Signal Transduction
- Tyrosine phosphorylation of Munc18‐1 inhibits synaptic transmission by preventing SNARE assembly
- Marieke Meijer1,
- Bernhard Dörr2,
- Hanna CA Lammertse3,
- Chrysanthi Blithikioti3,
- Jan RT van Weering1,
- Ruud FG Toonen3,
- Thomas H Söllner2 and
- Matthijs Verhage (matthijs{at}cncr.vu.nl)*,1,3
- 1Department of Clinical Genetics, Center for Neurogenomics and Cognitive Research (CNCR), Neuroscience Campus Amsterdam (NCA) VU University Medical Center, Amsterdam, The Netherlands
- 2Heidelberg University Biochemistry Center (BZH), Heidelberg, Germany
- 3Department of Functional Genomics, Center for Neurogenomics and Cognitive Research (CNCR), Neuroscience Campus Amsterdam (NCA) VU University Amsterdam, Amsterdam, The Netherlands
- ↵*Corresponding author. Tel: +31205986936; E‐mail: matthijs{at}cncr.vu.nl
Phosphorylation by Src‐family kinases allows acute negative regulation of synaptic vesicle priming at the post‐docking step of SNARE complex templating and membrane fusion.
Synopsis
This study identifies a novel regulatory site on the presynaptic protein Munc18‐1, which phosphorylated state prevents Synaptobrevin2/VAMP2 binding, SNARE‐templating and synaptic vesicle priming. Tyrosine phosphorylation of Munc18‐1 is a potent way to shut down synaptic transmission.
Y473 on Munc18‐1 is a substrate for several neuronal members of Src family kinase.
A single point mutation (Y473D) designed to mimic tyrosine phosphorylation interfered with Synaptobrevin2/VAMP2 binding and the stimulatory effect of Munc18‐1 on SNARE‐complex formation.
Hippocampal munc18‐1 null neurons expressing Munc18‐1Y473D are defective in synaptic vesicle priming, but not docking.
Synaptic transmission was largely restored by high frequency stimulation or by promoting helix 12 extension in domain 3a of Munc18‐1.
The EMBO Journal (2018) 37: 300–320
- Received January 9, 2017.
- Revision received October 12, 2017.
- Accepted October 16, 2017.
- © 2017 The Authors. Published under the terms of the CC BY NC ND 4.0 license
This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs 4.0 License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
- Tumor suppressor Tsc1 is a new Hsp90 co‐chaperone that facilitates folding of kinase and non‐kinase clients
- Mark R Woodford1,2,†,
- Rebecca A Sager1,2,3,†,
- Elijah Marris1,2,3,
- Diana M Dunn1,2,3,
- Adam R Blanden2,3,
- Ryan L Murphy1,2,
- Nicholas Rensing4,5,
- Oleg Shapiro1,2,
- Barry Panaretou6,
- Chrisostomos Prodromou7,
- Stewart N Loh2,3,
- David H Gutmann4,
- Dimitra Bourboulia1,2,3,
- Gennady Bratslavsky1,2,
- Michael Wong4,5 and
- Mehdi Mollapour (mollapom{at}upstate.edu)*,1,2,3
- 1Department of Urology, SUNY Upstate Medical University, Syracuse, NY, USA
- 2Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY, USA
- 3Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY, USA
- 4Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA
- 5Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA
- 6Institute of Pharmaceutical Science, King's College London, London, UK
- 7Genome Damage and Stability Centre, University of Sussex, Brighton, UK
- ↵*Corresponding author. Tel: +1 315 464 8749; E‐mail: mollapom{at}upstate.edu
↵† These authors contributed equally to this work
Besides stabilizing Tsc2 and forming the mTOR‐regulating TSC complex, Tsc1 plays a more general role as a co‐chaperone for Hsp90 on a range of client proteins.
Synopsis
Besides stabilizing Tsc2 and forming the mTOR‐regulating TSC complex, Tsc1 plays a more general role as a co‐chaperone for Hsp90 on a range of client proteins.
Tsc1 is a new co‐chaperone for the molecular chaperone heat shock protein‐90 (Hsp90).
The interaction between Tsc1 and Hsp90 stabilises mTOR‐regulator Tsc2.
The co‐chaperone Tsc1 binds to both subunits of the Hsp90 dimer and inhibits its ATPase activity.
Tsc1 blocks the interaction between Hsp90 and the activating co‐chaperone Aha1.
Tsc1 is a facilitator of Hsp90‐mediated folding of kinase and non‐kinase clients.
The EMBO Journal (2017) 36: 3650–3665
- Received February 8, 2017.
- Revision received September 15, 2017.
- Accepted October 2, 2017.
- © 2017 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- A TNF‐p100 pathway subverts noncanonical NF‐κB signaling in inflamed secondary lymphoid organs
- Tapas Mukherjee1,2,
- Budhaditya Chatterjee1,3,
- Atika Dhar2,
- Sachendra S Bais1,2,
- Meenakshi Chawla1,2,
- Payel Roy1,2,
- Anna George2,
- Vineeta Bal2,
- Satyajit Rath2 and
- Soumen Basak (sobasak{at}nii.ac.in)*,1,2
- 1Systems Immunology Laboratory National Institute of Immunology, New Delhi, India
- 2National Institute of Immunology, New Delhi, India
- 3Kusuma School of Biological Sciences, IIT‐Delhi, New Delhi, India
- ↵*Corresponding author. Tel: +91 11 26703853; Fax: +91 11 26742626; E‐mail: sobasak{at}nii.ac.in
Depletion of homeostatic chemokines associated with microbial infection is also observed during non‐infectious and chronic inflammation, resulting in diminished lymphocyte trafficking.
Synopsis
Noncanonical NF‐κB signaling produces homeostatic chemokines, which direct naïve lymphocytes into secondary lymphoid organs (SLOs). TNF accumulation in inflamed SLOs alters this homeostasis by subverting noncanonical signaling.
LTβR‐stimulated noncanonical RelB NF‐κB signaling produces homeostatic chemokines in SLOs.
TNF abrogates LTβR‐stimulated noncanonical RelB activity.
TNF inhibits NIK and induces the production inhibitory p100‐IκBδ.
A TNF‐p100 pathway downregulates homeostatic chemokines in inflamed SLOs.
The EMBO Journal (2017) 36: 3501–3516
- Received March 10, 2017.
- Revision received August 22, 2017.
- Accepted September 18, 2017.
- © 2017 The Authors
- The p53‐inducible long noncoding RNA TRINGS protects cancer cells from necrosis under glucose starvation
- Muhammad Riaz Khan1,†,
- Shaoxun Xiang1,†,
- Zhiyin Song (songzy{at}whu.edu.cn)*,2 and
- Mian Wu (wumian{at}ustc.edu.cn)*,1,3
- 1CAS Key Laboratory of Innate Immunity and Chronic Disease, CAS Center for Excellence in Cell and Molecular Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, University of Science & Technology of China, Hefei, Anhui, China
- 2Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, Hubei, China
- 3Translational Research Institute, School of Medicine, Henan Provincial People's Hospital, Henan University, Zhengzhou, China
- ↵*
Corresponding author. Tel: +86 027 68752235; E‐mail: songzy{at}whu.edu.cn
Corresponding author. Tel: +86 551 63606264; E‐mail: wumian{at}ustc.edu.cn
↵† These authors contributed equally to this work
Nutrient removal from cancer cells is counterbalanced through p53‐dependent induction of pro‐survival lncRNA TRINGS and suppression of cell death signalling.
Synopsis
A screen for pathways by which p53 can play protective roles in tumor cell survival identifies the long non‐coding (lnc) RNA TRINGS (Tp53‐regulated inhibitor of necrosis under glucose starvation) as pro‐survival factor in cancer cells under nutrient stress, shedding light on tumorigenic roles of p53.
The p53‐dependent lncRNA TRINGS is expressed in human cancer cells upon glucose starvation.
p53 binding to the TRINGS promoter and transcriptional activity are required for TRINGS expression.
TRINGS depletion causes stress‐induced necrotic cell death and decreased cancer cell growth in vitro and in vivo.
TRINGS physically interacts with scaffold protein STRAP, leading to its destabilisation through the ubiquitin‐proteasome system.
TRINGS‐promoted cell survival is mediated via STRAP‐GSK3β‐NF‐κB signalling.
The EMBO Journal (2017) 36: 3483–3500
- Received December 3, 2016.
- Revision received September 14, 2017.
- Accepted September 15, 2017.
- © 2017 The Authors
- Tumor‐associated macrophages (TAMs) depend on ZEB1 for their cancer‐promoting roles
- Marlies Cortés1,
- Lidia Sanchez‐Moral1,†,
- Oriol de Barrios1,†,
- María J Fernández‐Aceñero2,
- MC Martínez‐Campanario1,
- Anna Esteve‐Codina3,
- Douglas S Darling4,
- Balázs Győrffy5,
- Toby Lawrence6,
- Douglas C Dean7,8 and
- Antonio Postigo (idib412{at}clinic.cat)*,1,8,9
- 1Group of Transcriptional Regulation of Gene Expression, Department of Oncology and Hematology, IDIBAPS, Barcelona, Spain
- 2Department of Pathology, Hospital Clínico San Carlos, Madrid, Spain
- 3CNAG‐CRG, Centre for Genomic Regulation, Barcelona Institute of Science & Technology, and Universitat Pompeu Fabra, Barcelona, Spain
- 4Department of Oral Immunology, and Center for Genetics and Molecular Medicine, University of Louisville, Louisville, KY, USA
- 5MTA TTK Lendület Cancer Biomarker Research Group, Institute of Enzymology, and Semmelweis University 2nd Department of Pediatrics, Budapest, Hungary
- 6Centre d'Immunologie de Marseille‐Luminy, INSERM U1104 and CNRS MR7280, Marseille, France
- 7Department of Ophthalmology and Visual Sciences and Birth Defects Center, University of Louisville, Louisville, KY, USA
- 8Molecular Targets Program, James G. Brown Cancer Center, Louisville, KY, USA
- 9ICREA, Barcelona, Spain
- ↵*Corresponding author. Tel: +34 93 227 5400; E‐mail: idib412{at}clinic.cat
↵† These authors contributed equally to this work
Tumor‐associated macrophages express the EMT‐associated transcription factor ZEB1, which drives their tumor‐promoting and chemotherapy‐resistance functions in mouse ovarian cancer models.
Synopsis
Tumor‐associated macrophages (TAMs) require the expression of the EMT transcription factor ZEB1 for their cancer‐promoting functions.
ZEB1 activates a F4/80low phenotype in macrophages and inhibits their maturation into F4/80high macrophages.
ZEB1 is required for the activation of macrophages toward pro‐tumor F4/80low TAMs.
ZEB1 induces a Ccr2‐Mmp9‐Ccl2 positive loop between TAMs and cancer cells to enhance tumor progression.
Expression of ZEB1 in TAMs and cancer cells correlates with poorer prognosis in human ovarian carcinomas.
The EMBO Journal (2017) 36: 3336–3355
- Received May 15, 2017.
- Revision received September 18, 2017.
- Accepted September 20, 2017.
- © 2017 The Authors
- Crosstalk between PKA and PKG controls pH‐dependent host cell egress of Toxoplasma gondii
- Yonggen Jia1,3,4,†,
- Jean‐Baptiste Marq1,†,
- Hugo Bisio1,
- Damien Jacot1,
- Christina Mueller1,5,
- Lu Yu2,
- Jyoti Choudhary2,
- Mathieu Brochet (mathieu.brochet{at}unige.ch)*,1 and
- Dominique Soldati‐Favre (dominique.soldati-favre{at}unige.ch)*,1
- 1Department of Microbiology and Molecular Medicine, CMU, University of Geneva, Geneva 4, Switzerland
- 2Proteomic Mass‐spectrometry Team, Wellcome Trust Sanger Institute, Hinxton, UK
- 3Present Address: Beijing Institute of Tropical Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- 4Present Address: Beijing Key Laboratory for Research on Prevention and Treatment of Tropical Diseases, Beijing, China
- 5Present Address: Biotech Research and Innovation Center, University of Copenhagen, Copenhagen N, Denmark
- ↵*
Corresponding author. Tel: +41 22 37 95021; E‐mail: mathieu.brochet{at}unige.ch
Corresponding author. Tel: +41 22 379 56 72; E‐mail: dominique.soldati-favre{at}unige.ch
↵† These authors contributed equally to this work
PKA1 inhibits PKG activity to prevent premature parasite exit from the host cell due to intracellular acidification.
Synopsis
In the human pathogen Toxoplasma gondii, the cAMP‐dependent protein kinase A1 (PKA1) prevents premature exit from the host cell induced by intracellular acidification. This is achieved by downregulating the activity of cGMP‐dependent protein kinase G (PKG).
PKAc1 is maintained inactive at the pellicle by interacting with the dually acylated PKAr.
Genetic perturbations of PKAc1 activity lead to premature egress of the parasite and unproductive invasion.
PKG inhibitors block premature egress caused by PKAc1 inactivation.
PKAc1 delays intracellular acidification–induced parasite exit from the host cell.
PKAc1 and pH act as balancing regulators of PKG signalling to control parasite egress.
The EMBO Journal (2017) 36: 3250–3267
- Received March 4, 2017.
- Revision received September 8, 2017.
- Accepted September 12, 2017.
- © 2017 The Authors
- RBPJ/CBF1 interacts with L3MBTL3/MBT1 to promote repression of Notch signaling via histone demethylase KDM1A/LSD1
- Tao Xu1,†,
- Sung‐Soo Park1,†,
- Benedetto Daniele Giaimo2,†,
- Daniel Hall3,
- Francesca Ferrante2,
- Diana M Ho4,
- Kazuya Hori4,10,
- Lucas Anhezini5,11,
- Iris Ertl6,12,
- Marek Bartkuhn7,
- Honglai Zhang1,
- Eléna Milon1,
- Kimberly Ha1,
- Kevin P Conlon1,
- Rork Kuick8,
- Brandon Govindarajoo9,
- Yang Zhang9,
- Yuqing Sun1,
- Yali Dou1,
- Venkatesha Basrur1,
- Kojo SJ Elenitoba‐Johnson1,
- Alexey I Nesvizhskii1,9,
- Julian Ceron6,
- Cheng‐Yu Lee5,
- Tilman Borggrefe2,
- Rhett A Kovall3 and
- Jean‐François Rual (jrual{at}umich.edu)*,1
- 1Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA
- 2Institute of Biochemistry, University of Giessen, Giessen, Germany
- 3Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
- 4Department of Cell Biology, Harvard Medical School, Boston, MA, USA
- 5Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA
- 6Cancer and Human Molecular Genetics, Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat, Barcelona, Spain
- 7Institute for Genetics, University of Giessen, Giessen, Germany
- 8Center for Cancer Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, USA
- 9Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI, USA
- 10Present Address: Department of Pharmacology, University of Fukui, Fukui, Japan
- 11Present Address: Instituto de Ciências Biológicas e Naturais, Universidade Federal do Triângulo Mineiro, Uberaba, MG, Brazil
- 12Present Address: Department of Urology, Medical University of Vienna, Vienna, Austria
- ↵*Corresponding author. Tel: +1 734 764 6975; E‐mail: jrual{at}umich.edu
↵† These authors contributed equally to this work
The methyl‐lysine reader L3MBTL3 switches the Notch coactivator RBPJ to a transcriptional repressor by mediating removal of activating histone marks at Notch target genes.
Synopsis
The methyl‐lysine reader L3MBTL3 interacts with the Notch co‐activator RBPJ and switches it to a transcriptional repressor via KDM1A demethylase‐mediated removal of activating histone marks at the enhancers of Notch target genes.
RBPJ physically and functionally interacts with L3MBTL3.
L3MBTL3 competes with NOTCH intracellular domain for binding to RBPJ and for the control of Notch signaling.
L3MBTL3 recruits histone demethylase KDM1A to repress Notch target gene expression.
Genetic analyses in Drosophila and Caenorhabditis elegans demonstrate that the RBPJ/L3MBTL3 link is evolutionarily conserved in metazoans.
The EMBO Journal (2017) 36: 3232–3249
- Received January 13, 2017.
- Revision received August 31, 2017.
- Accepted September 12, 2017.
- © 2017 The Authors. Published under the terms of the CC BY NC ND 4.0 license
This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs 4.0 License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
- Initiating meiosis in a dish
Embryonic germ cells are formed from embryonic progenitors through a highly complex differentiation process, recapitulation of which in vitro has proved challenging. Two new studies in The EMBO Journal report culture conditions for embryonic stem cell‐derived primordial germ cell‐like cells (PGCLCs) that enable global DNA demethylation (Ohta et al, 2017), and subsequent initiation of meiosis (Miyauchi et al, 2017), allowing future manipulations to elucidate mechanisms driving germ line differentiation.
See also: H Ohta et al (July 2017) and
H Miyauchi et al (November 2017)
Two new studies establish conditions for culturing ESC‐derived germ cells, enabling global DNA demethylation and subsequent female sex determination.
- © 2017 The Authors
- LncRNA wires up Hippo and Hedgehog signaling to reprogramme glucose metabolism
- Xin Zheng1,†,
- Han Han2,†,
- Guang‐Ping Liu1,†,
- Yan‐Xiu Ma1,
- Ruo‐Lang Pan1,
- Ling‐Jie Sang1,
- Rui‐Hua Li1,
- Luo‐Jia Yang1,
- Jeffrey R Marks3,
- Wenqi Wang (wenqiw6{at}uci.edu)*,2 and
- Aifu Lin (linaifu{at}zju.edu.cn)*,1
- 1College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, China
- 2Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA, USA
- 3Division of Surgical Science, Department of Surgery, School of Medicine, Duke University, Durham, NC, USA
- ↵*
Corresponding author. Tel: +1 949 824 4888; E‐mail: wenqiw6{at}uci.edu
Corresponding author. Tel: +86 571 88981750; E‐mail: linaifu{at}zju.edu.cn
↵† These authors contributed equally to this work
Yes‐associated protein activation triggers transcription of long noncoding RNA BCAR4, leading to GLI2‐mediated expression of key glycolytic enzymes.
Synopsis
Yes‐associated protein promotes cancer formation by reprogramming glucose metabolism. A long noncoding RNA BCAR4 is a key downstream effector of YAP, in regulation of glycolysis and tumorigenesis via GLI2‐mediated expression of key glycolytic enzymes.
BCAR4 is a direct transcriptional target of YAP.
BCAR4 promotes glycolysis by increasing the expression of HK2 and PFKFB3.
GLI2 activation is required for the expression of glycolytic enzymes downstream of BCAR4
High YAP and BCAR4 expression levels positively correlate in breast cancer patient samples and are linked to poor clinical outcomes.
Inhibition of BCAR4 via Locked Nucleic Acids (LNAs) attenuated YAP‐dependent glycolysis and tumor growth.
The EMBO Journal (2017) 36: 3325–3335
- Received June 16, 2017.
- Revision received August 29, 2017.
- Accepted September 1, 2017.
- © 2017 College of Life Sciences, Zhejiang University
- Casein kinase 1‐epsilon or 1‐delta required for Wnt‐mediated intestinal stem cell maintenance
- Yael Morgenstern1,†,
- Upasana Das Adhikari1,†,
- Muneef Ayyash1,
- Ela Elyada1,
- Beáta Tóth2,
- Andreas Moor2,
- Shalev Itzkovitz2 and
- Yinon Ben‐Neriah (yinonb{at}ekmd.huji.ac.il)*,1
- 1The Lautenberg Center for Immunology, Institute of Medical Research, Hebrew University‐Hadassah Medical School, Jerusalem, Israel
- 2Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
- ↵*Corresponding author. Tel: +972 2 6758718; E‐mail: yinonb{at}ekmd.huji.ac.il
↵† These authors contributed equally to this work
Casein kinase isoforms CKIδ and CKIε facilitate Wnt‐mediated intestinal homeostasis and stem cell survival.
Synopsis
Casein kinase 1 (CKI) isoforms CKIδ and CKIε facilitate Wnt‐mediated intestinal homeostasis and stem cell survival.
Combined deletion of CKIδ/ε in the mouse intestine induces tissue atrophy and cell‐cycle arrest in p53‐independent manner.
Combined deletion of CKIδ/ε in Lgr5+ intestinal stem cells (ISCs) compromises self‐renewal, leading to Wnt inhibition and apoptosis.
Wnt suppression in ISCs is associated with reduced levels of nuclear Dvl and Fzd7 expression.
Exogenous expression of nuclear Dvl rescues CKIδ/ε ‐deleted organoids, which resume Fzd7 and Lgr5 expression.
The EMBO Journal (2017) 36: 3046–3061
- Received December 6, 2016.
- Revision received August 9, 2017.
- Accepted August 11, 2017.
- © 2017 The Authors
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