AccessZyxin regulates endothelial von Willebrand factor secretion by reorganizing actin filaments around exocytic granules
The adaptor protein zyxin is known for its mechanosensing function in the maintenance of actin network. Here the authors show that zyxin is key to blood homeostasis and thrombosis by controlling the endothelial release of von Willebrand factor and the formation of actin scaffolds on exocytic granules.
- Xiaofan Han
- , Pin Li
- & Jincai Luo
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Article
| Open AccessPotassium channels Kv1.3 and KCa3.1 cooperatively and compensatorily regulate antigen-specific memory T cell functions
Potassium channels are essential for modulating T-cell functions. Here, by characterizing rat models and analysing human T cells, the authors identify differential requirements of two potassium channel proteins, Kv1.3 and KCa3.1, for the induction of conventional versus autoreactive T-cell responses.
- Eugene Y. Chiang
- , Tianbo Li
- & Jane L. Grogan
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Article
| Open AccessNur77 suppresses hepatocellular carcinoma via switching glucose metabolism toward gluconeogenesis through attenuating phosphoenolpyruvate carboxykinase sumoylation
Gluconeogenesis is downregulated in hepatocellular carcinoma. Here, the authors show that nuclear receptor Nur77 acts as a tumour suppressor sustaining gluconeogenesis by enhancing phosphoenolpyruvate carboxykinase (PEPCK1) stability via regulating its interaction with the SUMO-conjugating enzyme Ubc9.
- Xue-li Bian
- , Hang-zi Chen
- & Qiao Wu
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Article
| Open AccessDrebrin-mediated microtubule–actomyosin coupling steers cerebellar granule neuron nucleokinesis and migration pathway selection
Neuronal migration is vital for neuronal circuit morphogenesis and is thought to rely on microtubule-actomyosin crosstalk. Here, the authors use super-resolution imaging and the drebrin microtubule-actin crosslinking protein to show that microtubule-actomyosin coupling controls the direction of centrosome and somal motility.
- Niraj Trivedi
- , Daniel R. Stabley
- & David J. Solecki
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Article
| Open AccessOxidation of F-actin controls the terminal steps of cytokinesis
Cytokinetic abscission relies on the local constriction after cytoskeleton disassembly, but it is not known how the actin filaments are disassembled. Here, the authors show that the redox enzyme MICAL1 is recruited by Rab35 and induces oxidation-mediated depolymerization of actin, which is required to recruit ESCRT-III and complete abscission.
- Stéphane Frémont
- , Hussein Hammich
- & Arnaud Echard
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Article
| Open AccessEnsemble and single-molecule dynamics of IFT dynein in Caenorhabditis elegans cilia
Cytoplasmic dynein 2 drives retrograde intraflagellar transport but little is known about its dynamics. Here the authors use fluorescence microscopy to track labelled dynein 2 inC. elegansat the single-molecule level and report diffusion at the ciliary base, and pausing and directional switches along the cilium.
- Jona Mijalkovic
- , Bram Prevo
- & Erwin J. G. Peterman
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Article
| Open AccessCellular senescence mediates fibrotic pulmonary disease
Removal of senescent cells rejuvenates lungs of aged mice. Here the authors show that elimination of senescent cells using either genetic or pharmacological means improves lung function and physical health in a mouse model of idiopathic pulmonary fibrosis (IPF), suggesting potential therapy for treatment of human IPF.
- Marissa J. Schafer
- , Thomas A. White
- & Nathan K. LeBrasseur
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Article
| Open AccessDissecting the molecular organization of the translocon-associated protein complex
The translocon-associated protein complex (TRAP) is a crucial component of the endoplasmic reticulum protein translocon. Here the authors study native translocon structures from human disease patients and algae cells to determine the molecular organization of the TRAP complex.
- Stefan Pfeffer
- , Johanna Dudek
- & Friedrich Förster
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Article
| Open AccessProtein disulfide isomerase secretion following vascular injury initiates a regulatory pathway for thrombus formation
What keeps blood from clotting in homeostasis is a puzzle. Here, the authors suggest that lack of the enzyme disulfide isomerase (PDI) in the blood is key, and show that PDI is secreted only after vascular injury to act on substrates that include vitronectin, affecting its binding to αVβ3 and αIIbβ3 integrins and enabling thrombus formation.
- Sheryl R. Bowley
- , Chao Fang
- & Bruce Furie
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Article
| Open AccessProteolysis regulates cardiomyocyte maturation and tissue integration
Proper heart development and synchronous cardiomyocyte contraction rely on tissue integrity. Here the authors show that the ubiquitin-proteasome system and the E3 ubiquitin ligase ASB2 in particular are crucial for cardiomyocyte maturation and tissue integrity through the degradation of the TCF3 transcription factor.
- Ryuichi Fukuda
- , Felix Gunawan
- & Didier Y. R. Stainier
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Article
| Open AccessMitochondrial ATP transporter depletion protects mice against liver steatosis and insulin resistance
Adenine nucleotide translocase (ANT) 2 promotes ADP/ATP exchange across the mitochondrial inner membrane. Choet al. show that liver specific Ant2 deletion increases uncoupled respiration and protects mice against fatty liver and obesity-induced insulin resistance.
- Joonseok Cho
- , Yujian Zhang
- & Naohiro Terada
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Article
| Open AccessA class of extracellular vesicles from breast cancer cells activates VEGF receptors and tumour angiogenesis
Extracellular vesicles (EVs) contain VEGF and can contribute to tumour angiogenesis, although the mechanism remains unclear. Here, the authors find that a form of VEGF (VEGF90K) resistant to Bevacizumab but sensitive to HSP90 inhibitors, associates with EVs through its interaction with Hsp90.
- Qiyu Feng
- , Chengliang Zhang
- & Richard A. Cerione
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Article
| Open AccessHormetic heat stress and HSF-1 induce autophagy to improve survival and proteostasis in C. elegans
Mild heat stress has beneficial effects on organismal health and survival. Here, Kumstaet al. show that a mild heat shock and HSF-1 overexpression induce autophagy in multiple tissues of C. elegansand autophagy-related genes are essential for both heat shock-induced and HSF-1–mediated stress resistance and longevity.
- Caroline Kumsta
- , Jessica T. Chang
- & Malene Hansen
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Article
| Open AccessHaploinsufficiency networks identify targetable patterns of allelic deficiency in low mutation ovarian cancer
Cancers accumulate multiple single copy number alterations, but their impact is unclear. Here, the authors computationally demonstrate a disruption of genes associated with autophagy in ovarian cancer, show impact on autophagic flux, and note the efficacy of autophagy drugs in preclinical models.
- Joe Ryan Delaney
- , Chandni B. Patel
- & Dwayne G. Stupack
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Article
| Open AccessUsp9x regulates Ets-1 ubiquitination and stability to control NRAS expression and tumorigenicity in melanoma
Usp9x is a deubiquitinating enzyme with altered expression in melanoma; however its functional contribution in this context is not clear. Here the authors show that Usp9x regulates the stability of the transcription factor Ets-1 that in turn impacts metastatic melanoma through increased expression of NRAS.
- Harish Potu
- , Luke F. Peterson
- & Nicholas J. Donato
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Article
| Open AccessSecreted CLIC3 drives cancer progression through its glutathione-dependent oxidoreductase activity
The secretome from cancer and stromal cells contributes to the creation of a microenvironment, which in turn contributes to invasion and angiogenesis. Here, the authors compare the secretomes of immortalized normal fibroblasts and cancer-derived fibroblast and identify CLIC3 as a driver of cancer progression.
- Juan R. Hernandez-Fernaud
- , Elena Ruengeler
- & Sara Zanivan
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Article
| Open AccessDub3 inhibition suppresses breast cancer invasion and metastasis by promoting Snail1 degradation
Snail1 is a key factor controlling epithelial-to-mesenchymal transition and cancer metastasis. While the E3 ligases responsible for Snail1 ubiquitination and degradation have been defined, the deubiquitinating enzyme is unknown. Here Zhou and colleagues show that Dub3 stabilizes Snail1 by removing ubiquitin, thus impacting breast cancer cell metastasis.
- Yadi Wu
- , Yu Wang
- & Binhua P. Zhou
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Article
| Open AccessSelf-organizing actin patterns shape membrane architecture but not cell mechanics
In vitro models of actin organization show the formation of vortices, asters and stars. Here Fritzsche et al. show that such actin structures form in living cells in a manner dependent on the Arp2/3 complex but not myosin, and such structures influence membrane architecture but not cortex elasticity.
- M. Fritzsche
- , D. Li
- & C. Eggeling
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Article
| Open AccessAbnormal degradation of the neuronal stress-protective transcription factor HSF1 in Huntington’s disease
Huntington’s disease (HD) is caused by misfolding of mutant Htt protein. The authors find that in HD models, the decreased expression of heat shock transcription factor 1 that usually protects against protein misfolding, is in part caused by elevated CK2α’ kinase and Fbxw7 E3 ligase expression.
- Rocio Gomez-Pastor
- , Eileen T. Burchfiel
- & Dennis J. Thiele
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Article
| Open AccessOptogenetic control of cellular forces and mechanotransduction
Cellular mechanical forces are regulated by Rho GTPases. Here the authors develop an optogenetic system to control the spatiotemporal activity of RhoA, and show that directing a RhoA activator to the plasma membrane causes contraction and YAP nuclear localization, whereas directing it to the mitochondria causes relaxation.
- Léo Valon
- , Ariadna Marín-Llauradó
- & Xavier Trepat
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Article
| Open AccessAstrocyte deletion of Bmal1 alters daily locomotor activity and cognitive functions via GABA signalling
Core clock genes, such asBmal1, are expressed in astrocytes, but their contribution to the timekeeping system is unknown. Barca-Mayo et al. report that deletion of Bmal1in Glast+ astrocytes alters the neuronal clock through GABA signalling, leading to abnormal circadian locomotor behaviour and impaired cognition in mice.
- Olga Barca-Mayo
- , Meritxell Pons-Espinal
- & Davide De Pietri Tonelli
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Article
| Open AccessExpression of β-globin by cancer cells promotes cell survival during blood-borne dissemination
Circulating tumour cells contribute to metastatic spread. Here the authors find that beta-chain of haemoglobin is overexpressed in those cells and protects them from oxidative stress, prolonging their survival in circulation and thereby increasing the likelihood of metastasis formation.
- Yu Zheng
- , David T. Miyamoto
- & Daniel A. Haber
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Article
| Open AccessArrestin-biased AT1R agonism induces acute catecholamine secretion through TRPC3 coupling
Angiotensin II type 1 receptor (AT1R)-mediated acute catecholamine release is modulated by β-arrestin. Here the authors show that β-arrestin-1 recruits the Ca2+channel TRPC3 and the PLCγ to the AT1R-β-arrestin complex, triggering G protein-independent calcium influx and catecholamine secretion.
- Chun-Hua Liu
- , Zheng Gong
- & Jin-Peng Sun
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Article
| Open AccessRIP1 autophosphorylation is promoted by mitochondrial ROS and is essential for RIP3 recruitment into necrosome
Mitochondrial reactive oxygen species (ROS) promote necroptosis and the receptor interacting protein 1 (RIP1) is a key player in this form of cell death. Here, the authors show that cysteine residues in RIP1 sense ROS and oxidation of the cysteines triggers RIP1 autophosphorylation, which promotes functional necrosome formation.
- Yingying Zhang
- , Sheng Sean Su
- & Jiahuai Han
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Article
| Open AccessLncRNA AK023948 is a positive regulator of AKT
The function of many human long non-coding RNAs (lncRNAs) is still undetermined. Here, the authors setup a gain of function CRISPR-based screen and identify a lncRNA that positively regulates AKT activity by interacting with the RNA helicase DHX9 resulting in stabilization of PI3K regulatory subunit p85.
- Pratirodh Koirala
- , Jianguo Huang
- & Yin-Yuan Mo
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Article
| Open AccessUfd2p synthesizes branched ubiquitin chains to promote the degradation of substrates modified with atypical chains
How ubiquitination affects the proteins it modifies varies according to the type of linkage between ubiquitin moieties. Here, Liuet al. show how yeast Udf2p promotes K48 linkage formation onto K29-linked chains to generate branched K29-K48 ubiquitin chains that target its substrate to the proteasome.
- Chao Liu
- , Weixiao Liu
- & Wei Li
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Article
| Open AccessFAK signalling controls insulin sensitivity through regulation of adipocyte survival
The kinase FAK is important for integrin signalling and promotes cell survival. Here, the authors demonstrate FAK regulates adipocyte survival, and is particularly important for maintaining insulin sensitivity during adipose tissue expansion in the context of a calorie-rich diet.
- Cynthia T. Luk
- , Sally Yu Shi
- & Minna Woo
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Article
| Open AccessStructure of the homodimeric androgen receptor ligand-binding domain
The androgen receptor is crucial for the development and physiology of reproductive organs. Here the authors present the structure of the androgen receptor ligand-binding domain bound to dihydrotestosterone, identifying a homodimerization interface that is crucial for receptor activityin vivo.
- Marta Nadal
- , Stefan Prekovic
- & Eva Estébanez-Perpiñá
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Article
| Open AccessIdentification of BPIFA1/SPLUNC1 as an epithelium-derived smooth muscle relaxing factor
Asthma is characterized by abnormal airway hyperresponsiveness. Here the authors identify BPIFA1 as a factor secreted by airway epithelial cells, and show that it regulates contractility of airway smooth muscle cells by binding to and regulating the Orai1 Ca2+channel.
- Tongde Wu
- , Julianne Huang
- & Robert Tarran
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Article
| Open AccessmTORC1-independent TFEB activation via Akt inhibition promotes cellular clearance in neurodegenerative storage diseases
The transcription factor EB (TFEB) is a master regulator of lysosomal biogenesis. Here authors show that trehalose, an mTOR-independent autophagy inducer, alleviates the pathological phenotypes in a mouse model of neurodegenerative disease. Trehalose acts by inhibiting Akt, which normally suppresses TFEB via an mTORC1-independent mechanism.
- Michela Palmieri
- , Rituraj Pal
- & Marco Sardiello
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Article
| Open Accessβ-arrestin-2 is an essential regulator of pancreatic β-cell function under physiological and pathophysiological conditions
Beta-arrestins have key roles in development and metabolic functions as euglycaemic control and insulin sentitivity. Here Zhuet al. show that beta-arrestin-2 regulates insulin secretion and glucose tolerance in mice by promoting CAMKII functions in beta cells.
- Lu Zhu
- , Joana Almaça
- & Jürgen Wess
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Article
| Open AccessA Rab5 endosomal pathway mediates Parkin-dependent mitochondrial clearance
Damaged mitochondria are normally cleared through canonical and alternative autophagy pathways. Here, the authors report that mitochondria can be cleared through an autophagy-independent endosomal-lysosomal pathway that depends on Parkin-dependent sequestration of mitochondria in Rab5-positive early endosomes.
- Babette C. Hammerling
- , Rita H. Najor
- & Åsa B. Gustafsson
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Article
| Open AccessKIF13B establishes a CAV1-enriched microdomain at the ciliary transition zone to promote Sonic hedgehog signalling
The ciliary transition zone (TZ) regulates the protein and membrane composition of the primary cilium. Here the authors identify the kinesin-3 motor protein KIF13B as a regulator of TZ membrane composition that controls the ciliary accumulation of Smoothened, which is involved in activation of Sonic hedgehog signalling.
- Kenneth B. Schou
- , Johanne B. Mogensen
- & Lotte B. Pedersen
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Article
| Open AccessCellular mechano-environment regulates the mammary circadian clock
Circadian clocks regulate physiological and behavioural rhythms. Here, the authors show that the stiffness of the extracellular environment regulates circadian clocks in murine breast epithelium via Rho signalling, and explain how extracellular matrix stiffening in aging affects circadian rhythm, with implication in disease.
- Nan Yang
- , Jack Williams
- & Qing-Jun Meng
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Article
| Open AccessOrthogonal ubiquitin transfer identifies ubiquitination substrates under differential control by the two ubiquitin activating enzymes
The transfer of ubiquitin (UB) to cellular targets is mediated sequentially by three groups of enzymes, UB activating enzyme (E1), UB conjugating enzyme (E2) and UB ligase (E3). Here the authors provide evidence that the two mammalian E1 enzymes, Uba1 and Uba6, exert biologically distinct functions.
- Xianpeng Liu
- , Bo Zhao
- & Hiroaki Kiyokawa
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Article
| Open AccessαV-class integrins exert dual roles on α5β1 integrins to strengthen adhesion to fibronectin
Interaction of fibronectin with αv-class and α5β1 integrins results in formation of cell adhesion complexes, but the initial events (<120 s) remain unclear. Here, the authors show that αv-class integrins bind fibronectin faster than α5β1 integrins and subsequently signal to α5ß1 integrins to strengthen the adhesion.
- Mitasha Bharadwaj
- , Nico Strohmeyer
- & Daniel J. Müller
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Article
| Open AccessRhomboid family member 2 regulates cytoskeletal stress-associated Keratin 16
Keratin 16 is an epithelial protein highly expressed at pressure bearing sites and during wound healing and cancer. Here the authors show that K16 interacts with the inactive protease Rhbdf2, associated with Tylosis with oesophageal cancer, and that this interaction drives increased keratinocyte proliferation.
- Thiviyani Maruthappu
- , Anissa Chikh
- & David P. Kelsell
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Article
| Open AccessmTORC2 signalling regulates M2 macrophage differentiation in response to helminth infection and adaptive thermogenesis
mTORC1 and mTORC2 are alternatively required for differentiation of T cells into Th1/Th17 or Th2 cells. Here the authors show mTORC2 signalling is also needed for IL-4-induced M2 activation with functional evidence provided by aN. brasiliensisinfection model and cold challenge to model adaptive thermogenesis.
- R. W. Hallowell
- , S. L. Collins
- & M. R. Horton
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Article
| Open AccessProton pumping accompanies calcification in foraminifera
Despite their role in oceanic CaCO3production, the physiological processes responsible for calcification in foraminifera are poorly understood Here, the authors show that calcification is driven by rapid transformation of bicarbonate to carbonate inside the cytoplasm, achieved by active outward proton pumping.
- Takashi Toyofuku
- , Miki Y. Matsuo
- & Hiroshi Kitazato
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Article
| Open AccessA critical role of DDRGK1 in endoplasmic reticulum homoeostasis via regulation of IRE1α stability
DDRGK1 is an ER membrane protein that is subject to Ufm1 modification, but its function in ER homeostasis is unknown. Here, the authors show that ufmylated DDRGK1 interacts with and stabilizes the ER-stress sensor protein IRE1a, in turn repressing ER stress and apoptosis.
- Jiang Liu
- , Ying Wang
- & Yu-Sheng Cong
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Article
| Open AccessSnf1-related kinase improves cardiac mitochondrial efficiency and decreases mitochondrial uncoupling
The Snf1-related kinase (SNRK) is widely expressed and yet its function is poorly understood. Here the authors show that SNRK regulates mitochondrial coupling via the Trib3-PPARα-UCP3 pathway and that cardiac overexpression of SNRK decreases metabolic substrate usage and oxygen consumption but maintains cardiac function and energy in mice.
- Amy K. Rines
- , Hsiang-Chun Chang
- & Hossein Ardehali
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Article
| Open AccessTemporal and compartment-specific signals coordinate mitotic exit with spindle position
The mitotic exit network (MEN) triggers mitotic exit and can be blocked by the spindle position checkpoint (SPOC). Here the authors show that SPOC kinase Kin4 counterbalances MEN activation by the Cdc fourteen early anaphase release (FEAR) network in the mother cell and that in the absence of FEAR mitotic exit requires daughter cell-confined factors.
- Ayse Koca Caydasi
- , Anton Khmelinskii
- & Gislene Pereira
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Article
| Open AccessmTORC1 inhibition in cancer cells protects from glutaminolysis-mediated apoptosis during nutrient limitation
Inhibitors of the mTORC1 pathway are considered anti-cancer drugs. Here, the authors show that on nutrient restriction, glutaminolysis-induced activation of mTORC1 induces apoptosis via inhibiting autophagy, highlighting that under such conditions inhibition of mTORC1 results in survival of cancer cells.
- Victor H. Villar
- , Tra Ly Nguyen
- & Raúl V. Durán
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Article
| Open AccessSec3 promotes the initial binary t-SNARE complex assembly and membrane fusion
Membrane fusion during exocytosis is mediated by interaction between SNARE proteins on vesicles and the cell membrane, but how SNARE complex assembly is initiated remains unknown. Here, the authors show that interaction of Sec3 with Sso2 on the plasma membrane promotes formation of an Sso2–Sec9 complex, an early step in SNARE assembly, likely by inhibiting Sso2 auto-inhibition.
- Peng Yue
- , Yubo Zhang
- & Wei Guo
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Article
| Open AccessFibronectin-guided migration of carcinoma collectives
Tumour microenvironment influences the migration of cancer cells. Here the authors analyse the proteomic constitution of the extracellular matrix and identify a role for fibronectin in regulating the collective migration of squamous cell carcinoma cells.
- Sandeep Gopal
- , Laurence Veracini
- & Ellen Van Obberghen-Schilling
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Article
| Open AccessGlucocorticoid receptor signalling activates YAP in breast cancer
Activation of YAP contributes to tumorigenesis in several tissues. Here, the authors show that in breast cancer cells glucocorticoids induce expression of fibronectin that in turn activates focal adhesion kinase/Src signalling to promote YAP nuclear translocation and transcriptional activity.
- Giovanni Sorrentino
- , Naomi Ruggeri
- & Giannino Del Sal
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Article
| Open AccessOptimality and sub-optimality in a bacterial growth law
Organisms improve their fitness by adjusting their gene expression to the environment, for example bacteria scale the expression of metabolic enzymes near linearly to their growth rate. Here, the authors show that such linear scaling often maximizes growth rate, but that linear scaling is suboptimal under some conditions.
- Benjamin D. Towbin
- , Yael Korem
- & Uri Alon
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Article
| Open Accessα3 Chains of type V collagen regulate breast tumour growth via glypican-1
Collagen has a role in cancer and is particularly important for breast cancer. Here the authors show that the expression of α3 type V collagen and one of its receptors- glipican-1- in the same cell, contributes to a deregulated growth of breast cancer cells.
- Guorui Huang
- , Gaoxiang Ge
- & Daniel S. Greenspan
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Article
| Open AccessGα13 negatively controls osteoclastogenesis through inhibition of the Akt-GSK3β-NFATc1 signalling pathway
Osteoclasts are bone resorptive cells and an attractive target to treat diseases characterized by excessive bone loss, but little is known about osteoclast inhibition. Here the authors identify Gα13 as an intracellular inhibitor of osteoclastogenesis that can prevent bone loss in mice via Akt activation and inhibition of RhoA signalling.
- Mengrui Wu
- , Wei Chen
- & Yi-Ping Li
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