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| Open AccessSerotonin signaling regulates actomyosin contractility during morphogenesis in evolutionarily divergent lineages
Serotonin signaling is well known for modulating animal behavior. Here the authors discovered it plays a developmental role in regulating actomyosin contractility driven cellular mechanics and tissue flows during gastrulation of insect and bird.
- Sanjay Karki
- , Mehdi Saadaoui
- & Thomas Lecuit
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Article
| Open AccessIntegrin β3 directly inhibits the Gα13-p115RhoGEF interaction to regulate G protein signaling and platelet exocytosis
Zhang et al. show that the adhesion receptor integrin β3 directly inhibits G protein mediated RhoA activation and granule secretion. A peptide mimicking this effect selectively inhibits platelet secretion but not integrin-mediated platelet adhesion.
- Yaping Zhang
- , Xiaojuan Zhao
- & Xiaoping Du
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Article
| Open AccessDeficiency of gluconeogenic enzyme PCK1 promotes metabolic-associated fatty liver disease through PI3K/AKT/PDGF axis activation in male mice
Phosphoenolpyruvate carboxykinase 1 (Pck1) is an enzyme involved in glucose production that also regulates lipogenesis and has been linked to liver steatosis. Here the authors report that deficiency of Pck1 in the liver leads to nonalcoholic fatty liver disease via activation of the RhoA/PI3K/AKT pathway in a study with male mice.
- Qian Ye
- , Yi Liu
- & Ni Tang
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Article
| Open AccessSH3 domain regulation of RhoGAP activity: Crosstalk between p120RasGAP and DLC1 RhoGAP
Inhibition of DLC1 RhoGAP by p120RasGAP allows for crosstalk between the Rho and Ras pathways. Here, Chau et al. present the co-crystal structure of DLC1 RhoGAP domain and p120RasGAP SH3 domain and probe the interaction with biochemical studies.
- Jocelyn E. Chau
- , Kimberly J. Vish
- & Amy L. Stiegler
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Article
| Open AccessG-protein-coupled receptor P2Y10 facilitates chemokine-induced CD4 T cell migration through autocrine/paracrine mediators
P2Y10 is a G-protein-coupled receptor that is expressed in CD4 T cells. Here authors show that its ligands, lysophosphatidylserine and ATP, are induced in T cells upon chemokine stimulation and regulate RhoA activation and migration through an autocrine/paracrine loop.
- Malarvizhi Gurusamy
- , Denise Tischner
- & Nina Wettschureck
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Article
| Open AccessRegulation of local GTP availability controls RAC1 activity and cell invasion
Changes in intracellular GTP levels are not considered as a regulatory event in RAC1 activation in live cells since total GTP levels are substantially higher than the RAC1 GTP dissociation constant determined in vitro. Here, the authors demonstrate that the availability of free GTP in live cells controls the activity of RAC1 and cell invasion.
- Anna Bianchi-Smiraglia
- , David W. Wolff
- & Mikhail A. Nikiforov
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Article
| Open AccessNance-Horan Syndrome-like 1 protein negatively regulates Scar/WAVE-Arp2/3 activity and inhibits lamellipodia stability and cell migration
Cell migration is essential for many physiological processes. Its deregulation causes cancer metastasis and it is not well understood how it is tightly controlled. We identify NHSL1 as a negative regulator of actin nucleating Scar/WAVE-Arp2/3 complexes, cell protrusion stability, and cell migration.
- Ah-Lai Law
- , Shamsinar Jalal
- & Matthias Krause
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Article
| Open AccessEFA6B regulates a stop signal for collective invasion in breast cancer
Reduced expression of EFA6B is found in highly metastatic breast cancer subtypes. Here, the authors report that loss of EFA6B promotes collective invasion through activation of the epithelial-to-mesenchymal transition program and CDC42-dependent signalling pathways in breast cancer.
- Racha Fayad
- , Monserrat Vázquez Rojas
- & Frédéric Luton
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Article
| Open Accessβ-Pix-dependent cellular protrusions propel collective mesoderm migration in the mouse embryo
Mesodermal directional cell migration is needed to establish body plan but how this is regulated is unclear. Here, the authors show that loss of the guanine nucleotide exchange factor for Rac1 and Cdc42, β-Pix, at mouse gastrulation disrupts the orderly, collective anterior migration of mesoderm cells due to defective cell protrusions.
- Tatiana Omelchenko
- , Alan Hall
- & Kathryn V. Anderson
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Article
| Open AccessVav2 catalysis-dependent pathways contribute to skeletal muscle growth and metabolic homeostasis
Skeletal muscle plays a key role in regulating systemic glucose and metabolic homeostasis. Here, the authors show that the catalytic activity of Vav2, an activator of Rho GTPases, modulates those processes by favoring the responsiveness of this tissue to insulin and related factors.
- Sonia Rodríguez-Fdez
- , L. Francisco Lorenzo-Martín
- & Xosé R. Bustelo
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Article
| Open AccessWNT11-FZD7-DAAM1 signalling supports tumour initiating abilities and melanoma amoeboid invasion
Amoeboid cells are associated with melanoma invasive capacity. Here, the authors show that the WNT11-FZD7-DAAM1 pathway regulates tumour-initiating potential, invasion and metastasis lead by amoeboid cells in the invasive front of melanoma tumours.
- Irene Rodriguez-Hernandez
- , Oscar Maiques
- & Victoria Sanz-Moreno
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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 AccessVAV2 signaling promotes regenerative proliferation in both cutaneous and head and neck squamous cell carcinoma
The Rho signalling pathway is frequently activated in squamous carcinomas. Here, the authors find that the Rho GEF VAV2 is over expressed in both cutaneous and head and neck squamous cell carcinomas and that at the molecular level VAV2 promotes a pro-tumorigenic stem cell-like signalling programme.
- L. Francisco Lorenzo-Martín
- , Natalia Fernández-Parejo
- & Xosé R. Bustelo
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Article
| Open AccessMisshapen coordinates protrusion restriction and actomyosin contractility during collective cell migration
Directed motility of cell clusters requires coordination of protrusion formation at the front of leader cells and contractility at the rear. Here the authors show that the kinase Misshapen restricts protrusions to the leader cell and promotes contractile forces at the rear of the cluster.
- Cédric Plutoni
- , Sarah Keil
- & Gregory Emery
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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 AccessOptogenetic dissection of Rac1 and Cdc42 gradient shaping
A steep gradient of Cdc42 is at the front of migrating cells, whereas the active Rac1 gradient is graded. Here the authors show that Cdc42 gradients follow the distribution of GEFs and govern direction of migration, while Rac1 gradients require the activity of the GAP β2-chimaerin and control cell speed.
- S. de Beco
- , K. Vaidžiulytė
- & M. Coppey
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Article
| Open AccessIdentification of a novel anoikis signalling pathway using the fungal virulence factor gliotoxin
Gliotoxin (GT), produced by the pulmonary pathogen A. fumigatus, induces detachment-induced apoptosis (anoikis) of lung epithelial cells and likely promotes invasion. Here, the authors show that GT covalently modifies integrins at the RGD binding site followed by activation of RhoA-ROCK-MKK4/7-JNK signalling leading to Bim-mediated anoikis.
- Florian Haun
- , Simon Neumann
- & Christoph Borner
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Article
| Open AccessSTEF/TIAM2-mediated Rac1 activity at the nuclear envelope regulates the perinuclear actin cap
The perinuclear actin cap determines nuclear morphology but its regulation is currently poorly understood. Here, the authors find that an activator of the Rac1 GTPase, STEF/TIAM2, localises to the nuclear envelope and contributes to perinuclear actin and myosin tension, which in turn regulates the actin cap.
- Anna Woroniuk
- , Andrew Porter
- & Angeliki Malliri
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Article
| Open AccessAtrx inactivation drives disease-defining phenotypes in glioma cells of origin through global epigenomic remodeling
ATRX inactivation frequently occurs in glioma. Here, the authors explore the role of ATRX inactivation in oncogenesis, highlighting ATRX deficiency driven epigenomic changes that influence the expression of genes crucial to the oncogenic phenotype.
- Carla Danussi
- , Promita Bose
- & Jason T. Huse
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Article
| Open AccessCell shape information is transduced through tension-independent mechanisms
It is not known whether the shape of a cell can regulate cellular phenotype independently. Here, the authors show that culturing kidney podocytes or smooth muscle cells on 3-D biomimetic surfaces results in phenotypic changes and that cell shape is sensed by integrin β3 in a tension-independent manner.
- Amit Ron
- , Evren U. Azeloglu
- & Ravi Iyengar
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Article
| Open AccessAsymmetric localization of DLC1 defines avian trunk neural crest polarity for directional delamination and migration
Following epithelial-mesenchymal transition, avian trunk neural crest cell polarity determines directional migration but how this is established is unclear. Here, the authors find that the RhoGAP, Deleted in liver cancer 1, is asymmetrically localized in the cytoplasm, governing neural crest migratory polarization.
- Jessica Aijia Liu
- , Yanxia Rao
- & Martin Cheung
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Article
| Open AccessA cdk1 gradient guides surface contraction waves in oocytes
Surface contraction waves (SCWs) are prominent shape changes coupled to cell cycle transitions in oocytes. Here the authors show that SCWs are patterned by the spatiotemporal integration of two conserved modules, cdk1-cyclinB for cell cycle regulation and RhoA/Rok/NMYII for actomyosin contractility.
- Johanna Bischof
- , Christoph A. Brand
- & Péter Lénárt
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Article
| Open AccessOptogenetic activation of Plexin-B1 reveals contact repulsion between osteoclasts and osteoblasts
Osteoclasts induce chemotaxis of osteoblasts during bone remodelling, but maintain spatial segregation. Here the authors show that osteoclasts repel osteoblasts via contact inhibition of locomotion mediated by Semaphorin-Plexin signalling and develop an optogenetic tool for Plexin-B1 to show how this signalling axis induces cell repolarization.
- Abhijit Deb Roy
- , Taofei Yin
- & Yi I. Wu
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Article
| Open AccessA Cdc42/RhoA regulatory circuit downstream of glycoprotein Ib guides transendothelial platelet biogenesis
Platelets derive from large precursor cells (megakaryocytes) in the bone marrow. Düttinget al. show that megakaryocyte polarization and platelet biogenesis in the bone-marrow sinusoids are directed by adhesion receptor GPIb signalling and resulting balanced antagonism between RhoA (stop-signal) and Cdc42 (go-signal).
- Sebastian Dütting
- , Frederique Gaits-Iacovoni
- & Bernhard Nieswandt
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Article
| Open AccessOptogenetic control of RhoA reveals zyxin-mediated elasticity of stress fibres
Cellular contractility is regulated by the GTPase RhoA, but how local signals are translated to a cell-level response is not known. Here the authors show that targeted RhoA activation results in propagation of force along stress fibres and actin flow, and identify zyxin as a regulator of stress fibre mechanics and homeostasis.
- Patrick W. Oakes
- , Elizabeth Wagner
- & Margaret L. Gardel
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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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Article
| Open AccessStructure and vascular function of MEKK3–cerebral cavernous malformations 2 complex
The protein kinase MEKK3 interacts with CCM2, which is associated with the predominantly cerebrovascular CCM disease. Here the authors use structural, biochemical, cell biology and in vivotechniques to show that regulation of Rho signalling by the CCM2:MEKK3 complex is needed to maintain neurovascular integrity.
- Oriana S. Fisher
- , Hanqiang Deng
- & Bing Su
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Article |
Speed control for neuronal migration in the postnatal brain by Gmip-mediated local inactivation of RhoA
In the postnatal mouse brain, RhoA signalling regulates the saltatory movement of new neurons migrating from the ventricular–subventricular zone to the olfactory bulb. Here the authors show that a RhoA-specific GTPase-activating protein, Gmip, serves as a brake for RhoA-mediated saltatory movement of new neurons during migration.
- Haruko Ota
- , Takao Hikita
- & Kazunobu Sawamoto