Signal Transduction
- Brd4‐Brd2 isoform switching coordinates pluripotent exit and Smad2‐dependent lineage specification
- Rosalia Fernandez‐Alonso1,
- Lindsay Davidson2,
- Jens Hukelmann3,
- Michael Zengerle4,
- Alan R Prescott3,
- Angus Lamond3,
- Alessio Ciulli4,
- Gopal P Sapkota1 and
- Greg M Findlay (g.m.findlay{at}dundee.ac.uk)*,1
- 1The MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, The University of Dundee, Dundee, UK
- 2Pluripotent Stem Cell Facility, School of Life Sciences, The University of Dundee, Dundee, UK
- 3Centre for Gene Regulation and Expression, School of Life Sciences, The University of Dundee, Dundee, UK
- 4Biological Chemistry and Drug Discovery, School of Life Sciences, The University of Dundee, Dundee, UK
- ↵*Corresponding author. Tel: +44 1382 386066; E‐mail: g.m.findlay{at}dundee.ac.uk
BET bromodomain proteins are key regulators of Nodal‐Smad2 signalling during mesendoderm differentiation of mESCs. In this system distinct functionalities of the BET family proteins Brd2 and Brd4 coordinate the exit from pluripotency with mesendoderm specification.
Synopsis
BET bromodomain proteins are key regulators of Nodal‐Smad2 signalling during mesendoderm differentiation of mESCs. In this system distinct functionalities of the BET family proteins Brd2 and Brd4 coordinate the exit from pluripotency with mesendoderm specification.
BET bromodomain activity regulates the Nodal‐Smad2 pathway and mesendoderm specification.
Brd2‐Brd4 recruitment controls Nodal expression and Smad2 signalling in differentiating mESCs.
Distinct Brd2‐Brd4 roles ensure that pluripotent exit coordinates with mesendoderm specification.
Brd2 is a novel specific regulator of Nodal‐Smad2 signalling and mesendoderm differentiation.
EMBO Reports (2017) 18: 1108–1122
- Received October 18, 2016.
- Revision received April 15, 2017.
- Accepted April 24, 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.
- The signaling lipid phosphatidylinositol‐3,5‐bisphosphate targets plant CLC‐a anion/H+ exchange activity
- Armando Carpaneto1,
- Anna Boccaccio1,
- Laura Lagostena1,
- Eleonora Di Zanni1 and
- Joachim Scholz‐Starke (joachim.scholzstarke{at}ge.ibf.cnr.it)*,1
- ↵*Corresponding author. Tel: +39 010 6475593; Fax: +39 010 6475500; E‐mail: joachim.scholzstarke{at}ge.ibf.cnr.it
This study identifies inhibition of CLC‐a dependent anion/H+ exchange as a vacuolar target of the signaling lipid phosphatidylinositol‐3,5‐bisphosphate. This provides a clue to the lipid's positive effect on vacuolar acidification in plant cells.
Synopsis
This study identifies inhibition of CLC‐a dependent anion/H+ exchange as a vacuolar target of the signaling lipid phosphatidylinositol‐3,5‐bisphosphate. This provides a clue to the lipid's positive effect on vacuolar acidification in plant cells.
PI(3,5)P2 does not affect major vacuolar H+ pump activities.
Vacuolar acidification elicited by prolonged H+ pumping activity revealed a novel H+‐dependent chloride conductance mediated by the anion/H+ exchanger CLC‐a.
CLC‐a anion/H+ exchange activity is reversibly inhibited by PI(3,5)P2 at low nanomolar concentrations.
CLC‐a inhibition contributes to vacuolar acidification.
EMBO Reports (2017) 18: 1100–1107
- Received December 14, 2016.
- Revision received April 20, 2017.
- Accepted April 21, 2017.
- © 2017 The Authors
- Structural basis for ligand capture and release by the endocytic receptor ApoER2
- Hidenori Hirai1,†,
- Norihisa Yasui2,†,
- Keitaro Yamashita3,
- Sanae Tabata1,
- Masaki Yamamoto3,
- Junichi Takagi1 and
- Terukazu Nogi (nogi{at}tsurumi.yokohama-cu.ac.jp)*,4
- 1Institute for Protein Research, Osaka University, Osaka, Japan
- 2Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
- 3RIKEN SPring‐8 Center, Hyogo, Japan
- 4Graduate School of Medical Life Science, Yokohama City University, Yokohama, Japan
- ↵*Corresponding author. Tel: +81 45 508 7226; Fax: +81 45 508 7365; E‐mail: nogi{at}tsurumi.yokohama-cu.ac.jp
↵† These authors contributed equally to this work
The crystal structure of the ApoER2 ectodomain in complex with reelin serves as a representative model for the pH‐dependent ligand uptake mechanism conserved within the LDLR family.
Synopsis
ApoER2 is a close homologue of the LDL receptor. The crystal structure of the ApoER2 ectodomain in complex with the signaling‐competent fragment of reelin serves as a representative model for the pH‐dependent ligand uptake mechanism conserved within the LDLR family.
The structure of the ApoER2 ectodomain in complex with its physiological ligand has been determined by X‐ray crystallography.
The LA2 module of ApoER2 serves as a low‐affinity auxiliary interface for reelin and is expected to modulate ligand‐receptor interactions during endocytosis.
The conformation of ligand‐bound ApoER2 resembles that of the closed state of LDLR at acidic pH rather than that of the extended state at neutral pH, indicating that ApoER2 is primed for ligand release even before internalization.
EMBO Reports (2017) 18: 982–999
- Received October 14, 2016.
- Revision received March 9, 2017.
- Accepted March 15, 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.
- USP26 regulates TGF‐β signaling by deubiquitinating and stabilizing SMAD7
- Sarah Kit Leng Lui1,
- Prasanna Vasudevan Iyengar1,
- Patrick Jaynes1,
- Zul Fazreen Bin Adam Isa1,
- Brendan Pang1,
- Tuan Zea Tan1 and
- Pieter Johan Adam Eichhorn (pieter_eichhorn{at}nus.edu.sg)*,1,2
- 1Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
- 2Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- ↵*Corresponding author. Tel: +65 65165475; Fax: +65 68739664; E‐mail: pieter_eichhorn{at}nus.edu.sg
As part of a negative feedback loop TGF‐β induces SMAD7 and complexes with SMURF2 to degrade the TGF‐β receptor. TGF‐β signaling also induces expression of USP26, which deubiquitinates and stabilizes SMAD7 resulting in downregulation of TGF‐β activity.
Synopsis
As part of a negative feedback loop TGF‐β induces SMAD7 and complexes with SMURF2 to degrade the TGF‐β receptor. TGF‐β signaling also induces expression of USP26, which deubiquitinates and stabilizes SMAD7 resulting in downregulation of TGF‐β activity.
TGF‐β enhances USP26 expression in breast cancer and glioblastoma.
USP26 acts as a negative regulator of the TGF‐β pathway by stabilizing SMAD7.
USP26 is mutated in glioblastoma and may be used as a biomarker for TGF‐β inhibitors.
EMBO Reports (2017) 18: 797–808
- Received August 26, 2016.
- Revision received March 8, 2017.
- Accepted March 8, 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.
- Parkinson's disease‐associated receptor GPR37 is an ER chaperone for LRP6
- Birgit S Berger1,†,
- Sergio P Acebron (s.perezacebron{at}DKFZ-Heidelberg.de)*,1,†,
- Jessica Herbst1,
- Stefan Koch1 and
- Christof Niehrs (niehrs{at}DKFZ-Heidelberg.de)*,1,2
- 1Division of Molecular Embryology, DKFZ‐ZMBH Alliance, Heidelberg, Germany
- 2Institute of Molecular Biology, Mainz, Germany
- ↵*
Corresponding author. Tel: +49 6221 42 4690; Fax: +49 6221 42 4692; E‐mail: s.perezacebron{at}DKFZ-Heidelberg.de
Corresponding author. Tel: +49 6221 42 4690; Fax: +49 6221 42 4692; E‐mail: niehrs{at}DKFZ-Heidelberg.de
↵† These authors contributed equally to this work
Using a genome‐wide siRNA screen, this study identifies the Parkinson's disease‐associated receptor GPR37 as a novel ER chaperone for the Wnt co‐receptor LRP6. In neural progenitor cells GPR37 functions to promote Wnt‐driven neurogenesis.
Synopsis
Using a genome‐wide siRNA screen, this study identifies the Parkinson's disease‐associated receptor GPR37 as a novel ER chaperone for the Wnt co‐receptor LRP6. In NPCs GPR37 functions to promote Wnt‐driven neurogenesis.
GPR37 promotes the maturation of the N‐terminal domains E1‐2 of LRP6, thereby promoting Wnt signaling.
GPR37 protects LRP6 from ER‐associated degradation (ERAD).
In NPCs, GPR37 and LRP6 promote neuronal fate.
EMBO Reports (2017) 18: 712–725
- Received October 28, 2016.
- Revision received February 14, 2017.
- Accepted February 22, 2017.
- © 2017 The Authors
- CUE domain‐containing protein 2 promotes the Warburg effect and tumorigenesis
- Xiuying Zhong1,†,
- Shengya Tian1,†,
- Xiang Zhang1,
- Xinwei Diao2,
- Fangting Dong2,
- Jie Yang2,
- Zhaoyong Li1,
- Linchong Sun1,
- Lin Wang1,
- Xiaoping He1,
- Gongwei Wu1,
- Xin Hu1,
- Lihua Wang1,
- Libing Song3,
- Huafeng Zhang1,
- Xin Pan2,
- Ailing Li (liailing{at}hotmail.com)*,2 and
- Ping Gao (pgao2{at}ustc.edu.cn)*,1
- 1Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, Innovation Center for Cell Signaling Network, School of Life Sciences, University of Science and Technology of China, Hefei, China
- 2Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China
- 3State Key Laboratory of Oncology in Southern China and Departments of Experimental Research, Sun Yat‐sen University Cancer Center, Guangzhou, China
- ↵*
Corresponding author. Tel: +86 10 66930344; E‐mail: liailing{at}hotmail.com
Corresponding author. Tel: +86 551 63607033; E‐mail: pgao2{at}ustc.edu.cn
↵† These authors contributed equally to this work
CUEDC2 has originally been described to promote proteasome function, but regulates also other cellular key events, including tumorigenesis. This study shows that CUEDC2 facilitates the Warburg effect in cancer cells by up‐regulating the glycolytic enzymes GLUT3 and LDHA.
Synopsis
CUEDC2 has originally been described to promote proteasome function, but regulates also other cellular key events, including tumorigenesis. This study shows that CUEDC2 facilitates the Warburg effect in cancer cells by up‐regulating the glycolytic enzymes GLUT3 and LDHA.
CUEDC2 facilitates the Warburg effect in cancer cells by regulating GLUT3 and LDHA.
CUEDC2 activates GLUT3 and LDHA by stabilizing the glucocorticoid receptor and 14‐3‐3ζ.
Enhanced aerobic glycolysis is essential for CUEDC2 to drive cancer progression.
Clinical HCC samples show aberrant expression of CUEDC2, GLUT3 and LDHA.
EMBO Reports (2017) 18: 809–825
- Received November 2, 2016.
- Revision received February 5, 2017.
- Accepted February 15, 2017.
- © 2017 The Authors
- Nuclear retention of the lncRNA SNHG1 by doxorubicin attenuates hnRNPC–p53 protein interactions
- Yuan Shen1,2,†,
- Shanshan Liu1,3,†,
- Jiao Fan1,4,
- Yinghua Jin (yhjin{at}jlu.edu.cn)*,3,
- Baolei Tian1,
- Xiaofei Zheng (xfzheng100{at}126.com)*,1 and
- Hanjiang Fu (fuhj75{at}126.com)*,1
- 1Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, China
- 2Department of Advanced Interdisciplinary Studies, Institute of Basic Medical Sciences and Tissue Engineering Research Center, Beijing Institute of Basic Medical Sciences, Beijing, China
- 3Key Laboratory for Molecular Enzymology and Engineering (The Ministry of Education), College of Life Sciences, Jilin University, Changchun, Jilin, China
- 4Institute of Geriatrics, Chinese PLA General Hospital, Beijing, China
- ↵*
Corresponding author. Tel: +86 431 85155221; E‐mail: yhjin{at}jlu.edu.cn
Corresponding author. Tel: +86 10 68214653; E‐mail: xfzheng100{at}126.com
Corresponding author. Tel: +86 10 66931237; Fax: +86 10 80705115; E‐mail: fuhj75{at}126.com
↵† These authors contributed equally to this work
p53 is a crucial regulator of cellular responses to toxic stress. This study identifies hnRNPC as a destabilizing p53 regulator. Doxorubicin treatment induces the nuclear retention and subsequent interaction of the lncRNA SNHG1 with hnRNPC, which impairs p53 destabilization.
Synopsis
p53 is a crucial regulator of cellular responses to toxic stress. This study identifies hnRNPC as a destabilizing p53 regulator. Doxorubicin treatment induces the nuclear retention and subsequent interaction of the lncRNA SNHG1 with hnRNPC, which impairs p53 destabilization.
The ribonucleoprotein hnRNPC directly binds to p53.
The hnRNPC interaction destabilizes p53 and prevents its activation.
Doxorubicin treatment retains the lncRNA SNHG1 in the nucleus through its binding with nucleolin.
Nuclear SNHG1 traps hnRNPC, which stabilizes p53 and promotes p53‐dependent apoptosis.
EMBO Reports (2017) 18: 536–548
- Received July 29, 2016.
- Revision received January 26, 2017.
- Accepted February 6, 2017.
- © 2017 The Authors
- NDR1 protein kinase promotes IL‐17‐ and TNF‐α‐mediated inflammation by competitively binding TRAF3
- Chunmei Ma1,†,
- Wenlong Lin1,†,
- Zhiyong Liu1,
- Wei Tang1,
- Rahul Gautam1,
- Hui Li2,
- Youcun Qian3,
- He Huang4 and
- Xiaojian Wang (wangxiaojian{at}cad.zju.edu.cn)*,1
- 1Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou, China
- 2Department of Chemotherapy, Zhejiang Cancer Hospital, Hangzhou, China
- 3Stem Cell Biology, Institute of Health Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China
- 4Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- ↵*Corresponding author. Tel: +86 571 88206268; E‐mail: wangxiaojian{at}cad.zju.edu.cn
↵† These authors contributed equally to this work
IL‐17 induces tissue inflammation and is involved in many autoimmune reactions. This study shows that the nuclear kinase NDR1 interacts with TRAF3 and promotes the formation of IL‐17R‐Act1‐TRAF6 complexes, which trigger downstream signal transduction and inflammation.
Synopsis
IL‐17 induces tissue inflammation and is involved in many autoimmune reactions. This study shows that the nuclear kinase NDR1 interacts with TRAF3 and promotes the formation of IL‐17R‐Act1‐TRAF6 complexes, which trigger downstream signal transduction and inflammation.
The nuclear Dbf2‐related kinase 1 (NDR1) promotes IL‐17‐induced inflammation in vitro and in vivo.
NDR1 enhances IL‐17‐dependent signaling and inflammation by targeting TRAF3.
NDR1 deficiency protects mice from experimental autoimmune encephalomyelitis (EAE) and TNBS‐induced colitis.
NDR1 expression is increased in the colon of ulcerative colitis (UC) patients.
EMBO Reports (2017) 18: 586–602
- Received January 30, 2016.
- Revision received January 15, 2017.
- Accepted January 18, 2017.
- © 2017 The Authors
- MARK4 inhibits Hippo signaling to promote proliferation and migration of breast cancer cells
- Emad Heidary Arash1,†,
- Ahmed Shiban1,†,
- Siyuan Song1 and
- Liliana Attisano (liliana.attisano{at}utoronto.ca)*,1
- ↵*Corresponding author. Tel: +1 416 946 3129; E‐mail: liliana.attisano{at}utoronto.ca
↵† These authors contributed equally to this work
Hippo signaling regulates tissue size and aberrations in the pathway can lead to cancer. This study identifies MARK family kinases as negative regulators of Hippo signaling by promoting the activity of YAP and TAZ via the inhibition of the Hippo kinase cascade.
Synopsis
Hippo signaling regulates tissue size and aberrations in the pathway can lead to cancer. This study identifies MARK family kinases as negative regulators of Hippo signaling by promoting the activity of YAP and TAZ via the inhibition of the Hippo kinase cascade.
Abrogation of MARK4 expression promotes YAP/TAZ phosphorylation and degradation.
MARK4 phosphorylates the Hippo core cassette components MST and SAV, thereby disrupting LATS‐mediated phosphorylation of YAP/TAZ.
Loss of MARK4 attenuates cell proliferation and migration of breast cancer cells independently of MST and SAV.
EMBO Reports (2017) 18: 420–436
- Received March 29, 2016.
- Revision received December 22, 2016.
- Accepted January 6, 2017.
- © 2017 The Authors
- A single MIU motif of MINDY‐1 recognizes K48‐linked polyubiquitin chains
- Yosua Adi Kristariyanto1,
- Syed Arif Abdul Rehman1,
- Simone Weidlich1,
- Axel Knebel1 and
- Yogesh Kulathu (ykulathu{at}dundee.ac.uk)*,1
- 1MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, UK
- ↵*Corresponding author. Tel: +44 1382 388163; Fax: +44 1382 223778; E‐mail: ykulathu{at}dundee.ac.uk
This study reveals the structural basis for how a single motif interacting with ubiquitin (MIU) at the C‐terminus of MINDY‐1 mediates selective binding to K48‐linked polyUb. Weak ubiquitin interactions from an adjacent MIU motif enhance binding to polyubiquitin.
Synopsis
This study reveals the structural basis for how a single motif interacting with ubiquitin (MIU) at the C‐terminus of MINDY‐1 mediates selective binding to K48‐linked polyUb. Weak ubiquitin interactions from an adjacent MIU motif enhance binding to polyubiquitin.
The tandem MIU repeats of MINDY‐1 preferably bind to longer K48‐polyUb chains.
A single MIU (MIU2) contains three distinct ubiquitin‐binding sites to simultaneously bind to three ubiquitin moieties within a K48‐linked chain.
MIU1 alone has low affinity for ubiquitin but cooperates with MIU2 to achieve high affinity binding.
EMBO Reports (2017) 18: 392–402
- Received August 12, 2016.
- Revision received December 13, 2016.
- Accepted December 16, 2016.
- © 2017 The Authors
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