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| Open AccessMechanically activated ion channel Piezo1 modulates macrophage polarization and stiffness sensing
Macrophages perform diverse functions during immune responses, but the molecular mechanisms by which physical properties of the tissue regulate macrophage behavior remain unknown. Here the authors find that Piezo1 is a mechanosensor of stiffness, and that its activity modulates macrophage polarization responses.
- Hamza Atcha
- , Amit Jairaman
- & Wendy F. Liu
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Article
| Open AccessMolecular motion and tridimensional nanoscale localization of kindlin control integrin activation in focal adhesions
Focal adhesions (FAs) initiate chemical and mechanical signals involved in cell polarity, migration, proliferation and differentiation. Here, authors combine single protein tracking, super-resolution microscopy and functional assays, which allow correlating the molecular behaviour and 3D nanoscale localization of kindlin with its function in integrin activation inside FAs.
- Thomas Orré
- , Adrien Joly
- & Grégory Giannone
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Article
| Open AccessMitofusin-2 stabilizes adherens junctions and suppresses endothelial inflammation via modulation of β-catenin signaling
Endothelial tissues must have intact barrier function, but this may be disrupted during inflammation. Here, the authors show that the mitochondrial protein Mitofusin-2 stabilizes cell–cell adherens junctions in endothelial cells during homeostasis and binds the transcriptional activator β-catenin upon inflammatory stimulation.
- Young-Mee Kim
- , Sarah Krantz
- & Jalees Rehman
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Article
| Open AccessMapping the molecular and structural specialization of the skin basement membrane for inter-tissue interactions
The basement membrane is located at tissue interfaces, but how it mediates distinct inter-tissue interactions is unclear. Here, the authors systematically define the spatial heterogeneity of skin basement membrane composition and show its functional importance in inter-tissue interactions.
- Ko Tsutsui
- , Hiroki Machida
- & Hironobu Fujiwara
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Article
| Open AccessA junctional PACSIN2/EHD4/MICAL-L1 complex coordinates VE-cadherin trafficking for endothelial migration and angiogenesis
Communication between endothelial leader and follower cells during collective cell migration is crucial for vascular development. Here, the authors show that PACSIN2 guides collective cell migration and angiogenesis by recruiting a protein trafficking complex to asymmetric cell-cell junctions, controlling local junction plasticity.
- Tsveta S. Malinova
- , Ana Angulo-Urarte
- & Stephan Huveneers
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Article
| Open AccessLoss of Ambra1 promotes melanoma growth and invasion
The absence of scaffold protein Ambra1 leads to hyperproliferation and growth in mouse models. Here the authors show that Ambra1 deficiency accelerates melanoma growth and increases metastasis in mouse models of melanoma through FAK1 hyperactivation.
- Luca Di Leo
- , Valérie Bodemeyer
- & Francesco Cecconi
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Article
| Open AccessForce-FAK signaling coupling at individual focal adhesions coordinates mechanosensing and microtissue repair
How adhesive forces are transduced and integrated into biochemical signals at focal adhesions (FAs) is poorly understood. Here authors show that force- FAK signaling coupling coordinates cell migration and tissue-scale forces to promote microtissue repair.
- Dennis W. Zhou
- , Marc A. Fernández-Yagüe
- & Andrés J. García
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Article
| Open AccessProteome-wide and matrisome-specific alterations during human pancreas development and maturation
The pancreatic extracellular matrix (ECM) is known to differ between species, age groups and physiological states, but its compositional changes throughout human life are not well understood. Here, the authors study how the proteome of pancreatic ECM changes during human development and maturation.
- Zihui Li
- , Daniel M. Tremmel
- & Lingjun Li
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Article
| Open AccessQuantitative single-protein imaging reveals molecular complex formation of integrin, talin, and kindlin during cell adhesion
Single-molecule localisation microscopy is limited by low labeling and detection efficiencies of the molecular probes. Here the authors report a framework to obtain absolute molecular quantities on a true molecular scale; the data reveal a ternary adhesion complex underlying cell-matrix adhesion.
- Lisa S. Fischer
- , Christoph Klingner
- & Carsten Grashoff
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Article
| Open AccessFilopodia-based contact stimulation of cell migration drives tissue morphogenesis
Contact stimulation of migration drives tissue morphogenesis. Here the authors report that filopodia-based contact-dependent asymmetry of cell–matrix adhesion drives directional movement, whereas contractile actin cables contribute to the integrity of the migrating cell cluster in the myotubes of Drosophila developing testes.
- Maik C. Bischoff
- , Sebastian Lieb
- & Sven Bogdan
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Article
| Open AccessAdhesion-mediated heterogeneous actin organization governs apoptotic cell extrusion
Cell extrusion regulates monolayer cell density and is critical in maintaining epithelia integrity, which has implications in homeostasis, development, and cancer progression. Here the authors describe how monolayer integrate mechanical signals from tissue mechanics, cell-cell adhesion, cell-substrate adhesion and cytoskeleton coordinate cell extrusion.
- Anh Phuong Le
- , Jean-François Rupprecht
- & Benoît Ladoux
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Article
| Open AccessMetavinculin modulates force transduction in cell adhesion sites
Muscle cells express an adhesion molecule called metavinculin, which has been associated with cardiomyopathies. Here, the authors employed molecular tension sensors to reveal that metavinculin expression modulates cell adhesion mechanics and they develop a mouse model to demonstrate that the presence of metavinculin is not as critical for heart muscle function as previously thought.
- Verena Kanoldt
- , Carleen Kluger
- & Carsten Grashoff
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| Open AccessDifferential cell adhesion implemented by Drosophila Toll corrects local distortions of the anterior-posterior compartment boundary
The differential adhesion hypothesis is proposed to play a role during epithelial tissue morphogenesis but it has remained unclear. Here, the authors identify the Toll-1 receptor as a differentially expressed adhesion molecule that maintains lineage restriction boundaries in the Drosophila epidermal epithelium.
- Norihiro Iijima
- , Katsuhiko Sato
- & Daiki Umetsu
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Article
| Open AccessInjury triggers fascia fibroblast collective cell migration to drive scar formation through N-cadherin
Extensive scars develop in deep wounds as opposed to superficial wounds but it is unclear why. Here, the authors use live imaging of physiologic wounds and scars formed ex vivo to show that fascia fibroblasts upregulate N-cadherin allowing coordinated cell migration that drives extensive scar formation of deep wounds.
- Dongsheng Jiang
- , Simon Christ
- & Yuval Rinkevich
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Article
| Open AccessE-cadherin focuses protrusion formation at the front of migrating cells by impeding actin flow
The arrival of migratory cells at their targets relies on following precise routes within tissues. Here the authors demonstrate that the cell adhesion molecule E-cadherin can control the path of cell migration by confining the site where bleb-type protrusions form within the cell front.
- Cecilia Grimaldi
- , Isabel Schumacher
- & Erez Raz
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Article
| Open AccessThe Rho-GEF PIX-1 directs assembly or stability of lateral attachment structures between muscle cells
PIX proteins activate the small GTPases Rac and Cdc42, and are known to have numerous functions in a variety of cell types. Using a genetic screen in C. elegans, the authors find that PIX-1 is required for the assembly or stability of integrin adhesion complexes between muscle cells.
- Jasmine C. Moody
- , Hiroshi Qadota
- & Guy M. Benian
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Article
| Open AccessPINCH-1 regulates mitochondrial dynamics to promote proline synthesis and tumor growth
Proline metabolism is crucial to tumor proliferation. Here, the authors show PINCH-1 deficiency inhibited proline synthesis by promoting mitochondrial fragmentation via DRP1, downregulating PYCR1 expression and reducing cell proliferation in vitro and in vivo.
- Ling Guo
- , Chunhong Cui
- & Chuanyue Wu
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Article
| Open AccessStructure of the DOCK2−ELMO1 complex provides insights into regulation of the auto-inhibited state
DOCK2 is a guanine nucleotide exchange factor (GEF) that activates RHO GTPases and interacts with ELMO1, which stimulates its GEF activity. Here, the authors provide mechanistic insights into how ELMO1 regulates DOCK2 activity by determining the structure of the DOCK2–ELMO1 binary complex representing the closed, auto-inhibited state and the DOCK2−ELMO1−RAC1 ternary complex structure, where DOCK2−ELMO1 adopts an open, active conformation.
- Leifu Chang
- , Jing Yang
- & David Barford
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Article
| Open AccessUncovering mutation-specific morphogenic phenotypes and paracrine-mediated vessel dysfunction in a biomimetic vascularized mammary duct platform
In vitro models of the human mammary gland have struggled to mimic the 3D morphogenic processes that occur in vivo. Here the authors develop a 3D microfluidic platform of a vascularized human mammary duct that simulates diverse morphogenic transitions and paracrine crosstalk.
- Matthew L. Kutys
- , William J. Polacheck
- & Christopher S. Chen
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Article
| Open AccessDiaphanous-related formin mDia2 regulates beta2 integrins to control hematopoietic stem and progenitor cell engraftment
Bone marrow engraftment of haematopoietic stem and progenitor cells (HSPCs) requires homing and lodgement to the niche. Here, the authors show that mDia2 is required for HSPC polarization, nuclear MAL, and SRF-induced beta2 integrin expression during transendothelial migration of HSPCs required for engraftment.
- Yang Mei
- , Xu Han
- & Peng Ji
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Article
| Open AccessPost-surgical adhesions are triggered by calcium-dependent membrane bridges between mesothelial surfaces
Surgical adhesions are organ-joining bands of scar tissue that remain clinically untreatable. Here, the authors show that adhesions are formed through expansive mesothelial membrane bridges, and that blocking these with small molecules prevents formation of adhesions in mice.
- Adrian Fischer
- , Tim Koopmans
- & Yuval Rinkevich
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Article
| Open AccessRab11b-mediated integrin recycling promotes brain metastatic adaptation and outgrowth
Mechanisms governing adaptation of breast cancer to the brain metastatic microenvironment are unclear. Here, the authors use RNA-sequencing and Drosophila screening to identify Rab11b-mediated endosomal recycling as a unique mechanism for adaptation to a challenging metastatic microenvironment, which can be exploited by repurposing statins.
- Erin N. Howe
- , Miranda D. Burnette
- & Siyuan Zhang
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Article
| Open Accessβ-Catenin and FGFR2 regulate postnatal rosette-based adrenocortical morphogenesis
Multicellular rosettes are known to mediate complex cellular reorganization such as epithelial folding and branching during embryonal organogenesis. Here the authors show that rosette formation regulated by β-Catenin and FGFR2 mediate postnatal adrenal cortex zona glomerulosa morphogenesis.
- Sining Leng
- , Emanuele Pignatti
- & David T. Breault
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Article
| Open Accessc-di-GMP modulates type IV MSHA pilus retraction and surface attachment in Vibrio cholerae
Biofilm formation by Vibrio cholerae is regulated by c-di-GMP and requires the type IV MSHA pilus. Here, Floyd et al. show that the MSHA pilus is a dynamic system, and that both extension and retraction are directly controlled by c-di-GMP via regulation of activity of the extension ATPase MshE.
- Kyle A. Floyd
- , Calvin K. Lee
- & Fitnat H. Yildiz
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Article
| Open AccessMicroglia control vascular architecture via a TGFβ1 dependent paracrine mechanism linked to tissue mechanics
During development and pathologies of the central nervous system, blood vessels are closely connected with the innate immune cells, microglia. Here, the authors report that microglia adjust their angiogenic program to shape blood vessels and may depend on tissue stiffness.
- Tejasvi Dudiki
- , Julia Meller
- & Tatiana V. Byzova
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Article
| Open Accessβ4GALT1 controls β1 integrin function to govern thrombopoiesis and hematopoietic stem cell homeostasis
Mutations affecting sialylation and galactosylation affect megakaryocyte function and thrombopoiesis. Here the authors show that the enzyme β4GalT1 regulates thrombopoiesis and hematopoietic stem cell homeostasis by controlling beta-1 integrin function.
- Silvia Giannini
- , Melissa M. Lee-Sundlov
- & Karin M. Hoffmeister
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Article
| Open AccessStructural basis of liprin-α-promoted LAR-RPTP clustering for modulation of phosphatase activity
Leukocyte common antigen-related receptor protein tyrosine phosphatases (LAR-RPTPs) mediate guided axon growth and synapse formation and liprin-α proteins are their intracellular binding partners. Here the authors present the crystal structure of the phosphatase domains from the LAR-RPTP family member LAR bound to the SAM repeats of liprin-α3 and show that liprin-α binding enhances LAR cluster formation and reduces LAR phosphatase activity in cells.
- Xingqiao Xie
- , Ling Luo
- & Zhiyi Wei
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Article
| Open AccessForces during cellular uptake of viruses and nanoparticles at the ventral side
Many intracellular pathogens mimic extracellular matrix motifs to specifically interact with the host membrane which may influences virus particle uptake. Here authors use single molecule tension sensors to reveal the minimal forces exerted on single virus particles and demonstrate that the uptake forces scale with the adhesion energy.
- Tina Wiegand
- , Marta Fratini
- & Joachim P. Spatz
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Article
| Open AccessExtracellular matrix hydrogel derived from decellularized tissues enables endodermal organoid culture
Organoid cultures have been developed from multiple tissues, opening new possibilities for regenerative medicine. Here the authors demonstrate the derivation of GMP-compliant hydrogels from decellularized porcine small intestine which support formation and growth of human gastric, liver, pancreatic and small intestinal organoids.
- Giovanni Giuseppe Giobbe
- , Claire Crowley
- & Paolo De Coppi
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Article
| Open AccessIntegrin-linked kinase controls retinal angiogenesis and is linked to Wnt signaling and exudative vitreoretinopathy
Integrin-linked kinase (ILK) is an important mediator of integrin signaling. Here Park et al. show that mice with endothelial-specific deletion of Ilk develop vascular defects that resemble familial exudative vitreoretinopathy, and identify mutations in ILK in patients with exudative vitreoretinopathy suggesting a potential role in human pathogenesis.
- Hongryeol Park
- , Hiroyuki Yamamoto
- & Ralf H. Adams
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Article
| Open AccessModular actin nano-architecture enables podosome protrusion and mechanosensing
Podosomes are actin-based protrusions used by cells for invasion and local degradation but the structure underlying their protrusiveness and mechanosensitivity is unclear. Here, the authors report that podosomes have a modular actin nano-architecture whose organization differs on stiff or soft substrates.
- Koen van den Dries
- , Leila Nahidiazar
- & Alessandra Cambi
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Article
| Open AccessZEB1/NuRD complex suppresses TBC1D2b to stimulate E-cadherin internalization and promote metastasis in lung cancer
Non-small cell lung cancer (NSCLC) is often associated with metastasis to the lungs. Here, the authors perform independent screens and identify NuRD as a co-repressor of ZEB1, and demonstrate TBC1D2b as a downstream target of ZEB1/NuRD complex regulating NSCLC metastasis.
- Roxsan Manshouri
- , Etienne Coyaud
- & Don L. Gibbons
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Article
| Open AccessEpithelial CD47 is critical for mucosal repair in the murine intestine in vivo
The role of the transmembrane glycoprotein CD47 in healing injured intestinal mucosa is unclear. Here, the authors show that selective loss of CD47 in the murine intestinal epithelium results in defective mucosal repair after colonic wounding, with suggested impaired cell migration in vitro.
- Michelle Reed
- , Anny-Claude Luissint
- & Charles A. Parkos
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| Open AccessDNA mechanotechnology reveals that integrin receptors apply pN forces in podosomes on fluid substrates
Podosomes are protrusive structures that coordinate diverse functions related to cell invasion, migration, bone resorption and immune surveillance. Here the authors integrate DNA nanotechnology with FLIM-FRET to demonstrate that podosomes apply pN integrin tensile forces to sense and respond to substrate mechanics.
- Roxanne Glazier
- , Joshua M. Brockman
- & Khalid Salaita
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Article
| Open AccessSuperresolution architecture of cornerstone focal adhesions in human pluripotent stem cells
Pluripotent stem cell colonies are encircled by large cornerstone focal adhesions (FAs). Here, using super-resolution imaging, the authors describe features in the nanoscale makeup of these stable FAs such as inverted vinculin, lateral talin segregation and distinct kank protein distributions.
- Aki Stubb
- , Camilo Guzmán
- & Johanna Ivaska
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Article
| Open AccessZika virus enhances monocyte adhesion and transmigration favoring viral dissemination to neural cells
Zika virus (ZIKV) can infect the central nervous system, but it is not clear how it reaches the brain. Here, Ayala-Nunez et al. show in ex vivo and in vivo models that ZIKV can hitch a ride in monocytes in a Trojan Horse manner to cross the endothelium and disseminate the virus.
- Nilda Vanesa Ayala-Nunez
- , Gautier Follain
- & Raphael Gaudin
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Article
| Open AccessNuclear decoupling is part of a rapid protein-level cellular response to high-intensity mechanical loading
Cells must be robust to the mechanical demands of their environments. Here, Gilbert et al. expose cells to high-intensity strain cycling and use proteomics to identify a protein, SUN2, that behaves as a strain-induced breakpoint that can decouple the nucleoskeleton from the cytoskeleton.
- Hamish T. J. Gilbert
- , Venkatesh Mallikarjun
- & Joe Swift
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Article
| Open AccessMyosin IIA and formin dependent mechanosensitivity of filopodia adhesion
Fiolopodia are involved in cell migration and their attachment to the ECM is mediated by integrin receptors. Here the authors show that myosin X induced filipodia adhesion to fibronectin requires activity of myosin IIA at the filopodium base and formin at the tip to support force transmission through the actin core.
- N. O. Alieva
- , A. K. Efremov
- & A. D. Bershadsky
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Article
| Open AccessExtracellular matrix stiffness cues junctional remodeling for 3D tissue elongation
The extracellular matrix can shape developing organs, but how external forces direct intercellular morphogenesis is unclear. Here, the authors use 3D imaging to show that elongation of the Drosophila egg chamber involves polarized cell reorientation signalled by changes in stiffness of the surrounding extracellular matrix.
- Dong-Yuan Chen
- , Justin Crest
- & David Bilder
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Article
| Open AccessA small molecule promotes cartilage extracellular matrix generation and inhibits osteoarthritis development
Loss of cartilage tissue is a hallmark of osteoarthritis. Here the authors show that BNTA, a small molecule identified in a chemical screen, promotes ECM generation in human osteoarthritic chondrocytes and cartilage explants, and suppresses pathology in a rat model of osteoarthritis.
- Yuanyuan Shi
- , Xiaoqing Hu
- & Yingfang Ao
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Article
| Open AccessImmunoregulation of macrophages by dynamic ligand presentation via ligand–cation coordination
Control of macrophage adhesion and phenotype is important to biomaterial applications. Here, the authors report on the use of bisphosphonate coated gold nanoparticles by magnesium coordination for the controlled adhesion and polarisation of macrophages in vitro and in vivo and controlled cell release.
- Heemin Kang
- , Boguang Yang
- & Liming Bian
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Article
| Open AccessOscillatory cortical forces promote three dimensional cell intercalations that shape the murine mandibular arch
Morphogenesis of tissue sheets is well studied, but mechanisms that shape bulk tissues are unclear. Here, the authors show that mesenchymal cells intercalate in 3D to shape the mouse branchial arch, with cortical forces driving intercalations in a Wnt5a-, Yap/Taz- and Piezo1-dependent manner.
- Hirotaka Tao
- , Min Zhu
- & Sevan Hopyan
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Article
| Open AccessAssessment of corneal substrate biomechanics and its effect on epithelial stem cell maintenance and differentiation
The link between how the stiffness of the cornea affects stem cells is unclear. Here, the authors use Brillouin spectro-microscopy to show that mechanical properties of the cornea affect epithelial stem cells and after injury, treating the cornea with collagenase suppresses YAP activation, assisting in regeneration.
- Ricardo M. Gouveia
- , Guillaume Lepert
- & Che J. Connon
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Article
| Open AccessSterol regulatory element binding protein 1 couples mechanical cues and lipid metabolism
SREBP transcription factors activate lipid synthesis and generate raw materials to lipidate various proteins. Here, the authors show that a stiff cellular environment causes RhoA lipidation and acto-myosin contraction, which inhibits SREBP1 and connects the extracellular matrix to lipid metabolism.
- Rebecca Bertolio
- , Francesco Napoletano
- & Giannino Del Sal
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Article
| Open AccessMembrane-cytoskeletal crosstalk mediated by myosin-I regulates adhesion turnover during phagocytosis
Phagocytosis of pathogens is thought to proceed through the sequential engagement of Fc-receptors on the phagocyte with antibodies on the target surface. Here authors show that myosin 1e and myosin 1f link the actin cytoskeleton to the membrane and are required for efficient phagocytosis of antibody-opsonized targets.
- Sarah R. Barger
- , Nicholas S. Reilly
- & Nils C. Gauthier
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Article
| Open AccessActomyosin contractility-dependent matrix stretch and recoil induces rapid cell migration
How cells migrate in fibrous tissues is still poorly understood. Here, with synthetic 3D fibre matrices of controlled alignment and stiffness, the authors report that cells in stiff matrices move slowly and continuously, but in softer, deformable matrices cells can rapidly slingshot forward via stretch and recoil of matrix fibres.
- William Y. Wang
- , Christopher D. Davidson
- & Brendon M. Baker
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Article
| Open AccessKindlin-2 links mechano-environment to proline synthesis and tumor growth
The mechano-properties of the Extracellular Matrix (ECM) are important for tumorigenesis. Here, the authors show that the stiffening of the ECM promotes translocation of the focal adhesion protein—Kindlin-2—to the mitochondria, where it interacts with the proline synthesis enzyme PYCR1, stimulating proline synthesis and cell proliferation.
- Ling Guo
- , Chunhong Cui
- & Chuanyue Wu
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Article
| Open AccessMorphologic determinant of tight junctions revealed by claudin-3 structures
The main components of tight junctions (TJ) are claudins that polymerize and form meshwork architectures called TJ strands. Here the authors present the 3.6 Å crystal structure of murine claudin-3 and show that residue P134 causes a bending of the third transmembrane helix which affects the morphology and adhesiveness of the TJ strands.
- Shun Nakamura
- , Katsumasa Irie
- & Yoshinori Fujiyoshi
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Article
| Open AccessThrombospondin-3 augments injury-induced cardiomyopathy by intracellular integrin inhibition and sarcolemmal instability
Thrombospondin 4 has been shown to protect the heart and the skeletal muscle by enhancing matrix secretion and membrane stability thanks to its intracellular function. Here the authors show that thrombospondin 3 exacerbates injury-induced cardiomyopathy and promotes destabilization of the cardiomyocyte membrane by impairing integrin trafficking to the sarcolemma.
- Tobias G. Schips
- , Davy Vanhoutte
- & Jeffery D. Molkentin