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Article
| Open AccessThe Par3 polarity protein is an exocyst receptor essential for mammary cell survival
The exocyst delivers basolateral proteins from the secretory pathway to the plasma membrane of epithelial cells close to tight junctions. Here the authors show that Par3 acts as a docking site for the exocyst to regulate polarized delivery of basolateral proteins and this is essential to prevent apoptosis and promote mammary cell survival.
- Syed Mukhtar Ahmed
- & Ian G. Macara
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Article
| Open AccessDomain-dependent effects of insulin and IGF-1 receptors on signalling and gene expression
Despite being structurally similar, the insulin receptor (IR) and insulin growth factor I receptor (IGF1R) elicit distinct signalling pathways. Here the authors use receptor chimeras to unveil that IR and IGF1R signalling is related primarily to differences in their intracellular juxtamembrane region.
- Weikang Cai
- , Masaji Sakaguchi
- & C. Ronald Kahn
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Article
| Open AccessLight-sensing via hydrogen peroxide and a peroxiredoxin
While yeasts lack dedicated photoreceptors, they nonetheless possess metabolic rhythms responsive to light. Here the authors find that light signalling in budding yeast involves the production of H2O2, which in turn regulates protein kinase A through a peroxiredoxin-thioredoxin redox relay.
- Kristofer Bodvard
- , Ken Peeters
- & Mikael Molin
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Article
| Open AccessA chemical chaperone improves muscle function in mice with a RyR1 mutation
Mutations in the RyR1 channel cause core myopathies. Here the authors show that ER stress and the unfolded protein response underlie the pathology caused by a common RyR1 channel mutation, and show that treatment with a chemical chaperone restores muscle function in mice.
- Chang Seok Lee
- , Amy D. Hanna
- & Susan L. Hamilton
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Correspondence
| Open AccessCorrespondence: Reply to ‘Oncogenic MYC persistently upregulates the molecular clock component REV-ERBα’
- Anton Shostak
- , Bianca Ruppert
- & Michael Brunner
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Correspondence
| Open AccessCorrespondence: Oncogenic MYC persistently upregulates the molecular clock component REV-ERBα
- Brian J. Altman
- , Annie L. Hsieh
- & Chi V. Dang
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Article
| Open AccessA genome-wide screen identifies YAP/WBP2 interplay conferring growth advantage on human epidermal stem cells
Individual human epidermal cells differ in their self-renewal ability. Here the authors perform genome-wide pooled RNAi screens to uncover the molecular basis for this heterogeneity, and identify genes conferring a clonal growth advantage on normal and neoplastic human epidermal cells.
- Gernot Walko
- , Samuel Woodhouse
- & Fiona M. Watt
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Article
| Open AccessCell-free reconstitution reveals centriole cartwheel assembly mechanisms
The centriole is an organelle composed of rings of SAS-6 proteins that form a cartwheel structure. Here the authors develop a cell-free system to examine core cartwheel assembly ofC. reinhardtiiproteins and discover that CrSAS-6 has autonomous properties that facilitates self-organized stacking of pairs of rings.
- P. Guichard
- , V. Hamel
- & P. Gönczy
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Article
| Open AccessFMNL formins boost lamellipodial force generation
Actin polymerization in lamellipodia of cells is regulated by the Arp2/3 complex and FMNL family formins. Here the authors show that both FMNL2 and FMNL3 contribute to lamellipodium protrusion and structure, and abolishing FMNL2/3 reduces protrusion force generation and migration, without affecting Arp2/3 incorporation.
- Frieda Kage
- , Moritz Winterhoff
- & Klemens Rottner
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Article
| Open AccessA semisynthetic Atg3 reveals that acetylation promotes Atg3 membrane binding and Atg8 lipidation
Acetylation of Atg3 regulates lipidation of Atg8 and therefore autophagy, but the molecular mechanisms remain unclear. Here, Liet al. semi-synthesize diacetylated Atg3, allowing them to show that acetylated Atg3 enhances Atg8 lipidation by promoting interaction of Atg3 with liposomes containing physiological levels of phosphatidylethanolamine.
- Yi-Tong Li
- , Cong Yi
- & Lei Liu
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Article
| Open AccessProbing cytoskeletal modulation of passive and active intracellular dynamics using nanobody-functionalized quantum dots
Methods to probe transport dynamics within cells can shed insight into the nature of the cytoplasm. Here the authors develop a method to functionalize and deliver quantum dots intracellularly to show how the cytoskeleton influences non-equilibrium intracellular transport dynamics.
- Eugene A. Katrukha
- , Marina Mikhaylova
- & Lukas C. Kapitein
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Article
| Open AccessDNA damage during S-phase mediates the proliferation-quiescence decision in the subsequent G1 via p21 expression
Cell cycle arrest after DNA damage is achieved by the expression of the CDK inhibitor p21. Here the authors show that spontaneous DNA damage incurred in unperturbed cell cycles, leads to cell populations exhibiting a bistable state, with p53 and p21 regulating the proliferation-quiescence decision.
- Alexis R. Barr
- , Samuel Cooper
- & Chris Bakal
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Article
| Open AccessMutual reinforcement between telomere capping and canonical Wnt signalling in the intestinal stem cell niche
Mice lacking telomerase provide a model to study pathogenesis caused by critical telomere shortening. Here, the authors provide evidence that telomere shortening causes downregulation of Wnt signalling in intestinal crypts and that defects can be partially rescued by treatment with Wnt agonists.
- Ting-Lin B. Yang
- , Qijun Chen
- & F. Brad Johnson
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Article
| Open AccessThe scaffold protein p140Cap limits ERBB2-mediated breast cancer progression interfering with Rac GTPase-controlled circuitries
p140Cap adaptor proteins interfere with adhesion and growth factor-dependent signalling in cancer cells but the mechanisms are unclear. Here the authors show that p140Cap interferes with ERBB2-dependent activation of Rac GTPase-controlled circuitries reducing metastasis and cancer progression.
- Silvia Grasso
- , Jennifer Chapelle
- & Paola Defilippi
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Article
| Open AccessORAI2 modulates store-operated calcium entry and T cell-mediated immunity
Ca2+ release-activated Ca2+(CRAC) channels are essential for protective immunity, but the immunological functions of the three ORAI homologues that form CRAC channels are unclear. Here the authors show that ORAI1 and ORAI2 form heteromeric CRAC channels, which fine-tune T cell activation and immune responses.
- Martin Vaeth
- , Jun Yang
- & Stefan Feske
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Article
| Open AccessPhosphorylation of Rab-coupling protein by LMTK3 controls Rab14-dependent EphA2 trafficking to promote cell:cell repulsion
Ephrin receptors mediate contact inhibition, but their intracellular trafficking during this process is unknown. Here the authors show that EphA2 receptor trafficking is regulated by the Rab GTPase effector Rab-coupling protein, which associates with Rab14-endosomes upon LMTK3-mediated phosphorylation.
- Christine Gundry
- , Sergi Marco
- & Jim C. Norman
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Article
| Open AccessIdentification of common non-coding variants at 1p22 that are functional for non-syndromic orofacial clefting
Many genetic variants have been associated with complex congenital disorders, but their function is not always clear. Here, the authors develop a pipeline to functionally characterize such variants, and show potential roles for three SNPs in non-syndromic cleft lip and palate.
- Huan Liu
- , Elizabeth J. Leslie
- & Robert A. Cornell
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Article
| Open AccessPre-plaque conformational changes in Alzheimer’s disease-linked Aβ and APP
Studying the physiological confirmation of amyloid β (Aβ) and amyloid precursor protein (APP) often uses techniques that could disrupt their conformation. Here, the authors use non-destructive microscopy approaches to study the confirmation of Aβ and APP in mouse models of Alzheimer’s disease.
- O. Klementieva
- , K. Willén
- & G. K. Gouras
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Article
| Open AccessAllosteric modulation of peroxisomal membrane protein recognition by farnesylation of the peroxisomal import receptor PEX19
PEX19 is a chaperone and import receptor for peroxisomal membrane proteins (PMPs). Here the authors present the structure of the farnesylated C-terminal domain of PEX19, and its interaction with PMPs reveals how the farnesyl moiety allosterically reshapes the PMP binding surface and modulates PEX19 function.
- Leonidas Emmanouilidis
- , Ulrike Schütz
- & Michael Sattler
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Article
| Open AccessEGFR/ARF6 regulation of Hh signalling stimulates oncogenic Ras tumour overgrowth
EGFR signalling is required for oncogenic Ras driven tumorigenesis. In this study, using aDrosophilatumour model the authors demonstrate that depletion of Arf6, a Ras-related GTP-binding protein activated by EGFR, supresses oncogenic Ras driven overgrowth via modulation of Hedgehog signalling.
- Chiswili Chabu
- , Da-Ming Li
- & Tian Xu
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Article
| Open AccessLaser-mediated rupture of chlamydial inclusions triggers pathogen egress and host cell necrosis
Chlamydiae replicate in host cells within specialised vacuoles (inclusions), which are eventually ruptured to liberate the bacteria, leading to cell lysis. Here, Kerret al. use a laser ablation technique and videomicroscopy to show that inclusion rupture triggers a necrotic pathway in the host cell.
- Markus C. Kerr
- , Guillermo A. Gomez
- & Rohan D Teasdale
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Article
| Open AccessDeconvolution of Buparlisib’s mechanism of action defines specific PI3K and tubulin inhibitors for therapeutic intervention
Buparlisib/BKM120 is in phase 3 clinical trials as a phosphoinositide 3-kinase (PI3K) inhibitor. Here, Bohnackeret al. combine chemical biology and structural biology approaches to segregate BKM120’s biological actions, and suggest that it causes mitotic arrest predominantly by binding microtubules and disrupting their dynamics.
- Thomas Bohnacker
- , Andrea E. Prota
- & Matthias P. Wymann
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Article
| Open AccessStructure-guided mutagenesis reveals a hierarchical mechanism of Parkin activation
Parkin and PINK1 are involved in damaged mitochondria clearance; however the sequence of events of Parkin activation is not clear. Here, the authors show that binding to phospho-ubiquitin on mitochondria enables Parkin phosphorylation, which allows Repressor Element of Parkin removal, E3 ligase activation and mitophagy.
- Matthew Y. Tang
- , Marta Vranas
- & Edward A. Fon
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Article
| Open AccessRETRACTED ARTICLE: TRIB2 confers resistance to anti-cancer therapy by activating the serine/threonine protein kinase AKT
The emergence of drug resistance is a major obstacle in the treatment of cancer patients. Here, the authors show that TRIB2 expression increases resistance to PI3K inhibition by promoting AKT activation and the subsequent FOXO inactivation and disruption of p53 function.
- Richard Hill
- , Patricia A. Madureira
- & Wolfgang Link
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Article
| Open Accessα-amino trimethylation of CENP-A by NRMT is required for full recruitment of the centromere
Centromeres are chromosomal domains epigenetically specified by the presence of the CENP-A containing nucleosomes that control chromosome segregation. Here the authors show that α-amino trimethylation of CENP-A by the enzyme NRMT is required for centromere function, faithful chromosome segregation and cell survival.
- Kizhakke M. Sathyan
- , Daniele Fachinetti
- & Daniel R. Foltz
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Article
| Open AccessMisrouting of v-ATPase subunit V0a1 dysregulates lysosomal acidification in a neurodegenerative lysosomal storage disease model
Lysosomal acidification defects have been implicated in various neurodegenerative disorders. Baghet al. show that the V0a1 subunit of v-ATPase requires palmitoylation for correct sorting and trafficking to the lysosome membrane, and that such a process is impaired in a mouse model of a devastating neurodegenerative lysosomal storage disease, INCL.
- Maria B. Bagh
- , Shiyong Peng
- & Anil B. Mukherjee
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Article
| Open AccessLoss of ERα induces amoeboid-like migration of breast cancer cells by downregulating vinculin
Estrogen receptor alpha (ERα)-negative cells, which are enriched during endocrine therapy, are associated with metastatic relapse of breast cancer. Here the authors show that ERα inhibits breast cancer metastasis and suggest that ERα suppresses the amoeboid-like migration of breast cancer cells by upregulating vinculin.
- Yuan Gao
- , Zhaowei Wang
- & Yingqi Zhang
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Article
| Open AccessMalignant extracellular vesicles carrying MMP1 mRNA facilitate peritoneal dissemination in ovarian cancer
Ovarian cancer is particularly deadly because it is difficult to detect at the pre-metastatic stage; extracellular vesicles (EVs) on the other hand are involved in the pre-metastatic niche preparation. Here the authors show that EVs mediate ovarian cancer metastasis in the peritoneal area by targeting the mesothelium.
- Akira Yokoi
- , Yusuke Yoshioka
- & Takahiro Ochiya
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Article
| Open AccessLipid-mediated Wnt protein stabilization enables serum-free culture of human organ stem cells
There are two technical impediments for using purified Wnt proteins in serum-free stem cell cultures: rapid loss of activity and toxicity of detergents to stem cell self-renewal. Here, the authors show that lipid-stabilized Wnt3a can establish long-term culture of human intestinal and liver organoids.
- Nesrin Tüysüz
- , Louis van Bloois
- & Derk ten Berge
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Article
| 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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