• Regulation of cargo‐selective endocytosis by dynamin 2 GTPase‐activating protein girdin
    1. Liang Weng1,
    2. Atsushi Enomoto*,1,
    3. Hiroshi Miyoshi2,
    4. Kiyofumi Takahashi3,
    5. Naoya Asai1,
    6. Nobuhiro Morone4,
    7. Ping Jiang5,
    8. Jian An6,
    9. Takuya Kato1,
    10. Keisuke Kuroda7,
    11. Takashi Watanabe7,
    12. Masato Asai1,
    13. Maki Ishida‐Takagishi1,
    14. Yoshiki Murakumo8,
    15. Hideki Nakashima2,
    16. Kozo Kaibuchi7 and
    17. Masahide Takahashi*,1
    1. 1Department of Pathology, Nagoya University Graduate School of Medicine, Showa‐ku Nagoya, Japan
    2. 2Department of Microbiology, St. Marianna University School of Medicine, Miyamae Kawasaki, Japan
    3. 3Department of Neuropsychiatry, St. Marianna University School of Medicine, Miyamae Kawasaki, Japan
    4. 4Institute for Integrated Cell‐Material Sciences, Kyoto University, Sakyo‐ku Kyoto, Japan
    5. 5The Key Laboratory of Geriatrics, Beijing Hospital and Beijing Institute of Geriatrics Ministry of Health, Dong Dan Beijing, China
    6. 6Department of Respiratory Medicine, Xiangya Hospital Central South University, Kaifu District Changsha, China
    7. 7Department of Cell Pharmacology, Nagoya University Graduate School of Medicine, Showa‐ku Nagoya, Japan
    8. 8Department of Pathology, Kitasato University School of Medicine, Minami‐ku Sagamihara, Japan
    1. * Corresponding author. Tel: +81 52 744 2093; E‐mail: enomoto{at}

      Corresponding author. Tel: +81 52 744 2093; Fax: +81 52 744 2098; E‐mail: mtakaha{at}

    The actin binding protein girdin is a GAP for dynamin 2. Girdin regulates clathrin‐dependent endocytosis through a non‐canonical mechanism that involves competition between dynamin 2 and certain cargos for girdin binding, resulting in spatial control of protein internalization.


    The actin binding protein girdin is a GAP for dynamin 2. Girdin regulates clathrin‐dependent endocytosis through a non‐canonical mechanism that involves competition between dynamin 2 and certain cargos for girdin binding, resulting in spatial control of protein internalization.

    • The actin‐binding protein girdin is a GAP for dynamin 2 involved in clathrin‐dependent endocytosis.

    • Girdin inhibits endocytosis of certain cargos but is required for others at the center but not the periphery of the cell.

    • Competitive interaction between cargoes and dynamin 2 for girdin binding is involved in the selective endocytosis.

    • clathrin‐mediated endocytosis
    • dynamin
    • girdin
    • GTPase‐activating protein
    • selective endocytosis
    • Received February 20, 2014.
    • Revision received June 28, 2014.
    • Accepted July 1, 2014.

    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.

    Liang Weng, Atsushi Enomoto, Hiroshi Miyoshi, Kiyofumi Takahashi, Naoya Asai, Nobuhiro Morone, Ping Jiang, Jian An, Takuya Kato, Keisuke Kuroda, Takashi Watanabe, Masato Asai, Maki Ishida‐Takagishi, Yoshiki Murakumo, Hideki Nakashima, Kozo Kaibuchi, Masahide Takahashi
  • “Father knows best?”
    1. Ashley T Neff1,
    2. Jianbin Wang1 and
    3. Richard E Davis (richard.davis{at} 1
    1. 1Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO, USA

    Following fertilization, activation of a complex developmental program requires the differential expression of key genes. In most metazoa, the prevailing view is that early differential gene expression occurs primarily through post‐transcriptional regulation of maternally deposited products in the oocyte. Two novel studies published from the Rajewsky laboratory in this issue of The EMBO Journal add significantly to the emerging notion that this process may be more complex than previously appreciated.

    See also: M Stoeckius et al (August 2014a)

    and M Stoeckius et al (August 2014b)

    Systematic analyses of the oocyte‐to‐embryo transition (i) reveal the deposition of distinct classes of paternal RNAs in the oocyte and (ii) discover a very early, coordinated wave of maternal RNA clearance.

    Ashley T Neff, Jianbin Wang, Richard E Davis
  • Sox2, a marker for stem‐like tumor cells in skin squamous cell carcinoma and hedgehog subgroup medulloblastoma
    1. Oren J Becher (oren.becher{at} 1,2 and
    2. Eric C Holland (eholland{at} 3,4
    1. 1Division of Pediatric Hematology‐Oncology, Duke University Medical Center, Durham, NC, USA
    2. 2Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA
    3. 3Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
    4. 4Alvord Brain Tumor Center, University of Washington, Seattle, WA, USA

    Heterogeneity within tumors is becoming increasingly recognized as an important cause of treatment failure in cancer. Two recent studies use fate‐mapping and limiting dilution transplantation assays to identify SRY (sex determining region Y)‐box 2 (Sox2) as cancer stem‐cell marker and driver of cancer stemness.

    See also: RJ Vanner et al (July 2014),

    S Boumahdi et al (July 2014) and

    M Kool et al (March 2014)

    The identification of Sox2 as cancer stem‐cell marker and driver of cancer stemness in distinct tumor types suggests that each tumor resembles the hierarchical organization of the tissue from which it arises.

    Oren J Becher, Eric C Holland
  • BID‐dependent release of mitochondrial SMAC dampens XIAP‐mediated immunity against Shigella
    1. Maria Andree1,2,3,
    2. Jens M Seeger1,2,3,
    3. Stephan Schüll1,2,3,
    4. Oliver Coutelle1,2,3,
    5. Diana Wagner‐Stippich1,2,3,
    6. Katja Wiegmann1,
    7. Claudia M Wunderlich3,4,
    8. Kerstin Brinkmann1,2,3,
    9. Pia Broxtermann1,2,3,
    10. Axel Witt1,2,3,
    11. Melanie Fritsch1,2,3,
    12. Paola Martinelli2,3,4,
    13. Harald Bielig1,
    14. Tobias Lamkemeyer3,
    15. Elena I Rugarli2,3,4,
    16. Thomas Kaufmann5,
    17. Anja Sterner‐Kock6,
    18. F Thomas Wunderlich3,4,
    19. Andreas Villunger7,
    20. L Miguel Martins8,
    21. Martin Krönke1,2,3,
    22. Thomas A Kufer1,
    23. Olaf Utermöhlen1,2 and
    24. Hamid Kashkar*,1,2,3
    1. 1Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany
    2. 2Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
    3. 3Cologne Excellence Cluster on Cellular Stress Responses in Aging‐Associated Diseases (CECAD), University of Cologne, Cologne, Germany
    4. 4Max Planck Institute for Metabolism Research, Cologne, Germany
    5. 5Institute of Pharmacology, University of Bern, Bern, Switzerland
    6. 6Center for Experimental Medicine (CEM), University of Cologne, Cologne, Germany
    7. 7Division of Developmental Immunology, Biocenter, Innsbruck Medical University, Innsbruck, Austria
    8. 8Cell Death Regulation Laboratory, MRC Toxicology Unit, Leicester, UK
    1. *Corresponding author. Tel: +49 221 478 84092; Fax: +49 221 478 7288; E‐mail: h.kashkar{at}

    Invasive Shigella bacteria co‐opt the mitochondrial XIAP antagonist SMAC in ways that selectively decrease antibacterial inflammatory responses without triggering host cell apoptosis.


    XIAP is an essential mediator for the anti‐bacterial immune response against the Gram‐negative enteroinvasive bacterium Shigella flexneri. Shigella escapes this immune response by involving the calpain‐mediated activation of BID, which leads to the release of mitochondrial SMAC. Cytosolic SMAC antagonizes XIAP and dampens the immunity against Shigella.

    • XIAP is a crucial component of the pro‐inflammatory response against Shigella.

    • Shigella induces the activation of calpain, which cleaves and activates BID.

    • Activated BID induces the release of mitochondrial SMAC in Shigella‐infected cells.

    • Cytosolic SMAC antagonizes XIAP and dampens the anti‐bacterial inflammatory signalling.

    • inflammation
    • mitochondria
    • Shigella
    • SMAC
    • XIAP
    • Received October 25, 2013.
    • Revision received June 12, 2014.
    • Accepted June 13, 2014.
    Maria Andree, Jens M Seeger, Stephan Schüll, Oliver Coutelle, Diana Wagner‐Stippich, Katja Wiegmann, Claudia M Wunderlich, Kerstin Brinkmann, Pia Broxtermann, Axel Witt, Melanie Fritsch, Paola Martinelli, Harald Bielig, Tobias Lamkemeyer, Elena I Rugarli, Thomas Kaufmann, Anja Sterner‐Kock, F Thomas Wunderlich, Andreas Villunger, L Miguel Martins, Martin Krönke, Thomas A Kufer, Olaf Utermöhlen, Hamid Kashkar
  • Location, location, and location: compartmentalization of Hedgehog signaling at primary cilia
    1. Ganesh V Pusapati (ganesh22{at} 1 and
    2. Rajat Rohatgi (rrohatgi{at} 1
    1. 1Departments of Medicine and Biochemistry, Stanford University School of Medicine, Stanford, CA, USA

    Primary cilia are solitary, microtubule‐based organelles that serve as signaling hubs for the Hedgehog (Hh) pathway, which regulates embryonic development and adult tissue homeostasis. While protein localization studies have suggested that the dynamic trafficking of Hh components at cilia plays an important role, the molecular basis of Hh signal transduction at cilia is not well understood. In a recent study published in Nature Cell Biology (He et al, 2014), He and colleagues demonstrate that the kinesin KIF7, a conserved regulator of Hh signaling, limits ciliary length by acting at the plus‐ends of microtubules to both reduce growth rate and increase catastrophe frequency. They propose that this biochemical activity establishes a specialized compartment at the tip of the cilia where the activity the Gli family of Hh transcription factors is regulated.

    See also: M He et al

    KIF7 is a conserved kinesin involved in Hh signaling that associates with microtubule plus‐ends in cilia to regulate axonemal stability and length, and to generate a cilia‐tip compartment where Gli proteins processing is regulated.

    Ganesh V Pusapati, Rajat Rohatgi
  • Sharpening rhomboid specificity by dimerisation and allostery
    1. Kvido Strisovsky (kvido.strisovsky{at} 1 and
    2. Matthew Freeman2
    1. 1Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic
    2. 2Dunn School of Pathology University of Oxford, Oxford, UK

    In this issue of The EMBO Journal, mechanistic analyses of substrate cleavage by rhomboid intramembrane proteases suggest that catalytic efficiency towards natural, transmembrane substrates is allosterically stimulated by initial substrate interaction with an intramembrane exosite, whose formation depends on rhomboid dimerisation. In the realm of intramembrane proteolysis, dimerisation and allosteric cooperativity represent new concepts that, once confirmed more broadly, should radically alter our view of how these proteases work.

    See also: E Arutyunova et al

    The finding that allosteric cooperation between rhomboid protease dimers aids specific recognition of physiological substrates offers new concepts in the understanding of intramembrane proteolysis.

    Kvido Strisovsky, Matthew Freeman
  • Genome‐wide siRNA screen reveals coupling between mitotic apoptosis and adaptation
    1. Laura A Díaz‐Martínez1,
    2. Zemfira N Karamysheva14,
    3. Ross Warrington1,
    4. Bing Li1,
    5. Shuguang Wei2,
    6. Xian‐Jin Xie3,
    7. Michael G Roth2 and
    8. Hongtao Yu*,1
    1. 1Department of Pharmacology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA
    2. 2Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA
    3. 3Center for Biostatistics and Clinical Science, University of Texas Southwestern Medical Center, Dallas, TX, USA
    4. 4 Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
    1. *Corresponding author. Tel: +1 214 645 6161; Fax: +1 214 645 6156; E‐mail: hongtao.yu{at}

    An RNAi screen offers new insights into the regulatory networks governing the fate of cancer cells undergoing prolonged drug‐induced mitotic checkpoint arrest.


    Prolonged mitotic arrest induced by anti‐proliferative drugs eventually results in apoptotic cell death or in mitotic exit due to checkpoint adaptation. An RNAi screen in human cancer cells lines offers new insights into the regulatory networks underlying these processes.

    • Genome‐wide siRNA screen identifies regulators of mitotic cell death and checkpoint adaptation.

    • The BH3‐only protein Noxa promotes apoptosis during mitotic arrest.

    • The spindle checkpoint regulator p31comet suppresses mitotic adaptation and facilitates apoptosis.

    • A Bax/Bak mitochondrial module couples mitotic apoptosis and adaptation.

    • The mitochondrial fission factor Drp1 promotes mitotic checkpoint adaptation.

    • apoptosis
    • mitochondria
    • mitosis
    • mitotic slippage
    • the spindle checkpoint
    • Received January 3, 2014.
    • Revision received May 23, 2014.
    • Accepted June 18, 2014.
    Laura A Díaz‐Martínez, Zemfira N Karamysheva, Ross Warrington, Bing Li, Shuguang Wei, Xian‐Jin Xie, Michael G Roth, Hongtao Yu