Molecular Biology of the Cell (MOL BIOL CELL )

Publisher: American Society for Cell Biology, American Society for Cell Biology


Molecular Biology of the Cell, the journal owned and published by The American Society for Cell Biology, publishes papers that describe and interpret results of original research concerning the molecular aspects of cell structure and function. Studies whose scope bridges several areas of biology are particularly encouraged, for example cell biology and genetics. The aim of the Journal is to publish papers describing substantial research progress in full: papers should include all previously unpublished data and methods essential to support the conclusions drawn.

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  • Website
    Molecular Biology of the Cell website
  • Other titles
    Molecular biology of the cell, MBC
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  • Material type
    Periodical, Internet resource
  • Document type
    Journal / Magazine / Newspaper, Internet Resource

Publisher details

American Society for Cell Biology

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    • Author cannot archive a post-print version
  • Conditions
    • On author's personal website or institutional repository
    • Publisher's version/PDF must be used
    • In Press version must not be used
    • Publisher copyright and source must be acknowledged with citation
    • Must link to publisher version
    • Creative Commons Attribution Non-Commerical Share Alike 3.0 License
    • Articles are placed in PubMed Central after 2 months by publisher
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Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: Taxol (generic name paclitaxel) is a microtubule-stabilizing drug that is approved by the Food and Drug Administration for the treatment of ovarian, breast, and lung cancer, as well as Kaposi's sarcoma. It is used off-label to treat gastroesophageal, endometrial, cervical, prostate, and head and neck cancers, in addition to sarcoma, lymphoma, and leukemia. Paclitaxel has long been recognized to induce mitotic arrest, which leads to cell death in a subset of the arrested population. However, recent evidence demonstrates that intratumoral concentrations of paclitaxel are too low to cause mitotic arrest and result in multipolar divisions instead. It is hoped that this insight can now be used to develop a biomarker to identify the ∼50% of patients that will benefit from paclitaxel therapy. Here I discuss the history of paclitaxel and our recently evolved understanding of its mechanism of action.
    Molecular Biology of the Cell 09/2014; 25(18):2677-81.
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    ABSTRACT: Microtubule length control is essential for the assembly and function of the mitotic spindle. Kinesin-like motor proteins that directly attenuate microtubule dynamics make key contributions to this control, but the specificity of these motors for different subpopulations of spindle microtubules is not understood. Kif18A (kinesin-8) localizes to the plus-ends of the relatively slow growing kinetochore fibers (K-fibers) and attenuates their dynamics, while Kif4A (kinesin-4) localizes to mitotic chromatin and suppresses the growth of highly dynamic, non-kinetochore microtubules. While Kif18A and Kif4A similarly suppress microtubule growth in vitro, it remains unclear whether microtubule-attenuating motors control the lengths of K-fibers and non-kinetochore microtubules through a common mechanism. To address this question, we engineered chimeric kinesins that contain the Kif4A, Kif18B (kinesin-8) or Kif5B (kinesin-1) motor domain fused to the C-terminal tail of Kif18A. Each of these chimeric kinesins localizes to K-fibers, however, K-fiber length control requires an activity specific to kinesin-8s. Mutational studies of Kif18A indicate that this control depends on both its C-terminus and a unique, positively charged surface loop, called loop2, within the motor domain. These data support a model in which microtubule-attenuating kinesins are molecularly "tuned" to control the dynamics of specific subsets of spindle microtubules.
    Molecular Biology of the Cell 09/2014;
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    ABSTRACT: Recent work has shown that Staufen1 plays key roles in skeletal muscle, yet little is known about its pattern of expression during embryonic and postnatal development. Here, we first show that Staufen1 levels are abundant in mouse embryonic muscles and that its expression decreases thereafter, reaching low levels in mature muscles. A similar pattern of expression is seen as cultured myoblasts differentiate into myotubes. Muscle degeneration/regeneration experiments revealed that Staufen1 increases following cardiotoxin injection before returning to the low levels seen in mature muscles. We next prevented the decrease in Staufen1 during differentiation by generating stable C2C12 muscle cell lines overexpressing Staufen1. Cells overexpressing Staufen1 differentiated poorly as evidenced by reductions in the differentiation and fusion indices, and by decreases in MyoD, myogenin, MEF2A and MEF2C, independently of Staufen-Mediated mRNA Decay (SMD). However, levels of c-myc, a factor known to inhibit differentiation, were increased in C2C12 cells overexpressing Staufen1 through enhanced translation. By contrast, the knockdown of Staufen1 decreased c-myc levels in myoblasts. Collectively, our results show that Staufen1 is highly expressed during early stages of differentiation/development and that it can impair differentiation by regulating c-myc thereby highlighting the multifunctional role of Staufen1 in skeletal muscle cells.
    Molecular Biology of the Cell 09/2014;
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    ABSTRACT: The tumor suppressor Adenomatous polyposis coli (APC) is an essential negative regulator of Wnt signaling through its activity in the destruction complex with Axin, GSK3β and CK1 that targets ß-catenin/Armadillo (ß-cat/Arm) for proteosomal degradation. The destruction complex forms macromolecular particles we termed the destructosome. While APC functions in the complex through its ability to bind both ß-cat and Axin, we hypothesize that APC proteins play an additional role in destructosome assembly through self-association. Here we show that a novel N-terminal coil, the APC Self-Association Domain (ASAD), found in vertebrate and invertebrate APCs, directly mediates self-association of Drosophila APC2 and plays an essential role in the assembly and stability of the destructosome that regulates ß-cat degradation in Drosophila and human cells. Consistent with this, removal of the ASAD from the Drosophila embryo results in ß-cat/Arm accumulation and aberrant Wnt pathway activation. These results suggest that APC proteins are required not only for the activity of the destructosome, but also for the assembly and stability of this macromolecular machine.
    Molecular Biology of the Cell 09/2014;
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    ABSTRACT: The pathways driving desmosome and adherens junction assembly are temporally and spatially coordinated, but how they are functionally coupled is poorly understood. Here we show that the Armadillo protein plakophilin 3 (Pkp3) mediates both desmosome assembly and E-cadherin maturation through Rap1 GTPase, thus functioning in a manner distinct from the closely related plakophilin 2. Whereas Pkp2 and Pkp3 share the ability to mediate the initial phase of DP accumulation at sites of cell-cell contact, they play distinct roles in later steps: Pkp3 is required for assembly of a cytoplasmic population of DP-enriched junction precursors, while Pkp2 is required for transfer of the precursors to the membrane. Moreover, Pkp3 forms a complex with Rap1 GTPase, promoting its activation and facilitating desmosome assembly. We show further that Pkp3 deficiency causes disruption of an E-cadherin/Rap1 complex required for adherens junction sealing. These findings reveal Pkp3 as a coordinator of desmosome and adherens junction assembly and maturation, through its functional association with Rap1.
    Molecular Biology of the Cell 09/2014;
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    ABSTRACT: Neurons face a changeable microenvironment and therefore need mechanisms that allow rapid switch on/off of their cyto-protective and apoptosis-inducing signaling pathways. Cellular mechanisms which control apoptosis activation include the regulation of pro/anti-apoptotic mRNAs through their 3'-untranslated region (UTR). This region holds binding elements for RNA-binding proteins (RBPs) which can control mRNA translation. Here, we demonstrate that Heat shock protein 27 (Hsp27) prevents oxidative stress-induced cell death in cerebellar granule neurons (CGNs) by specific regulation of the mRNA for the proapoptotic BH3-only protein, Bim. Hsp27 depletion induced by oxidative stress using hydrogen peroxide (H2O2), correlated with bim gene activation and subsequent neuronal death, whereas enhanced Hsp27 expression prevented these. This effect could not be explained by proteasomal degradation of Bim or bim promoter inhibition, however it was associated with a specific increase in the levels of bim mRNA, and with its binding to Hsp27. Finally, we determined that enhanced Hsp27 expression in neurons exposed to H2O2 or glutamate prevented the translation of a reporter plasmid where bim-3'UTR mRNA sequence was cloned downstream of a luciferase gene. These results suggest that repression of bim mRNA translation through binding to the 3'UTR constitutes a novel cytoprotective mechanism of Hsp27 during stress in neurons.
    Molecular Biology of the Cell 09/2014;
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    ABSTRACT: Clathrin-mediated endocytosis (CME) is a fundamental property of eukaryotic cells. Classical CME proceeds via the formation of clathrin-coated pits (CCP) at the plasma membrane that invaginate to form clathrin-coated vesicles; a process that is well understood. However, clathrin also assembles into flat clathrin lattices (FCL); these structures remain poorly described and their contribution to cell biology is unclear. We have used quantitative imaging to provide the first comprehensive description of FCL and explore their influence on plasma membrane organization. Ultrastructural analysis by electron and super-resolution microscopy revealed two discrete populations of clathrin structures. CCP were typified by their sphericity, small size and homogeneity. FCL were planar, large and heterogeneous, and present on both the dorsal and ventral surfaces of cells. Live microscopy demonstrated that CCP are short-lived and culminate in a peak of dynamin recruitment, consistent with classical CME. In contrast, FCL were long-lived with sustained association with dynamin. We investigated the biological relevance of FCL using the chemokine receptor CCR5 as a model system. Agonist activation leads to sustained recruitment of CCR5 to FCL. Quantitative molecular imaging indicated that FCL partitioned receptors at the cell surface. Our observations suggest that FCL provide stable platforms for the recruitment of endocytic cargo.
    Molecular Biology of the Cell 08/2014;
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    ABSTRACT: Oscillation of chemical signals is a common biological phenomenon but its regulation is poorly understood. At the aggregation stage of Dictyostelium discoideum development, the chemoattractant cAMP is synthesized and released at 6 min intervals, directing cell migration. Although the G protein-coupled cAMP receptor cAR1 and ERK2 are both implicated in regulating the oscillation, the signaling circuit remains unknown. Here, we report that D. discoideum arrestins regulate the frequency of cAMP oscillation and may link cAR1 signaling to oscillatory ERK2 activity. Cells lacking arrestins (adcB(-)C(-)) display cAMP oscillations during the aggregation stage that are twice as frequent as wild type cells. The adcB(-)C(-) cells also have a shorter period of transient ERK2 activity and precociously reactivate ERK2 in response to cAMP stimulation. We show that AdcC associates with ERK2 and that activation of cAR1 promotes the transient membrane recruitment of AdcC and interaction with cAR1, indicating that arrestins function in cAR1-controlled periodic ERK2 activation and oscillatory cAMP signaling in the aggregation stage of D. discoideum development. In addition, ligand-induced cAR1 internalization is compromised in adcB(-)C(-) cells, suggesting that arrestins are involved in elimination of high-affinity cAR1 receptors from cell surface after the aggregation stage of multicellular development.
    Molecular Biology of the Cell 08/2014;
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    ABSTRACT: In autophagy, the double-membrane autophagosome delivers cellular components for their degradation in the lysosome. The conserved Ypt/Rab GTPases regulate all cellular trafficking pathways, including autophagy. These GTPases function in modules that include guanine-nucleotide exchange factor (GEF) activators and downstream effectors. Rab7 and its yeast homologue Ypt7, in the context of such a module, regulate the fusion of both late endosomes and autophagosomes with the lysosome. In yeast, the Rab5-related Vps21 is known for its role in early-to-late endosome transport. Here we show an additional role for Vps21 in autophagy. First, vps21∆ mutant cells are defective in selective and non-selective autophagy. Second, fluorescence and electron microscopy analyses show that vps21∆ mutant cells accumulate clusters of autophagosomal structures outside the vacuole. Finally, cells with mutations in other members of the endocytic Vps21 module, including the GEF Vps9 and factors that function downstream of Vps21, Vac1, CORVET, Pep12 and Vps45, are also defective in autophagy and accumulate clusters of autophagosomes. Lastly, Vps21 localizes to PAS. We propose that the endocytic Vps21 module also regulates autophagy. These findings support the idea that the two pathways leading to the lysosome, endocytosis and autophagy, converge through the Vps21 and Ypt7 GTPase modules.
    Molecular Biology of the Cell 08/2014;
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    ABSTRACT: The regulatory pathways required to maintain eukaryotic lipid homeostasis are still largely unknown. We developed a systematic approach to uncover new players in the regulation of lipid homeostasis. Through an unbiased mass spectrometry-based lipidomic screening, we quantified hundreds of lipid species, including glycerophospholipids, sphingolipids and sterols, from a collection of 129 mutants in protein kinase and phosphatase genes of Saccharomyces cerevisiae. Our approach successfully identified known kinases involved in lipid homeostasis and uncovered new ones. By clustering analysis, we found connections between nutrient sensing pathways and regulation of glycerophospholipids. Deletion of members of glucose and nitrogen sensing pathways showed reciprocal changes in glycerophospholipid acyl chain lengths. We also found several new candidates for the regulation of sphingolipid homeostasis, including a connection between inositol pyrophosphate metabolism and complex sphingolipid homeostasis through transcriptional regulation of AUR1 and SUR1. This robust, systematic lipidomic approach constitutes a rich, new source of biological information and can be used to identify novel gene associations and function.
    Molecular Biology of the Cell 08/2014;
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    ABSTRACT: When Dictyostelium cells are hyper-osmotically stressed STATc is activated by tyrosine phosphorylation. Unusually, activation is regulated by serine phosphorylation and consequent inhibition of a tyrosine phosphatase: PTP3. The identity of the cognate tyrosine kinase is unknown and we show that two Tyrosine Kinase-Like (TKL) enzymes, Pyk2 and Pyk3, share this function; thus for stress-induced STATc activation, single null mutants are only marginally impaired but the double mutant is non-activatable. When cells are stressed Pyk2 and Pyk3 undergo increased auto-catalytic tyrosine phosphorylation. The site(s) that are generated bind the SH2 domain of STATc and then STATc becomes the target of further kinase action. The signaling pathways that activate Pyk2 and Pyk3 are only partially overlapping and there may be a structural basis for this difference because Pyk3 contains both a TKL domain and a pseudokinase domain. The latter functions, like the JH2 domain of metazoan JAKs, as a negative regulator of the kinase domain. The fact that two differently regulated kinases catalyse the same phosphorylation event may facilitate specific targeting because under stress Pyk3 and Pyk2 accumulate in different parts of the cell; Pyk3 moves from the cytosol to the cortex while Pyk2 accumulates in cytosolic granules that colocalise with PTP3.
    Molecular Biology of the Cell 08/2014;
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    ABSTRACT: In mammalian cells, individual Golgi stacks fuse laterally to form the characteristic peri-nuclear ribbon structure. Yet, the purpose of this remarkable structure has been an enigma. Here we report that breaking-down the ribbon of mammalian cells strongly inhibits intra-Golgi transport of large cargoes without altering the rate of transport of smaller cargoes. In addition, insect cells that naturally harbor dispersed Golgi stacks have limited capacity to transport artificial over-sized cargoes. These results imply that the ribbon structure is an essential requirement for transport of large cargoes in mammalian cells, and we suggest that this is because it enables the dilated rims of cisternae (containing the aggregates) to move across the stack as they transfer among adjacent stacks within the ribbon structure.
    Molecular Biology of the Cell 08/2014;
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    ABSTRACT: The fission yeast Schizosaccharomyces pombe undergoes "closed" mitosis where the nuclear envelope (NE) stays intact throughout chromosome segregation. Here we show that Tts1, the fission yeast TMEM33 protein that was previously implicated in organizing the peripheral endoplasmic reticulum (ER), also functions in remodeling the NE during mitosis. Tts1 promotes insertion of spindle pole bodies (SPBs) in the NE at the onset of mitosis and modulates distribution of the nuclear pore complexes (NPCs) during mitotic NE expansion. Structural features that drive partitioning of Tts1 to the high-curvature ER domains are crucial for both aspects of its function. An amphipathic helix located at the C-terminus of Tts1 is important for ER shaping and modulating the mitotic NPC distribution. Interestingly, the evolutionarily conserved residues at the luminal interface of the third transmembrane region function specifically in promoting SPB-NE insertion. Our data illuminate cellular requirements for remodeling the NE during "closed" nuclear division and provide insight into the structure and functions of the eukaryotic TMEM33 family.
    Molecular Biology of the Cell 08/2014;
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    ABSTRACT: Following ER Ca(2+) depletion, STIM1 and Orai1 complexes assemble autonomously at ER-plasma membrane (PM) junctions to trigger store-operated Ca(2+) influx. One hypothesis to explain this process is a diffusion trap in which activated STIM1 diffusing in the ER becomes trapped at junctions through interactions with the PM, and STIM1 then traps Orai1 in the PM through binding of its CRAC activation domain. We tested this model by analyzing STIM1 and Orai1 diffusion using single-particle tracking, photoactivation of protein ensembles, and Monte Carlo simulations. In resting cells, STIM1 diffusion is Brownian while Orai1 is slightly subdiffusive. After store depletion both proteins slow to the same speeds, consistent with complex formation, and are confined to a corral similar in size to ER-PM junctions. While the escape probability at high STIM:Orai expression ratios is <1%, it is significantly increased by reducing the affinity of STIM1 for Orai1 or by expressing the two proteins at comparable levels. Our results provide direct evidence that STIM-Orai complexes are trapped by their physical connections across the junctional gap, but also reveal that the complexes are surprisingly dynamic, suggesting that readily reversible binding reactions generate free STIM1 and Orai1 which engage in constant diffusional exchange with extrajunctional pools.
    Molecular Biology of the Cell 07/2014;