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Signal Transduction

  • Role of Angiomotin‐like 2 mono‐ubiquitination on YAP inhibition
    Role of Angiomotin‐like 2 mono‐ubiquitination on YAP inhibition
    1. Miju Kim1,†,
    2. Minchul Kim1,†,
    3. Seong‐Jun Park2,
    4. Cheolju Lee2,3 and
    5. Dae‐Sik Lim*,1
    1. 1National Creative Research Center for Cell Division and Differentiation, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea
    2. 2Center for Theragnosis, Biomedical Research Institute Korea Institute of Science and Technology (KIST), Seoul, Korea
    3. 3Department of Biological Chemistry, University of Science and Technology, Daejeon, Korea
    1. ↵*Corresponding author. Tel: +82 42 350 2635; E‐mail: daesiklim{at}kaist.ac.kr

    1. ↵† These authors contributed equally to this work

    This study reports a new regulatory mechanism of the Hippo signaling governed by mono‐ubiquitination of AMOTL2. AMOTL2 mono‐ubiquitination is required to bind and activate LATS kinase and to inhibit YAP activity and is regulated by the USP9X deubiquitinase.

    Synopsis

    This study reports a new regulatory mechanism of the Hippo signaling governed by mono‐ubiquitination of AMOTL2. AMOTL2 mono‐ubiquitination is required to bind and activate LATS kinase and to inhibit YAP activity and is regulated by the USP9X deubiquitinase.

    • USP9X is a deubiquitinating enzyme activating YAP.

    • USP9X deubiquitinates AMOTL2 on its coiled‐coil domain.

    • Mono‐ubiquitination of AMOTL2 is required for its tumor suppressor function.

    • Mono‐ubiquitinated AMOTL2 activates LATS kinase through binding to the UBA domain of LATS.

    • AMOTL2
    • Hippo pathway
    • LATS‐YAP
    • mono‐ubiquitination
    • USP9X

    EMBO Reports (2016) 17: 64–78

    • Received June 6, 2015.
    • Revision received October 16, 2015.
    • Accepted October 20, 2015.
    Miju Kim, Minchul Kim, Seong‐Jun Park, Cheolju Lee, Dae‐Sik Lim
    Published online 01.01.2016
  • New frontiers: discovering cilia‐independent functions of cilia proteins
    New frontiers: discovering cilia‐independent functions of cilia proteins
    1. Anastassiia Vertii1,†,
    2. Alison Bright1,†,
    3. Benedicte Delaval2,
    4. Heidi Hehnly*,3 and
    5. Stephen Doxsey*,1
    1. 1Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA
    2. 2CRBM – CNRS Université de Montpellier, Montpellier, France
    3. 3Department of Cell and Developmental Biology, SUNY Upstate Medical University, Syracuse, NY, USA
    1. ↵* Corresponding author. Tel: +1 315 464 8528; E‐mail: HehnlyH{at}upstate.edu
      Corresponding author. Tel: +1 508 353 8904; E‐mail: Stephen.Doxsey{at}umassmed.edu

    1. ↵† These authors contributed equally to this work

    Various cilia proteins are crucial for other cellular processes, such as regulation of the cell cycle, polarized membrane trafficking and the DNA damage response. Thus, so called “ciliopathies” may be caused not only—or not at all—by faulty cilia.

    • Centrosome
    • Cilia
    • Ciliopathies
    • IFT
    • MTOC

    EMBO Reports (2015) 16: 1275–1287

    • Received May 4, 2015.
    • Revision received August 11, 2015.
    • Accepted August 17, 2015.
    Anastassiia Vertii, Alison Bright, Benedicte Delaval, Heidi Hehnly, Stephen Doxsey
    Published online 01.10.2015
  • EGFR kinase activity is required for TLR4 signaling and the septic shock response
    EGFR kinase activity is required for TLR4 signaling and the septic shock response
    1. Saurabh Chattopadhyay1,†,
    2. Manoj Veleeparambil1,†,
    3. Darshana Poddar1,
    4. Samar Abdulkhalek1,
    5. Sudip K Bandyopadhyay1,
    6. Volker Fensterl1 and
    7. Ganes C Sen*,1
    1. 1Department of Molecular Genetics, Lerner Research Institute Cleveland Clinic, Cleveland, OH, USA
    1. ↵*Corresponding author. Tel: +1 216 444 0636; Fax: +1 216 444 0513; E‐mail: seng{at}ccf.org

    1. ↵† These authors contributed equally to this work

    This study shows that EGFR kinase activity is necessary for the induction of interferon‐dependent, TLR4‐responsive genes. EGFR inhibition in vivo blocks septic shock and prevents death, suggesting a therapeutic avenue for this important pathology.

    Synopsis

    This study shows that EGFR kinase activity is necessary for the induction of interferon‐dependent, TLR4‐responsive genes. EGFR inhibition in vivo blocks septic shock and prevents death, suggesting a therapeutic avenue for this important pathology.

    • EGFR kinase activity differentially regulates TLR4‐induced gene expression.

    • EGFR activity is required for IRF activation.

    • EGFR activity is required for PI3K/AKT‐dependent phosphorylation of β‐catenin, a co‐activator of IRF3.

    • In vivo administration of an EGFR kinase inhibitor protects mice from LPS‐induced septic shock.

    • AKT
    • β‐catenin
    • EGFR
    • IRF
    • PI3 Kinase
    • septic shock
    • TLR

    EMBO Reports (2015) 16: 1535–1547

    • Received March 8, 2015.
    • Revision received August 10, 2015.
    • Accepted August 17, 2015.
    Saurabh Chattopadhyay, Manoj Veleeparambil, Darshana Poddar, Samar Abdulkhalek, Sudip K Bandyopadhyay, Volker Fensterl, Ganes C Sen
    Published online 01.11.2015
  • Open Access
    Hypoxia and loss of PHD2 inactivate stromal fibroblasts to decrease tumour stiffness and metastasis
    Hypoxia and loss of PHD2 inactivate stromal fibroblasts to decrease tumour stiffness and metastasis
    1. Chris D Madsen*,1,2,
    2. Jesper T Pedersen2,
    3. Freja A Venning2,
    4. Lukram Babloo Singh2,
    5. Emad Moeendarbary3,
    6. Guillaume Charras4,5,
    7. Thomas R Cox2,
    8. Erik Sahai*,1 and
    9. Janine T Erler*,2
    1. 1Tumour Cell Biology Laboratory, The Francis Crick Institute (formerly Cancer Research UK London Research Institute), London, UK
    2. 2Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark
    3. 3Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA
    4. 4Department of Cell and Developmental Biology, University College London, London, UK
    5. 5London Centre for Nanotechnology, University College London, London, UK
    1. ↵* Corresponding author. Tel: +45 35 32 56 47; Fax: +45 35 32 56 69; E‐mail: chris.madsen{at}bric.ku.dk
      Corresponding author. Tel: +44 20 7269 3165; E‐mail: erik.sahai{at}crick.ac.uk
      Corresponding author. Tel: +45 35 32 56 66; Fax: +45 35 32 56 69; E‐mail: janine.erler{at}bric.ku.dk

    Cancer‐associated fibroblasts induce cancer growth and spread. Here, chronic hypoxia and HIF‐1α stabilization are shown to deactivate CAFs, leading to impaired ECM remodelling and decreased metastasis in vivo.

    Synopsis

    Cancer‐associated fibroblasts—which are important mediators of cancer growth and spread—are shown to be deactivated by chronic hypoxia and HIF‐1α stabilization. Deactivated CAFs are impaired in ECM remodelling and lead to decreased metastasis in vivo.

    • Loss of PHD2 activity deactivates CAFs.

    • HIF‐1α suppresses αSMA expression.

    • Loss of PHD2 activity prevents CAF‐induced ECM remodelling.

    • Loss of PHD2 activity prevents CAF‐induced breast cancer metastasis.

    • cancer‐associated fibroblasts
    • hypoxia
    • PHD2
    • tumour invasion and metastasis
    • tumour stiffness

    EMBO Reports (2015) 16: 1394–1408

    • Received January 16, 2015.
    • Revision received August 4, 2015.
    • Accepted August 4, 2015.

    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.

    Chris D Madsen, Jesper T Pedersen, Freja A Venning, Lukram Babloo Singh, Emad Moeendarbary, Guillaume Charras, Thomas R Cox, Erik Sahai, Janine T Erler
    Published online 01.10.2015
  • MicroRNA‐455 regulates brown adipogenesis via a novel HIF1an‐AMPK‐PGC1α signaling network
    MicroRNA‐455 regulates brown adipogenesis via a novel HIF1an‐AMPK‐PGC1α signaling network
    1. Hongbin Zhang*,1,2,
    2. Meiping Guan1,3,
    3. Kristy L Townsend1,
    4. Tian Lian Huang1,
    5. Ding An1,
    6. Xu Yan1,
    7. Ruidan Xue1,
    8. Tim J Schulz1,4,
    9. Jonathon Winnay1,
    10. Marcelo Mori1,5,
    11. Michael F Hirshman1,
    12. Karsten Kristiansen6,
    13. John S Tsang7,
    14. Andrew P White8,
    15. Aaron M Cypess1,
    16. Laurie J Goodyear1 and
    17. Yu‐Hua Tseng*,1,9
    1. 1Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA
    2. 2Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
    3. 3Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
    4. 4Adipocyte Development Research Group, German Institute of Human Nutrition, Potsdam, Germany
    5. 5Department of Biophysics, Federal University of Sao Paulo, Sao Paulo, Brazil
    6. 6Department of Biology, University of Copenhagen, Copenhagen, Denmark
    7. 7Systems Genomics and Bioinformatics Unit, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases (NIAID) and Trans‐NIH Center for Human Immunology, National Institutes of Health, Bethesda, MD, USA
    8. 8Department of Orthopaedic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
    9. 9Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA
    1. ↵* Corresponding author. Tel: +1 45 3533 0484; E‐mail: hongbin{at}sund.ku.dk
      Corresponding author. Tel: +1 617 309 1967; Fax: +1 617 309 2650; E‐mail: yu-hua.tseng{at}joslin.harvard.edu

    miR‐455 promotes brown adipocyte differentiation and thermogenesis by targeting the key adipogenic inhibitors Necdin and Runx1t1 and by inducing a HIF1an‐AMPK‐PGC1α signaling cascade stimulating mitochondria biogenesis.

    Synopsis

    miR‐455 promotes brown adipocyte differentiation and thermogenesis by targeting the key adipogenic inhibitors Necdin and Runx1t1 and by inducing a HIF1an‐AMPK‐PGC1α signaling cascade stimulating mitochondria biogenesis.

    • miR‐455 is expressed in brown adipose tissue and induced by cold.

    • Fat‐specific miR‐455 transgenic mice show browning of subcutaneous white fat upon cold exposure.

    • miR‐455 induces brown/beige adipogenesis by targeting key brown adipogenic inhibitors such as Runx1t1 and Necdin.

    • miR‐455 activates a HIF1an‐AMPK‐PGC1α signaling cascade that promotes thermogenesis.

    • brown adipogenesis
    • differentiation
    • metabolism
    • microRNA
    • UCP1

    EMBO Reports (2015) 16: 1378–1393

    • Received June 11, 2015.
    • Revision received July 19, 2015.
    • Accepted July 24, 2015.
    Hongbin Zhang, Meiping Guan, Kristy L Townsend, Tian Lian Huang, Ding An, Xu Yan, Ruidan Xue, Tim J Schulz, Jonathon Winnay, Marcelo Mori, Michael F Hirshman, Karsten Kristiansen, John S Tsang, Andrew P White, Aaron M Cypess, Laurie J Goodyear, Yu‐Hua Tseng
    Published online 01.10.2015
  • Ins and outs of GPCR signaling in primary cilia
    Ins and outs of GPCR signaling in primary cilia
    1. Kenneth Bødtker Schou1,
    2. Lotte Bang Pedersen1 and
    3. Søren Tvorup Christensen*,1
    1. 1Department of Biology, University of Copenhagen, Copenhagen, Denmark
    1. ↵*Corresponding author. Tel: +45 51322997; E‐mail: stchristensen{at}bio.ku.dk

    GPCRs are involved in multiple signaling pathways in primary cilia. This article describes how GPCRs traffic into and out of the cilium and how they control ciliary and cellular functions. GPCR‐targeted drug strategies for the treatment of ciliopathies are also discussed.

    • ciliopathies
    • G protein‐coupled receptors
    • intraflagellar transport
    • neuronal signaling
    • primary cilia

    EMBO Reports (2015) 16: 1099–1113

    • Received April 10, 2015.
    • Revision received June 24, 2015.
    • Accepted July 1, 2015.
    Kenneth Bødtker Schou, Lotte Bang Pedersen, Søren Tvorup Christensen
    Published online 01.09.2015
  • PARD3 induces TAZ activation and cell growth by promoting LATS1 and PP1 interaction
    PARD3 induces TAZ activation and cell growth by promoting LATS1 and PP1 interaction
    1. Xian‐Bo Lv1,2,3,
    2. Chen‐Ying Liu4,
    3. Zhen Wang1,2,3,
    4. Yi‐Ping Sun1,2,3,
    5. Yue Xiong*,1,2,5,
    6. Qun‐Ying Lei*,1,2 and
    7. Kun‐Liang Guan*,1,2,6
    1. 1Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education and Department of Biochemistry and Molecular Biology Fudan University Shanghai Medical College, Shanghai, China
    2. 2Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
    3. 3School of Life Science, Fudan University, Shanghai, China
    4. 4Department of Colorectal and Anal Surgery, Shanghai Colorectal Cancer Research Center, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
    5. 5Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
    6. 6Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
    1. ↵* Corresponding author. Tel: +1 919 962 2142; E‐mail: yxiong{at}mai.unc.edu
      Corresponding author. Tel: +86 21 54237935; E‐mail: qlei{at}fudan.edu.cn
      Corresponding author. Tel: +1 858 822 7945; E‐mail: kuguan{at}ucsd.edu

    This study reports that cytoplasmic PARD3 promotes the interaction of PP1A and LATS to induce LATS inactivation, therefore leading to TAZ dephosphorylation and activation.

    Synopsis

    This study reports that cytoplasmic PARD3 promotes the interaction between PP1A and LATS to induce LATS inactivation, therefore leading to TAZ dephosphorylation and activation.

    • Demonstration of PARD3 as a new regulator of the Hippo pathway.

    • Elucidation of LATS inhibition by PARD3 via promoting LATS–PP1A interaction.

    • The function of PARD3 is cell density dependent and regulated by PAR1‐dependent phosphorylation.

    • Hippo pathway
    • PARD3
    • TAZ
    • tight junction

    EMBO Reports (2015) 16: 975–985

    • Received December 4, 2014.
    • Revision received May 18, 2015.
    • Accepted May 26, 2015.
    Xian‐Bo Lv, Chen‐Ying Liu, Zhen Wang, Yi‐Ping Sun, Yue Xiong, Qun‐Ying Lei, Kun‐Liang Guan
    Published online 01.08.2015
  • Open Access
    Binding to serine 65‐phosphorylated ubiquitin primes Parkin for optimal PINK1‐dependent phosphorylation and activation
    Binding to serine 65‐phosphorylated ubiquitin primes Parkin for optimal PINK1‐dependent phosphorylation and activation
    1. Agne Kazlauskaite1,
    2. R Julio Martínez‐Torres1,
    3. Scott Wilkie2,
    4. Atul Kumar1,
    5. Julien Peltier1,
    6. Alba Gonzalez1,
    7. Clare Johnson1,
    8. Jinwei Zhang1,
    9. Anthony G Hope2,
    10. Mark Peggie1,
    11. Matthias Trost1,
    12. Daan MF van Aalten1,
    13. Dario R Alessi1,
    14. Alan R Prescott3,
    15. Axel Knebel1,
    16. Helen Walden1 and
    17. Miratul MK Muqit*,1,4
    1. 1MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences University of Dundee, Dundee, UK
    2. 2Division of Biological Chemistry and Drug Discovery, College of Life Sciences University of Dundee, Dundee, UK
    3. 3Division of Cell Signalling and Immunology, College of Life Sciences University of Dundee, Dundee, UK
    4. 4College of Medicine, Dentistry & Nursing University of Dundee, Dundee, UK
    1. ↵*Corresponding author. Tel: +44 1382 388 377; E‐mail: m.muqit{at}dundee.ac.uk

    Binding of phosphorylated ubiquitin to Parkin is shown to induce a conformational change that allows Parkin phosphorylation and maximal activation by PINK1. Two residues crucial for the interaction between Parkin and ubiquitinphospho‐Ser65 are identified.

    Synopsis

    Binding of phosphorylated ubiquitin to Parkin is shown to induce a conformational change that allows Parkin phosphorylation and maximal activation by PINK1. The study also identifies two residues crucial for the interaction between Parkin and ubiquitinphospho‐Ser65.

    • Monoubiquitin, as well as diverse ubiquitin chain topologies phosphorylated at serine 65, enhance Parkin phosphorylation by PINK1.

    • Parkin His302 and Lys151 are required for optimal binding of phospho‐ubiquitin and likely line a phospho‐Ser65‐binding pocket of Parkin.

    • Parkin phosphorylation and activation at mitochondria is dependent on phospho‐ubiquitin binding.

    • Parkin
    • Parkinson's disease
    • phosphorylation
    • PINK1
    • ubiquitin

    EMBO Reports (2015) 16: 939–954

    • Received March 11, 2015.
    • Revision received June 9, 2015.
    • Accepted June 10, 2015.

    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.

    Agne Kazlauskaite, R Julio Martínez‐Torres, Scott Wilkie, Atul Kumar, Julien Peltier, Alba Gonzalez, Clare Johnson, Jinwei Zhang, Anthony G Hope, Mark Peggie, Matthias Trost, Daan MF van Aalten, Dario R Alessi, Alan R Prescott, Axel Knebel, Helen Walden, Miratul MK Muqit
    Published online 01.08.2015
  • LKB1 inhibition of NF‐κB in B cells prevents T follicular helper cell differentiation and germinal center formation
    LKB1 inhibition of NF‐κB in B cells prevents T follicular helper cell differentiation and germinal center formation
    1. Nicole C Walsh 1 ,
    2. Lynnea R Waters 2 ,
    3. Jessica A Fowler 1 ,
    4. Mark Lin 1 ,
    5. Cameron R Cunningham 3 ,
    6. David G Brooks 3 ,
    7. Jerold E Rehg 4 ,
    8. Herbert C Morse III 5 and
    9. Michael A Teitell * , 1 , 2 , 6
    1. 1 Department of Pathology & Laboratory Medicine, University of California, Los Angeles, CA, USA
    2. 2 Molecular Biology Institute, University of California, Los Angeles, CA, USA
    3. 3 Department of Microbiology, Immunology and Molecular Genetics and UCLA AIDS Institute University of California, Los Angeles, CA, USA
    4. 4 Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA
    5. 5 Virology and Cellular Immunology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases National Institutes of Health, Rockville, MD, USA
    6. 6 Broad Stem Cell Research Center, Departments of Pediatrics and Bioengineering, California NanoSystems Institute, and Jonsson Comprehensive Cancer Center University of California, Los Angeles, CA, USA
    1. ↵ *Corresponding author. Tel.: +1 310 206 6754; Fax: +1 310 206 0657; E‐mail: mteitell{at}mednet.ucla.edu

    LKB1‐mediated signaling in B cells is shown to have both cell‐intrinsic and cell‐extrinsic roles in regulating the differentiation of TFH cells and the formation of germinal centers, which occurs in part through enhanced IL‐6 secretion.

    Synopsis

    LKB1‐mediated signaling in B cells is shown to have both cell‐intrinsic and cell‐extrinsic roles in regulating the differentiation of TFH cells and the formation of germinal centers, which occurs in part through enhanced IL‐6 secretion.

    • Mice with B cells lacking LKB1 (BKO) form large GCs without specific antigen exposure

    • BKO B cells are activated and secrete TFH‐cell‐polarizing cytokines, including IL‐6

    • IL‐6 from BKO B cells induces IL‐21 in CD4+ T cells to optimize TFH‐differentiation

    • BKO B cells have increased nuclear accumulation of NF‐κB

    • B cell
    • TFH differentiation
    • germinal center
    • NF‐κB

    EMBO Reports (2015) 16: 753–768

    • Received August 25, 2014.
    • Revision received March 6, 2015.
    • Accepted March 16, 2015.
    Nicole C Walsh, Lynnea R Waters, Jessica A Fowler, Mark Lin, Cameron R Cunningham, David G Brooks, Jerold E Rehg, Herbert C Morse, Michael A Teitell
    Published online 01.06.2015
  • RNA metabolism: putting the brake on the UPR
    RNA metabolism: putting the brake on the UPR
    1. Amado Carreras‐Sureda1,2 and
    2. Claudio Hetz (chetz{at}med.uchile.cl) (chetz{at}hsph.harvard.edu) 1,2,3
    1. 1Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile
    2. 2Program of Cellular and Molecular Biology, Center for Molecular Studies of the Cell, Institute of Biomedical Sciences, University of Chile, Santiago, Chile
    3. 3Department of Immunology and Infectious diseases, Harvard School of Public Health, Boston, MA, USA

    The unfolded protein response (UPR) is a major signaling cascade that determines cell fate under conditions of endoplasmic reticulum (ER) stress. The kinetics and amplitude of UPR responses are tightly controlled by several feedback loops and the expression of positive and negative regulators. In this issue of EMBO Reports, the Wilkinson lab uncovers a novel function of nonsense‐mediated RNA decay (NMD) in fine‐tuning the UPR [1]. NMD is an mRNA quality control mechanism known to destabilize aberrant mRNAs that contain premature termination codons. In this work, NMD was shown to determine the threshold of stress necessary to activate the UPR, in addition to adjusting the amplitude of downstream responses and the termination phase. These effects were mapped to the control of the mRNA stability of IRE1, a major ER stress transducer. This study highlights the dynamic crosstalk between mRNA metabolism and the proteostasis network demonstrating the physiological relevance of normal mRNA regulation by the NMD pathway.

    See also: R Karam et al (May 2015)

    In this issue of EMBO Reports, nonsense‐mediated RNA decay (NMD) is shown to fine‐tune the unfolded protein response (UPR). NMD determines the threshold of UPR activation, the amplitude of downstream responses and its termination.

    Amado Carreras‐Sureda, Claudio Hetz
    Published online 01.05.2015

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