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Journal of Cell Science

Ralitza Staneva, Fatima El Marjou, Jorge Barbazan, Denis Krndija, Sophie Richon, Andrew Clark, Danijela Matic Vignjevic
In early stages of metastasis, cancer cells exit the primary tumor and enter the vasculature. Although most studies have focused on the tumor invasive front, cancer cells from the tumor core can also potentially metastasize. To address cell motility in the tumor core, we imaged tumor explants from spontaneously-forming tumors in real time using long-term two-photon microscopy. Cancer cells in the tumor core are remarkably dynamic and exhibit correlated migration patterns, giving rise to local "currents" and large-scale tissue dynamics...
February 14, 2019: Journal of Cell Science
Qiyu Wang, Zhao Peng, Huan Long, Xuan Deng, Kaiyao Huang
Cilia/flagella are structurally conserved and dynamic organelles; their assembly and disassembly are coordinated with the cell cycle and cell differentiation. Several post-translational modifications, including acetylation, methylation, phosphorylation and ubiquitylation, participate in ciliary disassembly. However, the detailed mechanism and the role of ubiquitylation in ciliary disassembly are unclear. This study identified 20 proteins that were ubiquitylated in shortening flagella of Chlamydomonas α-Tubulin was the most abundant ubiquitylated protein and it was labeled with K63 poly-ubiquitin chains primarily at K304...
February 14, 2019: Journal of Cell Science
Ming-Shih Hwang, Michael G Strainic, Elliot Pohlmann, Elzbieta Pluskota, Diana L Ramirez-Bergeron, Edward F Plow, M Edward Medof
Purified vascular endothelial cell (EC) growth factor receptor-2 (VEGFR2) auto-phosphorylates upon VEGF-A occupation in vitro arguing that VEGR2 confers its mitotic and viability signaling in and of itself. Herein, we show that in ECs, VEGFR2 function requires concurrent C3a/C5a receptor (C3ar1/C5ar1) and IL-6 receptor (IL-6R)-gp130 co-signaling. C3ar1/C5ar1 or IL-6R blockade totally abolished VEGFR2 auto-phosphorylation, downstream Src, ERK, AKT, mTOR, and STAT3 activation, and EC cell cycle entry. VEGF-A augmented production of C3a/C5a/IL-6 and their receptors via a two-step p-Tyk2/p-STAT3 process...
February 14, 2019: Journal of Cell Science
Tarik Exner, Inés Romero-Brey, Eden Yifrach, Jhon Rivera-Monroy, Bianca Schrul, Christos C Zouboulis, Wolfgang Stremmel, Masanori Honsho, Ralf Bartenschlager, Einat Zalckvar, Margarete Poppelreuther, Joachim Füllekrug
Fatty acyl-CoA reductase 1 (Far1) is an ubiquitously expressed peroxisomal membrane protein generating fatty alcohols required for the biosynthesis of ether lipids.Lipid droplet localization of exogenously expressed and endogenous human Far1 was observed by fluorescence microscopy under conditions of increased triglyceride synthesis in tissue culture cells. This unexpected finding was supported further by correlative light electron microscopy and subcellular fractionation. Selective permeabilization, protease sensitivity and N-glycosylation tagging suggested that Far1 is able to assume two different membrane topologies, differing in the orientation of the short hydrophilic C-terminus towards the lumen or the cytosol, respectively...
February 11, 2019: Journal of Cell Science
Paola Genevini, Maria Nicol Colombo, Rossella Venditti, Stefania Marcuzzo, Sara Francesca Colombo, Pia Bernasconi, Maria Antonietta De Matteis, Nica Borgese, Francesca Navone
VAPB and VAPA are ubiquitously expressed ER membrane proteins that play key roles in lipid exchange at membrane contact sites. A mutant, aggregation-prone, form of VAPB (P56S) is linked to a dominantly inherited form of ALS, however, it has been unclear whether its pathogenicity is due to toxic gain of function, to negative dominance, or simply to insufficient levels of the wild-type protein produced from a single allele (haploinsufficiency). To investigate whether reduced levels of functional VAPB, independently from the presence of the mutant form, affect the physiology of mammalian motoneuron-like cells, we generated NSC34 clones, from which VAPB was partially or nearly completely depleted...
February 11, 2019: Journal of Cell Science
Ana Bajc Česnik, Simona Darovic, Sonja Prpar Mihevc, Maja Štalekar, Mirjana Malnar, Helena Motaln, Youn-Bok Lee, Julija Mazej, Jure Pohleven, Markus Grosch, Miha Modic, Marko Fonovič, Boris Turk, Micha Drukker, Christopher E Shaw, Boris Rogelj
The GGGGCC (G4 C2 ) repeat expansion mutation in C9ORF72 gene is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Transcription of the repeat and formation of nuclear RNA foci, which sequester specific RNA-binding proteins is one of the possible pathological mechanisms. Here, we show that (G4 C2 )n repeat RNA predominantly associates with essential paraspeckle proteins SFPQ, NONO, RBM14, FUS and hnRNPH and co-localizes with known paraspeckle-associated RNA hLinc-p21...
February 11, 2019: Journal of Cell Science
Jan H Driller, Janine Lützkendorf, Harald Depner, Matthias Siebert, Benno Kuropka, Christoph Weise, Chengji Piao, Astrid G Petzoldt, Martin Lehmann, Ulrich Stelzl, René Zahedi, Albert Sickmann, Christian Freund, Stephan J Sigrist, Markus C Wahl
Protein scaffolds at presynaptic active zone membranes control information transfer at synapses. For scaffold biogenesis and maintenance, scaffold components must be safely transported along axons. A spectrum of kinases was suggested to control transport of scaffold components, but direct kinase/substrate relationships and operational principles steering phosphorylation-dependent active zone protein transport are presently unknown. Here we show that extensive phosphorylation of a 150-residue unstructured region at the N-terminus of the highly elongated BRP/ELKS active zone proteins is crucial for ordered active zone precursor transport...
February 11, 2019: Journal of Cell Science
Mingqi Han, Christine E Napier, Sonja Frölich, Erdahl Teber, Ted Wong, Jane R Noble, Eugene H Y Choi, Roger D Everett, Anthony J Cesare, Roger R Reddel
Cancers that utilize the Alternative Lengthening of Telomeres (ALT) mechanism for telomere maintenance are often difficult to treat and have a poor prognosis. They are also commonly deficient for expression of ATRX protein, a repressor of ALT activity, and a component of PML nuclear bodies (PML NBs) which are required for intrinsic immunity to various viruses. Here we asked whether ATRX-deficiency creates a vulnerability in ALT cancer cells that could be exploited for therapeutic purposes. We showed in a range of cell types that a mutant herpes simplex virus type 1 (HSV-1) lacking ICP0, a protein that degrades PML NB components including ATRX, was ten- to one thousand-fold more effective in killing ATRX-deficient cells...
February 11, 2019: Journal of Cell Science
Seiya Fukushima, Satomi Matsuoka, Masahiro Ueda
Spontaneous cell movement is underpinned by an asymmetric distribution of signaling molecules including small G proteins and phosphoinositides on the cell membrane. A fundamental question lies in the molecular network for the spontaneous symmetry breaking. Here we report that spatiotemporal dynamics of GTP bound Ras (Ras-GTP) breaks the symmetry due to excitability even in the absence of extracellular spatial cues and downstream signaling activities. A stochastic excitation of local and transient Ras activation induced PIP3 accumulation via direct interaction with PI3K, causing tightly coupled traveling waves propagating along the membrane...
February 11, 2019: Journal of Cell Science
Valentina Tassinari, Vincenzo De Gennaro, Gina La Sala, Daniela Marazziti, Giulia Bolasco, Salvatore Aguanno, Luciana De Angelis, Fabio Naro, Manuela Pellegrini
Ataxia Telangiectasia is a rare, multi system disease caused by ATM kinase deficiency. Atm knockout mice recapitulate premature aging, immunodeficiency, cancer predisposition, growth retardation and motor defects but not cerebellar neurodegeneration and ataxia. We explored if Atm loss is responsible of skeletal muscle defects by investigating myofiber morphology, oxidative/glycolytic activity, myocyte ultrastructural architecture and neuromuscular junctions. Atm knockout mice showed reduced muscle and fiber size...
February 11, 2019: Journal of Cell Science
Soung Yung Kim, Simon Völkl, Stephan Ludwig, Holm Schneider, Viktor Wixler, Jung Park
Fhl2 (Four and a half LIM domain protein 2) is an adaptor protein capable of mediating protein-protein interactions. Here, we report for the first time phenotypic changes in the brain of Fhl2-deficient mice. We showed that: (i) Fhl2 is expressed in neural stem cells, precursors, and mature cells of the neuronal lineage; (ii) Fhl2 deficiency leads to delayed neuroblast migration in vivo , to (iii) premature astroglial differentiation of neural stem cells (NSC) in vitro , and to (iv) a gliosis-like accumulation of GFAP+ astrocytes in vivo that substantially increases with age...
February 11, 2019: Journal of Cell Science
Lewis S C Ward, Lozan Sheriff, Jennifer L Marshall, Julia E Manning, Alexander Brill, Gerard B Nash, Helen M McGettrick
Mesenchymal stromal cells (MSC) up-regulate podoplanin at sites of infection, chronic inflammation, and cancer. We investigated the functional consequences of podoplanin expression on the migratory potential of MSC and their interactions with circulating platelets. Expression of podoplanin significantly enhanced the migration of MSC compared to MSC lacking podoplanin. Rac-1 inhibition altered the membrane localisation of podoplanin and in turn significantly reduced MSC migration. Blocking Rac-1 activity had no effect on the migration of MSC lacking podoplanin, indicating it was responsible for regulation of migration through podoplanin...
February 11, 2019: Journal of Cell Science
Indira Bag, Ryan K Dale, Cameron Palmer, Elissa P Lei
Chromatin insulators are DNA-protein complexes that establish independent higher order DNA domains to influence transcription. Insulators are functionally defined by two different properties: they can block communication between an enhancer and a promoter and also act as a barrier between heterochromatin and euchromatin. In Drosophila , the gypsy insulator complex contains three core components; Su(Hw), CP190 and Mod(mdg4)67.2. Here, we identify a novel role for Chromatin-linked adaptor for MSL proteins (CLAMP) in promoting gypsy chromatin insulator function...
February 4, 2019: Journal of Cell Science
Andrew J Davidson, Tom H Millard, Iwan R Evans, Will Wood
The actin cytoskeleton is the engine that powers the inflammatory chemotaxis of immune cells to sites of tissue damage or infection. Here we combine genetics with live, in vivo imaging to investigate how cytoskeletal rearrangements drive macrophage recruitment to wounds in Drosophila We find that the actin-regulatory protein Ena is a master regulator of lamellipodial dynamics in migrating macrophages where it remodels the cytoskeleton to form linear filaments that can then be bundled together by the cross-linker Fascin...
February 4, 2019: Journal of Cell Science
Christin Bissig, Pauline Croisé, Xavier Heiligenstein, Ilse Hurbain, Guy M Lenk, Emily Kaufman, Ragna Sannerud, Wim Annaert, Miriam H Meisler, Lois S Weisman, Graça Raposo, Guillaume van Niel
The metabolism of PI(3,5)P2 is regulated by the PIKfyve, VAC14 and FIG4 complex, whose mutations are associated with hypopigmentation in mice. These pigmentation defects indicate a key but yet unexplored physiological relevance of this complex in the biogenesis of melanosomes. Here we show that PIKfyve activity regulates formation of amyloid matrix composed of PMEL protein within early endosomes, called stage I melanosomes. PIKfyve activity controls the membrane remodeling of stage I melanosomes that increases PMEL abundance and impairs its sorting and processing...
February 1, 2019: Journal of Cell Science
Daniel Frank, David L Vaux, James M Murphy, James E Vince, Lisa M Lindqvist
Necroptosis is an inflammatory form of programmed cell death mediated by the pseudokinase mixed-lineage kinase domain-like protein (MLKL). Upon phosphorylation by receptor-interacting protein kinase-3 (RIPK3), MLKL oligomerizes, and translocates to and disrupts the plasma membrane, thereby causing necroptotic cell lysis. Herein, we show that activation of necroptosis in mouse dermal fibroblasts (MDFs) and HT-29 human colorectal cancer cells results in accumulation of the autophagic marker, lipidated LC3B, in an MLKL-dependent manner...
February 1, 2019: Journal of Cell Science
Ariel Diaz, Valerie Jeanneret, Paola Merino, Patrick McCann, Manuel Yepes
Neuronal depolarization induces the synaptic release of tissue-type plasminogen activator (tPA). Cyclin dependent kinase-5 (Cdk5) is a member of the family of cyclin-dependent kinases that regulates cell migration and synaptic function in postmitotic neurons. Cdk5 is activated by its binding to p35, a membrane-anchored protein that is rapidly degraded by the proteasome. Here we show that tPA prevents the degradation of p35 in the synapse by a plasminogen-dependent mechanism that requires open synaptic N-Methyl-D-Aspartate (NMDA) receptors...
February 1, 2019: Journal of Cell Science
Diego Huet, Thierry Blisnick, Sylvie Perrot, Philippe Bastin
Intraflagellar transport (IFT), the movement of protein complexes responsible for the assembly of cilia and flagella, is remarkably conserved from protists to humans. However, two IFT components (IFT25 and IFT27) are missing from multiple unrelated eukaryotic species. In mouse, IFT25 and IFT27 are not required for assembly of several cilia with the noticeable exception of the flagellum of spermatozoa. Here we show that the Trypanosoma brucei IFT25 protein is a proper component of the IFT-B complex and displays typical IFT trafficking...
February 1, 2019: Journal of Cell Science
Udo N Onwubiko, Paul J Mlynarczyk, Bin Wei, Julius Habiyaremye, Amanda Clack, Steven M Abel, Maitreyi E Das
During cytokinesis, fission yeast coordinates actomyosin ring constriction with septum ingression, resulting in concentric furrow formation by a poorly defined mechanism. We report that cells lacking the Cdc42 activator Gef1, combined with an activated allele of the formin, Cdc12, display non-concentric furrowing. Non-concentrically furrowing cells display uneven distribution of the scaffold Cdc15 along the ring. This suggests that after ring assembly, uniform Cdc15 distribution along the ring enables proper furrow formation...
February 1, 2019: Journal of Cell Science
Kan Etoh, Mitsunori Fukuda
Recycling endosomes are stations that sort endocytic cargoes to their appropriate destinations. Tubular endosomes have been characterized as a recycling endosomal compartment for clathrin-independent cargoes. However, the molecular mechanism by which tubular endosome formation is regulated is poorly understood. In this study we identified Rab10 as a novel protein localized at tubular endosomes by using a comprehensive localization screen of EGFP-tagged Rab small GTPases. Knockout of Rab10 completely abolished tubular endosomal structures in HeLaM cells...
January 30, 2019: Journal of Cell Science
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