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Journal of Cell Science

Samantha J Stehbens, Robert J Ju, Mark N Adams, Samuel Perry, Nikolas K Haass, David M Bryant, Pamela M Pollock
Fibroblast growth factor receptors (FGFRs) are a family of receptor tyrosine kinases that control a diverse range of biological processes during development and in adult tissues. We recently reported that somatic FGFR2 mutations are associated with shorter survival in endometrial cancer (EC). However, little is known about how these FGFR2 mutations contribute to EC metastasis. Here, we report that expression of the activating mutations, FGFR2N550K and FGFR2Y376C , in an EC cell model induce Golgi fragmentation, and loss of polarity and directional migration...
July 12, 2018: Journal of Cell Science
Emily R Moore, Yuchen Yang, Christopher R Jacobs
Although Prx1-expressing cells and their primary cilia are critical for embryonic development, they have yet to be studied in the context of postnatal skeletogenesis due to the lethality of mouse models. A tamoxifen-inducible Prx1 model has been developed and we determined that expression directed by this promoter is highly restricted to the cambium layers in the periosteum and perichondrium after birth. To determine the postnatal role of these cambium layer osteochondroprogenitors (CLOPs) and their primary cilia, we developed models to track the fate of CLOPs (Prx1CreER-GFP; Rosa26tdTomato ) and selectively disrupt their cilia (Prx1CreER-GFP; Ift88fl/fl )...
July 12, 2018: Journal of Cell Science
Tal Israeli, Yael Riahi, Ann Saada, Devorah Yefet, Erol Cerasi, Boaz Tirosh, Gil Leibowitz
AMPK-mTORC1 signaling senses nutrient availability thereby regulating autophagy. Surprisingly, we found that in β-cells the AMPK activator 5-amino-4-imidazolecarboxamide ribofuranoside (AICAR) inhibited, rather than stimulated, autophagy. AICAR is an intermediate in the generation of inosine monophosphate with subsequent conversion to other purine nucleotides. Adenosine regulated autophagy in a concentration-dependent manner: at high concentrations, it mimicked the AICAR effect on autophagy, whereas at low concentrations it stimulated autophagy through its cognate A1 receptor...
July 12, 2018: Journal of Cell Science
Pavlo G Gritsenko, Peter Friedl
Diffuse brain invasion by glioma cells prevents effective surgical or molecular-targeted therapy and underlies detrimental outcome. Migrating glioma cells are guided by complex anatomical brain structures, however exact mechanisms remain poorly defined. To identify adhesion receptor systems and matrix structures supporting glioma cell invasion into brain-like environments we used 2D and 3D organotypic invasion assays in combination with antibody-, peptide- and RNA-based interference. Combined interference with β1 and αV integrins abolished the migration of U-251 and E-98 glioma cells on reconstituted basement membrane, however invasion into primary brain slices or 3D astrocyte-based scaffolds and migration on astrocyte-deposited matrix was only partly inhibited...
July 10, 2018: Journal of Cell Science
Sena Homoto, Shingo Izawa
Short-term exposure to severe ethanol stress has adverse effects on yeast cells. However, limited information is available on the effects of long-term exposure to severe ethanol stress. In this study, we examined the effects of a long-term treatment with a high ethanol concentration (10% v/v) on yeast morphology. We found that long-term severe ethanol stress induced the continuous depolarization of the actin cytoskeleton and hypertrophy in yeast cells, accompanied by the aberrant localization of septins, which formed multiple small cortical rings (MSCRs)...
July 10, 2018: Journal of Cell Science
Philip T T Ly, Craig Stewart, Catherine J Pallen
Extrinsic signals that regulate oligodendrocyte maturation and subsequent myelination are essential for central nervous system development and regeneration. Deficiency in the extracellular factor laminin-2 (Lm2), as occurs in congenital muscular dystrophy, can lead to impaired oligodendroglial development and aberrant myelination, but many aspects of Lm2-regulated oligodendroglial signaling and differentiation remain undefined. We show that receptor-like protein tyrosine phosphatase alpha (PTPα) is essential for myelin basic protein expression and cell spreading during Lm2-induced oligodendrocyte differentiation...
July 10, 2018: Journal of Cell Science
Shinya Watanabe, Hiroki Fujiyama, Takuya Takafuji, Kota Kayama, Masaki Matsumoto, Keiichi I Nakayama, Kazumasa Yoshida, Nozomi Sugimoto, Masatoshi Fujita
GRWD1 is a Cdt1-binding protein that promotes MCM loading through its histone chaperone activity. GRWD1 acts as a tumor-promoting factor by downregulating p53 via the RPL11-MDM2-p53 axis. Here, we identified GRWD1-interacting proteins using a proteomics approach and showed that GRWD1 interacts with various proteins involved in transcription, translation, DNA replication and repair, chromatin organization, and ubiquitin-mediated proteolysis. We focused on the ribosomal protein RPL23, which positively regulates nucleolar stress responses through MDM2 binding and inhibition, thereby functioning as a tumor suppressor...
July 10, 2018: Journal of Cell Science
Sruthi S Balakrishnan, Urbashi Basu, Dhananjay Shinde, Rajan Thakur, Manish Jaiswal, Padinjat Raghu
The activation of phospholipase C (PLC) is a conserved mechanism of receptor activated cell signaling at the plasma membrane. PLC hydrolyzes the minor membrane lipid phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2 ] and continued signaling requires the resynthesis and availability of PI(4,5)P2 at the plasma membrane. PI(4,5)P2 is synthesized by the phosphorylation of phosphatidylinositol-4-phosphate (PI4P). Thus, a continuous supply of PI4P is essential to support ongoing PLC signaling. While the enzyme PI4KA has been identified to perform this function in cultured mammalian cells, its function in the context of an in vivo physiological model has not been established...
July 6, 2018: Journal of Cell Science
Zachary T Colburn, Jonathan C R Jones
Clusters of β4 integrin, organized into distinct puncta, localize along vimentin filaments within the lamellipodia at the cell edge of A549 cells, as assessed by interferometric photoactivated localization microscopy. Moreover, puncta and vimentin filaments exhibit a dynamic interplay in live cells viewed by structured-illumination microscopy with β4 integrin puncta that associate with vimentin persisting for longer than those that do not. Interestingly, in A549 cells β4 integrin regulates vimentin cytoskeleton organization...
July 4, 2018: Journal of Cell Science
Kévin Adam, Maëlle Cartel, Mireille Lambert, Laure David, Lingli Yuan, Arnaud Besson, Patrick Mayeux, Stéphane Manenti, Christine Didier
Although the kinase CHK1 is a key player in the DNA damage response (DDR), several studies have recently provided evidence of DDR-independent roles of CHK1, in particular following phosphorylation of its S280 residue. Here, we demonstrate that CHK1 S280 phosphorylation is cell cycle-dependent and peaks during mitosis. We found that this phosphorylation was catalyzed by the kinase PIM2, whose protein expression was also increased during mitosis. Importantly, we identified Polo-Like Kinase 1 (PLK1) as a direct target of CHK1 during mitosis...
July 4, 2018: Journal of Cell Science
Nicola De Franceschi, Maryam Alqabandi, Nolwenn Miguet, Christophe Caillat, Stephanie Mangenot, Winfried Weissenhorn, Patricia Bassereau
ESCRT-III family proteins catalyze membrane remodeling processes that stabilize and constrict membrane structures. It was proposed that stable ESCRT-III complexes containing CHMP2B could establish diffusion barriers at post-synaptic spine neck. In order to better understand this process, we developed a novel method based on fusion of Giant Unilamellar Vesicles to reconstitute ESCRT-III proteins inside GUVs, from which membrane nanotubes are pulled. The new assay ensures that ESCRT-III proteins polymerize only when they become exposed to physiologically relevant membrane topology mimicking the complex geometry of post-synaptic spines...
July 2, 2018: Journal of Cell Science
Cédric Yapo, Anu G Nair, Jeanette Hellgren Kotaleski, Pierre Vincent, Liliana R V Castro
Although it is known that Protein Kinase A (PKA) in the nucleus regulates gene expression, the specificities of nuclear PKA signaling remain poorly understood. Here, we combined computational modeling and live-cell imaging of PKA-dependent phosphorylation in mouse brain slices to investigate how transient dopamine signals are translated into nuclear PKA activity in cortical pyramidal neurons and striatal medium spiny neurons. We observed that the nuclear PKA signal in striatal neurons featured an ultrasensitive responsiveness, associated with fast, all or none responses, which is not consistent with the commonly accepted theory of a slow and passive diffusion of catalytic PKA in the nucleus...
July 2, 2018: Journal of Cell Science
Sourav Haldar, Elena Mekhedov, Chad D McCormick, Paul S Blank, Joshua Zimmerberg
While influenza kills about a half million people each year, even after excluding pandemics, there is only one set of antiviral drugs: neuraminidase inhibitors. Using a new approach utilizing giant unilamellar vesicles and infectious X-31 influenza virus and testing for the newly identified pore intermediate of membrane fusion, we observed ∼30 - 87 % poration as a function of lipid composition. Testing the hypothesis that spontaneous curvature (SC) of the lipid monolayer controls membrane poration, our Poisson model and Boltzmann energetic considerations suggest a transition from a leaky to a non-leaky fusion pathway depending on the SC of the target membrane...
July 2, 2018: Journal of Cell Science
Meera Saxena, Sai A Balaji, Neha Deshpande, Santhalakshmi Ranganathan, Sravanth Kumar Hindupur, Annapoorni Rangarajan
The developmental programme of epithelial-mesenchymal transition (EMT), involving loss of epithelial and acquisition of mesenchymal properties, plays an important role in the invasion-metastasis cascade of cancer cells. Here we show that activation of AMP-activated Protein Kinase (AMPK) using A769662 leads to a concomitant induction of EMT in multiple cancer cell types, as observed by enhanced expression of mesenchymal markers, decrease of epithelial markers, and increase in migration and invasion. In contrast, inhibition or depletion of AMPK led to a reversal of EMT...
June 27, 2018: Journal of Cell Science
Qiuling Li, Jie Jiao, Huijun Li, Huajing Wan, Caihong Zheng, Jun Cai, Shilai Bao
Branching morphogenesis is essential for the successful development of a functional lung to accomplish its gas exchange function. Although many studies have highlighted requirements for the bone morphogenetic protein (BMP) signaling pathway during branching morphogenesis, little is known about how BMP signaling is regulated. Here we report that the protein arginine methyltransferase 5 (Prmt5) and symmetric dimethylation at histone H4 arginine 3 (H4R3sme2) directly associate with chromatin of Bmp4 to suppress its transcription...
June 27, 2018: Journal of Cell Science
Paulina J Stanczyk, Monika Seidel, Judith White, Cedric Viero, Christopher H George, Spyros Zissimopoulos, F Anthony Lai
The cardiac muscle ryanodine receptor-Ca2+ release channel (RyR2) constitutes the sarcoplasmic reticulum (SR) Ca2+ efflux mechanism that initiates myocyte contraction, while cardiac myosin binding protein-C (cMyBP-C) mediates regulation of acto-myosin cross-bridge cycling. In this report, we provide the first evidence for the presence of direct interaction between these two proteins, forming a RyR2:cMyBP-C complex. The C-terminus of cMyBP-C binds with the RyR2 N-terminus in mammalian cells and is not mediated by a fibronectin-like domain...
June 21, 2018: Journal of Cell Science
S M Bestall, R P Hulse, Z Blackley, M Swift, N Ved, K Paton, N Beazley-Long, D O Bates, L F Donaldson
Many potential causes for painful diabetic neuropathy have been proposed including actions of cytokines and growth factors. High mobility group protein B1 (HMGB1) is a RAGE agonist, increased in diabetes, that contributes to pain by modulating peripheral inflammatory responses. HMGB1 enhances nociceptive behaviour in naïve animals through an unknown mechanism. We tested the hypothesis that HMGB1 causes pain through direct neuronal activation of RAGE and alteration of nociceptive neuronal responsiveness.HMGB1 and RAGE expression were increased in skin and primary sensory (DRG) neurons of diabetic rats at times when pain behaviour was enhanced...
June 21, 2018: Journal of Cell Science
Shuang Li, Yong Suk Cho, Bing Wang, Shuangxi Li, Jin Jiang
Hedgehog (Hh) transduces signal by promoting cell surface accumulation and activation of the G protein coupled receptor (GPCR)-family protein Smoothened (Smo) in Drosophila , but the molecular mechanism underlying the regulation of Smo trafficking has remained poorly understood. Here we identify a Cul4-DDB1 E3 ubiquitin ligase complex as essential for Smo ubiquitination and cell surface clearance. We find that the C-terminal intracellular domain of Smo recruits Cul4-DDB1 through the β subunit of trimeric G protein (Gβ), and that Cul4-DDB1-Gβ promotes the ubiquitination of both Smo and its binding partner G-protein-coupled-receptor-kinase 2 (Gprk2) and induces the internalization and degradation of Smo...
June 21, 2018: Journal of Cell Science
Ye Dee Tay, Marcin Leda, Andrew B Goryachev, Kenneth E Sawin
The conserved Rho-family GTPase Cdc42 plays a central role in eukaryotic cell polarity. The rod-shaped fission yeast Schizosaccharomyces pombe has two Cdc42 guanine-nucleotide exchange factors (GEFs), Scd1 and Gef1, but little is known about how they are coordinated in polarized growth. Although the microtubule cytoskeleton is normally not required for polarity maintenance in fission yeast, we show here that when scd1 function is compromised, disruption of microtubules or the polarity landmark proteins Tea1, Tea4, or Pom1 leads to disruption of polarized growth...
June 21, 2018: Journal of Cell Science
Steven L Gonias, Michael A Banki, Andrew S Gilder, Pardis Azmoon, Wendy M Campana, Elisabetta Mantuano
The fibrinolysis proteinase, tissue-type plasminogen activator (tPA), triggers cell-signaling and regulates cell physiology. In PC12 cells, Schwann cells, and macrophages, the N-methyl-D-aspartate receptor (NMDA-R) mediates tPA-signaling. Plasminogen activator Inhibitor-1 (PAI1) is a rapid inhibitor of tPA enzyme activity. Although tPA-initiated cell-signaling is not dependent on its enzyme active site, we show that tPA-signaling is neutralized by PAI1. In PC12 cells, PAI1 blocked ERK1/2 activation by tPA and neurite outgrowth...
June 21, 2018: Journal of Cell Science
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