Signal Transduction
- Nutrient sensing and TOR signaling in yeast and mammals
- ↵*Corresponding author. Tel: +41 61 207 21 50; E‐mail: m.hall{at}unibas.ch
As part of our metabolism focus, this review summarizes how nutrient availability is recognized and integrated by the conserved TOR cell growth regulator.
The EMBO Journal (2017) 36: 397–408
- Received November 3, 2016.
- Revision received December 12, 2016.
- Accepted December 15, 2016.
- © 2017 The Authors
- Discrete cytosolic macromolecular BRAF complexes exhibit distinct activities and composition
- Britta Diedrich1,2,†,
- Kristoffer TG Rigbolt1,2,10,†,
- Michael Röring3,†,
- Ricarda Herr3,
- Stephanie Kaeser‐Pebernard4,
- Christine Gretzmeier1,2,5,
- Robert F Murphy5,6,
- Tilman Brummer (tilman.brummer{at}zbsa.uni-freiburg.de)*,2,3,7,8,9,‡ and
- Jörn Dengjel (joern.dengjel{at}unifr.ch)*,1,2,4,5,7,‡
- 1Department of Dermatology, Medical Center ‐ University of Freiburg, Freiburg, Germany
- 2ZBSA Center for Biological Systems Analysis, University of Freiburg, Freiburg, Germany
- 3Faculty of Medicine, Institute of Molecular Medicine and Cell Research (IMMZ), University of Freiburg, Freiburg, Germany
- 4Department of Biology, University of Fribourg, Fribourg, Switzerland
- 5Freiburg Institute for Advanced Studies (FRIAS), University of Freiburg, Freiburg, Germany
- 6Computational Biology Department and Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA, USA
- 7Centre for Biological Signalling Studies BIOSS, University of Freiburg, Freiburg, Germany
- 8Comprehensive Cancer Centre, Freiburg, Germany
- 9German Cancer Consortium (DKTK), partner site Freiburg, and German Cancer Research Center (DKFZ), Heidelberg, Germany
- 10Gubra, Hørsholm, Denmark
- ↵*
Corresponding author. Tel: +49 761 2039610; E‐mail: tilman.brummer{at}zbsa.uni-freiburg.de
Corresponding author. Tel: +41 26 300 8631; E‐mail: joern.dengjel{at}unifr.ch
Proteomics‐based identification of distinct molecular interactions and modifications of wild‐type and melanoma‐associated mutant BRAF reveals the effects of BRAF activators and inhibitors on the quaternary structure of this major therapeutic target.
Synopsis
The serine/threonine kinase BRAF plays a key role in development and homeostasis and represents the most frequently mutated kinase in tumors. We characterize two macromolecular, cytosolic BRAF complexes of distinct molecular composition and phosphorylation status.
BRAF resides minimally in two distinct macromolecular cytosolic protein complexes.
Active BRAF forms larger complexes characterized by the presence of HSP90/CDC37.
Less active BRAF resides in smaller complexes characterized by 14‐3‐3 proteins.
Clinically relevant kinase inhibitors alter BRAF complex compositions depending on the expressed BRAF mutant.
The EMBO Journal (2017) 36: 646–663
- Received May 10, 2016.
- Revision received December 6, 2016.
- Accepted December 9, 2016.
- © 2017 The Authors
- ANGPTL2 expression in the intestinal stem cell niche controls epithelial regeneration and homeostasis
- Haruki Horiguchi (horiguti{at}kumamoto-u.ac.jp)*,1,2,
- Motoyoshi Endo (enmoto{at}gpo.kumamoto-u.ac.jp)*,1,
- Kohki Kawane3,
- Tsuyoshi Kadomatsu1,
- Kazutoyo Terada1,
- Jun Morinaga1,
- Kimi Araki2,
- Keishi Miyata1 and
- Yuichi Oike (oike{at}gpo.kumamoto-u.ac.jp)*,1
- 1Department of Molecular Genetics, Graduate School of Medical sciences, Kumamoto University, Chuo‐ku Kumamoto, Japan
- 2Institute of Resource Development and Analysis, Kumamoto University, Chuo‐ku Kumamoto, Japan
- 3Faculty of Life Sciences, Kyoto Sangyo University, Kita‐ku Kyoto, Japan
- ↵*
Corresponding author. Tel: +81 96 373 5140; Fax: +81 96 373 5145; E‐mail: horiguti{at}kumamoto-u.ac.jp
Corresponding author. Tel: +81 96 373 5140; Fax: +81 96 373 5145; E‐mail: enmoto{at}gpo.kumamoto-u.ac.jp
Corresponding author. Tel: +81 96 373 5140; Fax: +81 96 373 5145; E‐mail: oike{at}gpo.kumamoto-u.ac.jp
ANGPTL2 is secreted upon intestinal injury and regulates the balance between β‐catenin and BMP signaling to promote intestinal stem cell maintenance and proliferation.
Synopsis
ANGPTL2 regulates stem cell activity and epithelial regeneration in the intestine. Intestinal subepithelial myofibroblasts secrete ANGPTL2 to maintain the intestinal stem cell niche by modulating proper BMP levels and β‐catenin signaling.
ANGPTL2 is required for regeneration of intestinal epithelium after injury.
ANGPTL2 is expressed in intestinal subepithelial myofibroblasts.
Autocrine ANGPTL2 downregulates Bmp expression via integrin α5β1/NF‐κB signaling.
Aberrant BMP signaling in Angptl2‐deficient mice decreases intestinal epithelial stem cell activity.
The EMBO Journal (2017) 36: 409–424
- Received September 9, 2016.
- Revision received November 30, 2016.
- Accepted November 30, 2016.
- © 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.
- MRTF potentiates TEAD‐YAP transcriptional activity causing metastasis
- Tackhoon Kim (tackhoon.k{at}kaist.ac.kr)*,1,†,
- Daehee Hwang1,†,
- Dahye Lee1,
- Jeong‐Hwan Kim2,
- Seon‐Young Kim2 and
- Dae‐Sik Lim (daesiklim{at}kaist.ac.kr)*,1
- 1National Creative Research Initiatives Center for Cell Division and Differentiation, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea
- 2Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
- ↵*
Corresponding author. Tel: +82 42 350 2675; E‐mail: tackhoon.k{at}kaist.ac.kr
Corresponding author. Tel: +82 42 350 2635; E‐mail: daesiklim{at}kaist.ac.kr
↵† These authors contributed equally to this work
Crosstalk with transcription factor MRTF enhances TEAD‐YAP oncogenic activity, coordinating signal transduction of extracellular GPCR ligands involved in cancer cell invasion or actin cytoskeletal disruption.
Synopsis
Oncogenic activity of TEAD‐YAP transcription complex is enhanced by MRTF proteins, which recruit NcoA3. MRTF–YAP interaction highlights a novel mode of signal transduction that regulates YAP activity independently of subcellular localization.
MRTF family proteins activate TEAD‐YAP by direct binding through PPXY–WW domain interaction.
MRTF–YAP interaction is required for TEAD‐YAP target gene expression and promotion of cancer cell invasion and metastasis.
MRTF binding to TEAD‐YAP recruits NcoA3 for full potentiation of TEAD‐YAP activity.
MRTF–YAP interaction constitutes a LATS‐independent regulatory mechanism on TEAD‐YAP activity.
The EMBO Journal (2017) 36: 520–535
- Received June 28, 2016.
- Revision received November 25, 2016.
- Accepted November 28, 2016.
- © 2016 The Authors
- Negative regulation of type I IFN signaling by phosphorylation of STAT2 on T387
- Yuxin Wang1,2,
- Jing Nan2,3,
- Belinda Willard4,
- Xin Wang5,
- Jinbo Yang (yangjb{at}ouc.edu.cn)*,1,3 and
- George R Stark (starkg{at}ccf.org)*,2
- 1Key Laboratory of Marine Drugs, Ministry of Education Ocean University of China, Qingdao, Shandong, China
- 2Department of Cancer Biology, Lerner Research Institute The Cleveland Clinic Foundation, Cleveland, OH, USA
- 3Institute of Cancer Biology & Drug Screening, School of Life Sciences Lanzhou University, Lanzhou, Gansu, China
- 4Proteomics and Metabolomics Laboratory, Lerner Research Institute The Cleveland Clinic Foundation, Cleveland, OH, USA
- 5Department of Immunology, Lerner Research Institute The Cleveland Clinic Foundation, Cleveland, OH, USA
- ↵*
Corresponding author. Tel: +1 216 444 6062; E‐mail: starkg{at}ccf.org
Corresponding author. Tel: +86 532 80932635; E‐mail: yangjb{at}ouc.edu.cn
Cyclin‐dependent kinase‐promoted phosphorylation of STAT2 at T387 inhibits type I IFN‐dependent signaling with effects on viral and cell proliferative responses.
Synopsis
An analysis by mass spectrometry revealed that the majority of STAT2 in cells is phosphorylated on T387 constitutively. This modification negatively regulates signaling responses to type I interferons. T387 lies in a consensus site for cyclin‐dependent kinases, suggesting that CDK inhibitors might augment responses to type I interferons.
STAT2 is phosphorylated on T387, which is located in the DNA‐binding domain.
STAT2 T387 phosphorylation negatively regulates type I IFN signaling.
The glucocorticoid signaling pathway affects T387 phosphorylation.
CDK inhibitors downregulate STAT2 T387 phosphorylation.
The EMBO Journal (2017) 36: 202–212
- Received May 23, 2016.
- Revision received October 6, 2016.
- Accepted October 11, 2016.
- © 2016 The Authors
- The Arabidopsis CERK1‐associated kinase PBL27 connects chitin perception to MAPK activation
- Kenta Yamada1,†,
- Koji Yamaguchi1,†,
- Tomomi Shirakawa1,
- Hirofumi Nakagami2,‡,
- Akira Mine3,4,‡,
- Kazuya Ishikawa1,
- Masayuki Fujiwara5,
- Mari Narusaka6,
- Yoshihiro Narusaka6,
- Kazuya Ichimura2,7,
- Yuka Kobayashi1,
- Hidenori Matsui2,
- Yuko Nomura2,
- Mika Nomoto4,
- Yasuomi Tada4,
- Yoichiro Fukao8,
- Tamo Fukamizo1,
- Kenichi Tsuda3,
- Ken Shirasu2,
- Naoto Shibuya9 and
- Tsutomu Kawasaki (t-kawasaki{at}nara.kindai.ac.jp)*,1
- 1Department of Advanced Bioscience, Graduate School of Agriculture, Kindai University, Nakamachi Nara, Japan
- 2RIKEN Center for Sustainable Resource Science, Tsurumi‐ku Yokohama, Japan
- 3Department of Plant Microbe Interactions, Max Planck Institute for Plant Breeding Research, Cologne, Germany
- 4Center for Gene Research, Nagoya University, Chikusa‐Ku Nagoya, Japan
- 5Institute for Advanced Biosciences, Keio University, Tsuruoka Yamagata, Japan
- 6Research Institute for Biological Sciences Okayama, Kaga‐gun Okayama, Japan
- 7Faculty of Agriculture, Kagawa University, Miki‐cho Kita‐gun Kagawa, Japan
- 8Department of Bioinformatics, Ritsumeikan University, Kusatsu Shiga, Japan
- 9Department of Life Sciences, School of Agriculture, Meiji University, Tama‐ku Kawasaki Kanagawa, Japan
- ↵*Corresponding author. Tel: +81 742 43 7335; E‐mail: t-kawasaki{at}nara.kindai.ac.jp
Chitin receptor CERK1 transmits immune signals to the intracellular MAPK cascade in plants. This occurs via phosphorylation of MAPKKK5 by the CERK1‐associated kinase PBL27, providing a missing link between pathogen perception and signaling output.
Synopsis
Chitin receptor CERK1 transmits immune signals to the intracellular MAPK cascade in plants. This occurs via phosphorylation of MAPKKK5 by the CERK1‐associated kinase PBL27, providing a missing link between pathogen perception and signaling output.
CERK1‐associated kinase PBL27 interacts with MAPKKK5 at the plasma membrane.
Chitin perception induces disassociation of PBL27 and MAPKKK5.
PBL27 functions as a MAPKKK kinase.
Phosphorylation of MAPKKK5 by PBL27 is enhanced upon phosphorylation of PBL27 by CERK1.
Phosphorylation of MAPKKK5 by PBL27 is required for chitin‐induced MAPK activation in planta.
The EMBO Journal (2016) 35: 2468–2483
- Received March 3, 2016.
- Revision received August 26, 2016.
- Accepted August 30, 2016.
- © 2016 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.
- Evi1 regulates Notch activation to induce zebrafish hematopoietic stem cell emergence
- Martina Konantz1,†,
- Elisa Alghisi1,†,
- Joëlle S Müller1,
- Anna Lenard1,
- Virginie Esain2,
- Kelli J Carroll2,
- Lothar Kanz3,
- Trista E North2,4 and
- Claudia Lengerke (claudia.lengerke{at}unibas.ch)*,1,3,5
- 1Department of Biomedicine, University Hospital Basel, Basel, Switzerland
- 2Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
- 3Department of Internal Medicine II, University Hospital Tuebingen, Tuebingen, Germany
- 4Harvard Stem Cell Institute, Cambridge, MA, USA
- 5Division of Hematology, University Hospital Basel, Basel, Switzerland
- ↵*Corresponding author. Tel: +41 61 55 65129; E‐mail: claudia.lengerke{at}unibas.ch
↵† These authors contributed equally to this work
A new VEGF‐independent pathway triggers Notch‐mediated conversion of dorsal aorta endothelial cells into definitive hematopoietic stem cells during embryonic endothelial‐to‐hematopoietic transition.
Synopsis
During embryonic development, definitive hematopoietic stem cells (HSCs) arise from aortic endothelial cells by a process known as endothelial‐to‐hematopoietic transition (EHT). While shh–vegf signaling is known to regulate EHT via Notch, here, a novel evi1–pAKT pathway is shown to be essential for activation of Notch signaling in ventral dorsal aorta endothelial cells and their subsequent conversion to HSCs.
The zebrafish transcriptional regulator evi1 activates pAKT and is critically required for Notch‐mediated EHT.
In vivo live imaging indicates that evi1 suppression impairs endothelial cell progression to hematopoietic fate cell autonomously.
Global or endothelial‐specific induction of notch, vegf, or pAKT can restore HSC formation in evi1 morphants.
evi1 overexpression induces Notch independently of Vegf and rescues HSC numbers in embryos treated with Vegf inhibitor.
The EMBO Journal (2016) 35: 2315–2331
- Received November 9, 2015.
- Revision received August 11, 2016.
- Accepted August 23, 2016.
- © 2016 The Authors
- IGFBP1 increases β‐cell regeneration by promoting α‐ to β‐cell transdifferentiation
- Jing Lu1,†,
- Ka‐Cheuk Liu1,†,
- Nadja Schulz1,†,
- Christos Karampelias1,
- Jérémie Charbord1,
- Agneta Hilding2,3,
- Linn Rautio1,
- Philippe Bertolino4,
- Claes‐Göran Östenson2,3,
- Kerstin Brismar2,3 and
- Olov Andersson (olov.andersson{at}ki.se)*,1
- 1Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
- 2Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- 3Department of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, Stockholm, Sweden
- 4Centre de Recherche en Cancérologie de Lyon, Inserm U1052, CNRS UMR5286, Université Lyon 1, Lyon, France
- ↵*Corresponding author. Tel: +46 733 462929; E‐mail: olov.andersson{at}ki.se
↵† These authors contributed equally to this work
In a zebrafish screen, insulin‐like growth factor binding protein 1 (Igfbp1) promotes β‐cell regeneration. Igfbp1 potentiates α‐ to β‐cell transdifferentiation in fish, mouse, and human islets. In humans, high IGFBP1 levels correlate with reduced type‐2 diabetes risk.
Synopsis
Harnessing endogenous regenerative mechanisms for insulin‐producing β cells may offer a cure for diabetes. We identified Igfbp1 as a promoter of β‐cell regeneration in zebrafish, and in complementary human studies highlight IGFBP1's clinical importance in diabetes.
In vivo screen in zebrafish for secreted proteins promoting β‐cell regeneration identified Igfbp1.
Igfbp1 potentiates β‐cell regeneration by increasing conversion of α to β cells (transdifferentiation) in zebrafish and isolated mouse/human islets.
Inhibition of the Igf pathway mimics Igfbp1a's regenerative effect.
A prospective study of 1,190 humans shows that high levels of IGFBP1 correlate with reduced diabetes risk.
The EMBO Journal (2016) 35: 2026–2044
- Received August 23, 2015.
- Revision received May 30, 2016.
- Accepted June 27, 2016.
- © 2016 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.
- The hVps34‐SGK3 pathway alleviates sustained PI3K/Akt inhibition by stimulating mTORC1 and tumour growth
- Ruzica Bago*,1,
- Eeva Sommer1,
- Pau Castel2,
- Claire Crafter3,
- Fiona P Bailey4,
- Natalia Shpiro1,
- José Baselga2,
- Darren Cross3,
- Patrick A Eyers4 and
- Dario R Alessi*,1
- 1MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences University of Dundee, Dundee, UK
- 2Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- 3Oncology iMED, AstraZeneca CRUK Cambridge Institute, Cambridge, UK
- 4Department of Biochemistry, Institute of Integrative Biology University of Liverpool, Liverpool, UK
- ↵*
Corresponding author. Tel: +44 1382385602; E‐mail: r.bago{at}dundee.ac.uk
Corresponding author. Tel: +44 1382385602; E‐mail: d.r.alessi{at}dundee.ac.uk
The hVps34‐SGK3 pathway activates mTORC1 following sustained inhibition of the PI3K/Akt signaling in breast cancer cells, explaining cancer resistance to PI3K signaling inhibitors.
Synopsis
Upon prolonged treatment with class I PI3K or Akt inhibitors breast cancer cells attain resistance and proliferate. As a novel evasive mechanism explaining this phenomenon, the hVps34‐SGK3 pathway maintains mTORC1 activity following sustained inhibition of the PI3K/Akt signalling pathway.
Continuous exposure of breast cancer cells to class I PI3K/Akt inhibitors increases expression and activation of the SGK3 kinase.
SGK3 activation is controlled by the endosomal lipid kinase hVps34 that generates 3‐phosphoinositide [PI(3)P].
SGK3 possesses a PX domain that binds to PI(3)P, promoting phosphorylation and activation of SGK3 by the PDK1 kinase.
SGK3 substitutes for Akt by phosphorylating TSC2, thereby stimulating mTORC1 and leading to tumour progression.
Combination of Akt and a novel selective SGK3 inhibitor termed 14h induces regression of BT‐474 breast cancer cell‐derived tumours in a nude mouse xenograft model.
The EMBO Journal (2016) 35: 1902–1922
- Received January 21, 2016.
- Revision received June 19, 2016.
- Accepted July 4, 2016.
- © 2016 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.
- SPATA2 – Keeping the TNF signal short and sweet
In this issue of The EMBO Journal, a multi‐layered global proteome resource, which comprehensively covers TNF‐induced phosphorylation and ubiquitination events as well as receptor interactions, has led to identification of SPATA2 as a novel player that contributes to TNF signalling by interacting with the LUBAC ubiquitin ligase and the CYLD deubiquitylase. Loss of SPATA2 augments transcriptional activation of NF‐κB and limits TNF‐induced necroptosis. A separate screen published in EMBO Reports corroborates these findings by showing that SPATA2 deficiency regulates CYLD activity, TNF‐induced NF‐κB signalling and cell death.
See also: SA Wagner et al (September 2016) and
Recent work published in The EMBO Journal and EMBO Reports yielded identification of SPATA2 as a novel player in TNF signalling, which interacts with the LUBAC ubiquitin ligase and the CYLD deubiquitylase. Loss of SPATA2 augments transcriptional activation of NF‐κB and limits TNF‐induced necroptosis.
- © 2016 The Authors
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