Signal Transduction
- 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
- The NLR protein SUMM2 senses the disruption of an immune signaling MAP kinase cascade via CRCK3
- Zhibin Zhang1,3,4,†,
- Yanan Liu1,†,
- Hao Huang2,†,
- Minghui Gao2,
- Di Wu1,
- Qing Kong1,5,6 and
- Yuelin Zhang (yuelin.zhang{at}ubc.ca)*,1
- 1Department of Botany, University of British Columbia, Vancouver, BC, Canada
- 2National Institute of Biological Sciences, Beijing, China
- 3Present Address: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA
- 4Present Address: Department of Pediatrics, Harvard Medical School, Boston, MA, USA
- 5Present Address: Department of Cancer Biology, Dana‐Farber Cancer Institute, Boston, MA, USA
- 6Present Address: Department of Genetics, Harvard Medical School, Boston, MA, USA
- ↵*Corresponding author. Tel: +1 604 827 3794; E‐mail: yuelin.zhang{at}ubc.ca
↵† These authors contributed equally to this work
Pathogen‐dependent disruption of the MEKK1‐MKK1/2‐MPK4 kinase cascade results in defence responses mediated by the NLR protein SUMM2. This study shows that SUMM2 senses this disruption via the MPK4 substrate CRCK3, which is also required for the SUMM2‐dependent autoimmune phenotypes in kinase cascade mutants.
Synopsis
Pathogen‐dependent disruption of the MEKK1‐MKK1/2‐MPK4 kinase cascade results in defence responses mediated by the NLR protein SUMM2. This study shows that SUMM2 senses this disruption via the MPK4 substrate CRCK3, which is also required for the SUMM2‐dependent autoimmune phenotypes in kinase cascade mutants.
CALMODULIN‐BINDING RECEPTOR‐LIKE CYTOPLASMIC KINASE 3 (CRCK3) is required for the autoimmune phenotypes in mekk1, mkk1 mkk2, and mpk4 mutants.
CRCK3 is a substrate of MPK4 monitored by the nucleotide binding and leucine‐rich repeat receptor (NLR) protein SUMM2.
Inactivation of MPK4 leads to reduced phosphorylation of CRCK3 and activation of SUMM2‐mediated immune responses.
EMBO Reports (2017) 18: 292–302
- Received May 10, 2016.
- Revision received October 25, 2016.
- Accepted November 4, 2016.
- © 2016 The Authors
- Osmotic stress‐induced phosphorylation by NLK at Ser128 activates YAP
- Audrey W Hong1,
- Zhipeng Meng1,
- Hai‐Xin Yuan1,2,
- Steven W Plouffe1,
- Sungho Moon3,
- Wantae Kim3,
- Eek‐hoon Jho3 and
- Kun‐Liang Guan (kuguan{at}ucsd.edu)*,1
- 1Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
- 2The Molecular and Cell Biology Laboratory, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
- 3Department of Life Science, University of Seoul, Dongdaemun‐gu, Seoul, Korea
- ↵*Corresponding author. Tel: +1 858 822 7945; E‐mail: kuguan{at}ucsd.edu
Yes‐associated protein (YAP) is the major transcriptional co‐activator of the Hippo pathway, and its activity is determined by its subcellular localization. This study shows that osmotic stress induces Ser128 phosphorylation of YAP by the nemo‐like kinase (NLK), which results in its nuclear accumulation and the induction of downstream targets.
Synopsis
Yes‐associated protein (YAP) is the major transcriptional co‐activator of the Hippo pathway, and its activity is determined by its subcellular localization. This study shows that osmotic stress induces Ser128 phosphorylation of YAP by the nemo‐like kinase (NLK), which results in its nuclear accumulation and the induction of downstream targets.
Osmotic stress induces transient nuclear localization of YAP, despite LATS‐dependent Ser127 phosphorylation.
Osmotic stress activates NLK to phosphorylate YAP on Ser128, which interferes with 14‐3‐3 binding and increases its nuclear localization.
NLK‐dependent transient YAP activation may serve as an early response for cells to adapt to osmotic stress.
EMBO Reports (2017) 18: 72–86
- Received May 5, 2016.
- Revision received November 7, 2016.
- Accepted November 11, 2016.
- © 2016 The Authors
- Phosphorylation by NLK inhibits YAP‐14‐3‐3‐interactions and induces its nuclear localization
- Sungho Moon1,†,
- Wantae Kim1,†,
- Soyoung Kim1,
- Youngeun Kim1,
- Yonghee Song1,
- Oleksii Bilousov2,
- Jiyoung Kim1,
- Taebok Lee1,
- Boksik Cha1,
- Minseong Kim1,
- Hanjun Kim1,
- Vladimir L Katanaev (vladimir.katanaev{at}unil.ch)*,2,3 and
- Eek‐hoon Jho (ej70{at}uos.ac.kr)*,1
- 1Department of Life Science, University of Seoul, Seoul, Korea
- 2Department of Pharmacology and Toxicology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
- 3School of Biomedicine, Far Eastern Federal University, Vladivostok, Russian Federation
- ↵*
Corresponding author. Tel: +41 21 692 5459; Fax: +41 21 692 5355; E‐mail: vladimir.katanaev{at}unil.ch
Corresponding author. Tel: +82 02 6490 2671; Fax: +82 02 6490 2664; E‐mail: ej70{at}uos.ac.kr
↵† These authors contributed equally to this work
Yes‐associated protein (YAP) is a key downstream effector of Hippo signaling and its activation, and nuclear localization is determined by its phosphorylation state. This study shows that the nemo‐like kinase (NLK) phosphorylates YAP at Ser128, thereby inhibiting its interaction with 14‐3‐3 and regulating its subcellular localization.
Synopsis
Yes‐associated protein (YAP) is a key downstream effector of Hippo signaling and its activation, and nuclear localization is determined by its phosphorylation state. This study shows that the nemo‐like kinase (NLK) phosphorylates YAP at Ser128, thereby inhibiting its interaction with 14‐3‐3 and regulating its subcellular localization.
NLK phosphorylates YAP at Ser128, which leads to reduced LATS‐mediated phosphorylation.
NLK promotes the nuclear localization of YAP by inhibiting its interaction with 14‐3‐3.
NLK localization and protein level are regulated in a cell density‐dependent manner.
EMBO Reports (2017) 18: 61–71
- Received May 5, 2016.
- Revision received October 11, 2016.
- Accepted October 13, 2016.
- © 2016 The Authors
- YAP needs Nemo to guide a Hippo
- Alexander Hergovich (a.hergovich{at}ucl.ac.uk)1
The Hippo growth control pathway coordinates cell proliferation, death, differentiation and stemness through regulatory phosphorylation of the YAP proto‐oncoprotein, a major nuclear effector of Hippo signalling. In particular, YAP phosphorylation on Ser127 can promote inhibitory 14‐3‐3 interactions and cytoplasmic sequestration. Two studies in this issue of EMBO Reports show that Ser128 phosphorylation of YAP by the Nemo‐like kinase (NLK) disrupts 14‐3‐3 interactions, thereby promoting nuclear accumulation of active YAP [1], [2]. Notably, Ser127‐phosphorylated YAP can be nuclear and co‐transcriptionally active upon osmotic stress, thus, challenging the dogma of YAP regulation by Ser127 phosphorylation.
See also: AW Hong et al (January 2017) and
S Moon et al (January 2017)
Two studies in this issue show that Ser128 phosphorylation of the Hippo pathway protein YAP by the Nemo‐like kinase (NLK) promotes nuclear accumulation of active YAP, challenging the dogma of YAP regulation via Ser127 phosphorylation.
- © 2016 The Author
- Phosphocysteine in the PRL‐CNNM pathway mediates magnesium homeostasis
- Irina Gulerez1,†,
- Yosuke Funato2,†,
- Howie Wu1,†,
- Meng Yang1,
- Guennadi Kozlov1,
- Hiroaki Miki (hmiki{at}biken.osaka-u.ac.jp)*,2 and
- Kalle Gehring (kalle.gehring{at}mcgill.ca)*,1
- 1Department of Biochemistry and Groupe de recherche axé sur la structure des protéines, McGill University, Montreal, Quebec, Canada
- 2Department of Cellular Regulation, Research Institute for Microbial Diseases Osaka University, Suita, Osaka, Japan
- ↵*
Corresponding author. Tel: +81 6 6879 8293; E‐mail: hmiki{at}biken.osaka-u.ac.jp
Corresponding author. Tel: +1 514 398 7287; E‐mail: kalle.gehring{at}mcgill.ca
↵† These authors contributed equally to this work
The PRL‐CNNM pathway regulates Mg2+ homeostasis and tumor progression. This study shows that the formation of a catalytic phosphocysteine PRL intermediate regulates binding to CNNM magnesium transporters and Mg2+ efflux.
Synopsis
The PRL‐CNNM pathway regulates Mg2+ homeostasis and tumor progression. This study shows that the formation of a catalytic phosphocysteine PRL intermediate regulates binding to CNNM magnesium transporters and Mg2+ efflux.
Phosphatases of regenerating liver (PRLs) bind to CNNM proteins to regulate membrane Mg2+ transport.
Binding is mediated by an aspartic acid on the CNNM CBS‐pair domain that acts as a substrate mimic.
Phosphorylation of the catalytic cysteine of PRLs during the catalytic cycle prevents CNNM binding.
Phosphorylation of PRLs in cultured cells changes in response to Mg2+ availability.
EMBO Reports (2016) 17: 1890–1900
- Received September 22, 2016.
- Revision received October 7, 2016.
- Accepted October 13, 2016.
- © 2016 The Authors
- The integrated stress response
- Karolina Pakos‐Zebrucka1,2,†,
- Izabela Koryga1,2,†,
- Katarzyna Mnich1,2,
- Mila Ljujic1,2,
- Afshin Samali1,2 and
- Adrienne M Gorman (adrienne.gorman{at}nuigalway.ie)*,1,2
- 1Apoptosis Research Centre, National University of Ireland Galway, Galway, Ireland
- 2School of Natural Sciences, National University of Ireland Galway, Galway, Ireland
- ↵*Corresponding author. Tel: +353 91 492417; E‐mail: adrienne.gorman{at}nuigalway.ie
↵† These authors contributed equally to this work
In order to restore cellular homeostasis, stress stimuli activate a common adaptive pathway termed the integrated stress response (ISR). This review highlights the current understanding of ISR pathways and how these regulate cell fate under diverse stress conditions.
EMBO Reports (2016) 17: 1374–1395
- Received February 12, 2016.
- Revision received August 3, 2016.
- Accepted August 23, 2016.
- © 2016 The Authors
- Pharmacological eEF2K activation promotes cell death and inhibits cancer progression
- Aude De Gassart1,
- Olivier Demaria2,
- Rébecca Panes1,
- Léa Zaffalon1,
- Alexey G Ryazanov3,
- Michel Gilliet2 and
- Fabio Martinon (fabio.martinon{at}unil.ch)*,1
- 1Department of Biochemistry, University of Lausanne, Epalinges, Switzerland
- 2Department of Dermatology, CHUV, Lausanne, Switzerland
- 3Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers The State University of New Jersey, Piscataway, NJ, USA
- ↵*Corresponding author. Tel: +41 21 692 5695; E‐mail: fabio.martinon{at}unil.ch
Elongation factor 2 kinase (eEF2K) is part of an adaptation pathway that enables cells to cope with nutrient deprivation by regulating translation rates. Pharmacological activation of the eEF2K pathway via the anti‐viral drug nelfinavir rewires this stress adaptation program into a response that is detrimental for tumor growth.
Synopsis
Elongation factor 2 kinase (eEF2K) is part of an adaptation pathway that enables cells to cope with nutrient deprivation by regulating translation rates. Pharmacological activation of the eEF2K pathway via the anti‐viral drug nelfinavir rewires this stress adaptation program into a response that is detrimental for tumor growth.
The anti‐viral and anti‐tumoral compound nelfinavir is a potent eEF2K activator.
eEF2K activation contributes to NFR‐mediated cell death.
eEF2K deficiency impairs nelfinavir‐mediated antitumoral activity.
EMBO Reports (2016) 17: 1471–1484
- Received February 11, 2016.
- Revision received July 21, 2016.
- Accepted July 22, 2016.
- © 2016 The Authors
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