Cell Adhesion, Polarity & Cytoskeleton
- E‐cadherin can limit the transforming properties of activating β‐catenin mutations
- David J Huels1,†,
- Rachel A Ridgway1,†,
- Sorina Radulescu1,
- Marc Leushacke2,
- Andrew D Campbell1,
- Sujata Biswas3,4,
- Simon Leedham3,4,
- Stefano Serra5,
- Runjan Chetty5,
- Guenievre Moreaux1,
- Lee Parry6,
- James Matthews6,
- Fei Song7,
- Ann Hedley1,
- Gabriela Kalna1,
- Fatih Ceteci1,
- Karen R Reed6,
- Valerie S Meniel6,
- Aoife Maguire8,
- Brendan Doyle1,8,
- Ola Söderberg9,
- Nick Barker2,
- Alastair Watson10,
- Lionel Larue11,
- Alan R Clarke6 and
- Owen J Sansom*,1
- 1Cancer Research UK Beatson Institute, Glasgow, UK
- 2A∗STAR Institute of Medical Biology, Singapore City, Singapore
- 3Gastrointestinal Stem Cell Biology Laboratory, Wellcome Trust Centre for Human Genetics University of Oxford, Oxford, UK
- 4Translational Gastroenterology Unit, Experimental Medicine Division, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford, Headington, UK
- 5Department of Pathology, University Health Network/Toronto Medical Laboratories, Toronto, Canada
- 6European Cancer Stem Cell Research Institute, Cardiff University, Cardiff, UK
- 7Institute of Physiology, Justus‐Liebig University Giessen, Giessen, Germany
- 8Department of Histopathology, Trinity College Dublin St James's Hospital, Dublin, Ireland
- 9Department of Immunology, Genetics and Pathology Science for Life Laboratory, BMC Uppsala University, Uppsala, Sweden
- 10Norwich Medical School, University of East Anglia, Norwich, UK
- 11Institut Curie, CNRS UMR3347 INSERM, U1021 Equipe labellisée – Ligue Nationale contre le Cancer, Orsay, France
- ↵*Corresponding author. Tel: +44 141 330 3953; Fax: +44 141 942 6521; E‐mail: o.sansom{at}beatson.gla.ac.uk
↵† These authors contributed equally to this study
In contrast to other Wnt‐driven malignancies colorectal cancer is usually linked to APC loss, and very rarely to β‐catenin activating mutations. Different E‐cadherin levels can explain the variation in transforming potential of β‐catenin mutations in different tumors.
Synopsis
In contrast to other Wnt‐driven malignancies colorectal cancer is usually linked to APC loss, and very rarely to β‐catenin activating mutations. Different E‐cadherin levels can explain the variation in transforming potential of β‐catenin mutations in different tumors.
Activating β‐catenin mutations in the mouse small intestine but not the colon lead to Wnt‐activation.
Increased E‐cadherin levels can buffer mutated β‐catenin in the colon epithelium.
β‐catenin activating mutations are linked to human cancers that show reduced levels of E‐cadherin.
The EMBO Journal (2015) 34: 2321–2333
- Received April 8, 2015.
- Revision received June 23, 2015.
- Accepted July 1, 2015.
- © 2015 Cancer Research UK Beatson Institute. 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.
- Cell cycle‐dependent ubiquitylation and destruction of NDE1 by CDK5‐FBW7 regulates ciliary length
- Dipak Maskey1,
- Matthew Caleb Marlin2,
- Seokho Kim1,
- Sehyun Kim1,3,
- E‐Ching Ong1,
- Guangpu Li2 and
- Leonidas Tsiokas*,1
- 1Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- 2Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- 3Laboratory of Pediatric Brain Disease, The Rockefeller University, New York, NY, USA
- ↵*Corresponding author. Tel: +1 405 271 8001 ext. 46211; E‐mail: ltsiokas{at}ouhsc.edu
Quiescence‐specific kinase CDK5 initiates NDE1 degradation to couple cell cycle state to length control of primary cilia.
Synopsis
Biogenesis and disassembly of primary cilia are coupled to the cell cycle by incompletely understood mechanisms. This study identifies such a link, by which a quiescence‐specific kinase controls the levels of a negative regulator of ciliary length.
Primary cilia are formed in quiescent cells.
NDE1, a negative regulator of ciliary length, is downregulated in quiescent cells.
CDK5, a kinase active in quiescent cells, phosphorylates NDE1 within an FBW7‐specific phosphodegron.
The FBW7 E3 ligase recognizes and targets phosphorylated NDE1 for degradation via the ubiquitin–proteasome system.
Destruction of NDE1 in G1/G0 allows cilia to reach their proper length.
The EMBO Journal (2015) 34: 2424–2440
- Received December 17, 2014.
- Revision received June 7, 2015.
- Accepted June 29, 2015.
- © 2015 The Authors
- Optochemistry to control the microtubule cytoskeleton
Microtubule drugs have a wide range of applications in cell biology research as well as cancer therapy; however their application was so far limited to the treatment of entire cell populations and tissues. In a recent paper in Cell, Borowiak et al (2015) now describe a novel type of switchable microtubule drugs. The activity of their drugs, denoted as “photostatins”, can be switched on and off by violet and green light, respectively, which allows for the first time a precise spatial and temporal control of the microtubule cytoskeleton in single cells and tissues.
See also: M Borowiak et al (July 2015)
Use of microtubule drugs is limited by their toxicity and the inability to precisely control spatial and temporal parameters of treatment. A recent report in Cell describes drugs—photostatins—that can be activated and deactivated by light to achieve precise spatiotemporal control.
- © 2015 The Authors
- JNK‐dependent gene regulatory circuitry governs mesenchymal fate
- Sanjeeb Kumar Sahu1,
- Angela Garding1,
- Neha Tiwari2,
- Sudhir Thakurela1,
- Joern Toedling1,
- Susanne Gebhard3,
- Felipe Ortega2,
- Nikolai Schmarowski4,
- Benedikt Berninger2,
- Robert Nitsch4,
- Marcus Schmidt3 and
- Vijay K Tiwari*,1
- 1Institute of Molecular Biology (IMB), Mainz, Germany
- 2Institute of Physiological Chemistry University Medical Center Johannes Gutenberg University, Mainz, Germany
- 3Department of Obstetrics and Gynecology, Johannes Gutenberg University, Mainz, Germany
- 4Institute for Microscopic Anatomy and Neurobiology University Medical Center Johannes Gutenberg University, Mainz, Germany
- ↵*Corresponding author. Tel: +49 6131 39 21460; E‐mail: v.tiwari{at}imb-mainz.de
Combining transcriptome analysis and patient data this study illustrates how JNK signaling drives EMT progression via a panel of specific transcription factors, several of which are linked to EMT for the first time.
Synopsis
Combining transcriptome analysis and patient data, this study illustrates how JNK signaling drives EMT progression via a panel of specific transcription factors, several of which are linked to EMT for the first time.
JNK signaling is essential for progression of epithelial to mesenchymal transition (EMT).
EMT relies on JNK‐dependent transcriptional reprogramming of many crucial EMT genes.
JNK‐induced novel transcription factors are critically required for acquisition and maintenance of the mesenchymal fate.
These novel factors are highly expressed in invasive cancer cells where they function in gene regulation to maintain metastatic identity.
These factors were also induced during neuronal development and function in neuronal migration in vivo.
The EMBO Journal (2015) 34: 2162–2181
- Received November 28, 2014.
- Revision received June 4, 2015.
- Accepted June 5, 2015.
- © 2015 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.
- Blocking integrin inactivation as an anti‐angiogenic therapy
During angiogenesis, endothelial cell migration is coordinated by integrin‐mediated contact with the extra‐cellular matrix (ECM), coupled with receptor tyrosine kinase signalling to regulate dynamic cytoskeletal and plasma membrane reorganization. A recent paper by Vitorino et al (2015) defined a new MAP4K4–moesin–talin–β1‐integrin pathway that could be therapeutically exploited to suppress pathologic angiogenesis.
See also: P Vitorino et al (March 2015)
A recent study in Nature reports on the discovery of a MAP4K4‐dependent mechanism for integrin inactivation and endothelial cell migration. This leads the authors to pharmacological exploration for anti‐angiogenic therapies.
- © 2015 The Authors
- Plasmolipin—a new player in endocytosis and epithelial development
Polarized vesicle sorting is essential not only for epithelial cell function but also for cell polarization and tissue morphogenesis. Endocytosis is a key determinant of the surface abundance of plasma membrane proteins and is highly regulated. In an important recent paper, Rodríguez‐Fraticelli et al (2015) identify a new player in apical endocytosis—a previously uncharacterized protein called Plasmolipin. They report not only its mechanism of action through binding to an epsin, but also highlight an essential role in regulating Notch signaling, which controls epithelial differentiation.
See also: AE Rodríguez-Fraticelli et al (March 2015)
Plasmolipin is a novel component of the apical endocytosis machinery that not only controls proper epithelial polarization, but is also involved in intestinal cell fate specification in zebrafish through the control of Notch signaling.
- © 2015 The Authors
- X‐ray and Cryo‐EM structures reveal mutual conformational changes of Kinesin and GTP‐state microtubules upon binding
- Manatsu Morikawa1,2,
- Hiroaki Yajima1,2,
- Ryo Nitta1,2,5,
- Shigeyuki Inoue1,2,
- Toshihiko Ogura3,
- Chikara Sato3 and
- Nobutaka Hirokawa*,1,2,4
- 1Department of Cell Biology and Anatomy, The University of Tokyo, Hongo Tokyo, Japan
- 2Department of Molecular Structure and Dynamics, Graduate School of Medicine, The University of Tokyo, Hongo Tokyo, Japan
- 3Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba Ibaraki, Japan
- 4Center of Excellence in Genomic Medicine Research (CEGMR), KAU, Jeddah, Saudi Arabia
- 5Center for Life Science Technologies, RIKEN, Yokohama, Kanagawa, Japan
- ↵*Corresponding author. Tel: +81 3 5841 3326; E‐mail: hirokawa{at}m.u-tokyo.ac.jp
Cryo‐EM and crystal structures of nucleotide‐free KIF5C with and without microtubules reveal their mutual conformational changes, providing insight into the preferential binding of KIF5C to GTP‐state microtubules that is crucial for polarized axonal transport in neurons.
Synopsis
Cryo‐EM and crystal structures of nucleotide‐free KIF5C with and without microtubules reveal their mutual conformational changes, providing insight into the preferential binding of KIF5C to GTP‐state microtubules that is crucial for polarized axonal transport in neurons.
Loop L11 of KIF5 recognizes and binds to GTP‐state microtubules, triggering conformational changes in both KIF5 and microtubules.
Under these conditions, KIF5 acquires a novel rigor conformation that favours effective ADP release.
Reciprocally, KIF5 binding causes a switch in the tubulin conformation and strengthens the microtubule lattice.
The EMBO Journal (2015) 34: 1270–1286
- Received November 18, 2014.
- Revision received January 17, 2015.
- Accepted February 13, 2015.
- © 2015 The Authors
- Chemokine‐guided cell migration and motility in zebrafish development
- 1Institute of Cell Biology, ZMBE, University of Münster, Münster, Germany
- 2Gorlaeus Laboratories, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands
- 3Gorlaeus Laboratories, Department of Molecular Cell Biology, Institute of Biology, Leiden University, Leiden, The Netherlands
- ↵*Corresponding author. Tel: +49 251 83 58606: E‐mail: erez.raz{at}uni-muenster.de
Chemokines are vertebrate‐specific molecules with a wide range of activities in different aspects of animal physiology. Bussmann and Raz review here their involvement in single and collective cell migration in zebrafish.
The EMBO Journal (2015) 34: 1309–1318
- Received September 18, 2014.
- Revision received February 2, 2015.
- Accepted February 4, 2015.
- © 2015 The Authors
- Cyclin O (Ccno) functions during deuterosome‐mediated centriole amplification of multiciliated cells
- Maja C Funk1,2,
- Agata N Bera1,3,
- Tabea Menchen4,
- Georg Kuales1,
- Kerstin Thriene5,
- Soeren S Lienkamp1,3,
- Jörn Dengjel3,5,
- Heymut Omran4,
- Marcus Frank6 and
- Sebastian J Arnold*,1,3
- 1University Medical Centre, Renal Department, Centre for Clinical Research, Freiburg, Germany
- 2Spemann Graduate School of Biology and Medicine, Freiburg, Germany
- 3BIOSS Centre of Biological Signalling Studies, Albert‐Ludwigs‐University, Freiburg, Germany
- 4Department of Pediatrics, University Hospital Muenster, Muenster, Germany
- 5Department of Dermatology, ZBSA Centre for Biological Systems Analysis, Medical Centre University of Freiburg, Freiburg, Germany
- 6Medical Biology and Electron Microscopy Centre, University Medicine Rostock, Rostock, Germany
- ↵*Corresponding author. Tel: +49 761 270 63120; E‐mail: sebastian.arnold{at}uniklinik-freiburg.de
Cyclin O mutations cause congenital mucociliary clearance disorder linked to a reduced number of motile cilia in the airway epithelium. This is caused by malfunctioning deuterosomes that lead to fewer and partially defective centrioles.
Synopsis
Cyclin O mutations cause congenital mucociliary clearance disorder linked to a reduced number of motile cilia in the airway epithelium. This is caused by malfunctioning deuterosomes that lead to fewer and partially defective centrioles.
Ccno is expressed early in the embryonic node, and in respiratory and ependymal multiciliated cells (MCCs) later on.
MCCs lacking Ccno generate fewer centrioles that often fail to dock to the plasma membrane, resulting in fewer motile cilia.
Deuterosomes of Ccno‐deficient MCCs are enlarged in size, reduced in number and functionally compromised.
These deuterosomes generate fewer and partially non‐functional centrioles.
The EMBO Journal (2015) 34: 1078–1089
- Received July 20, 2014.
- Revision received January 23, 2015.
- Accepted January 27, 2015.
- © 2015 The Authors
- The Spectrin cytoskeleton regulates the Hippo signalling pathway
- Georgina C Fletcher1,†,
- Ahmed Elbediwy1,†,
- Ichha Khanal1,†,
- Paulo S Ribeiro2,3,†,
- Nic Tapon*,2 and
- Barry J Thompson*,1
- 1Epithelial Biology Laboratory, Cancer Research UK – London Research Institute, London, UK
- 2Apoptosis and Cell Proliferation Laboratory, Cancer Research UK – London Research Institute, London, UK
- 3Barts Cancer Institute, Queen Mary University of London, London, UK
- ↵*
Corresponding author. E‐mail: nic.tapon{at}cancer.org.uk
Corresponding author. Tel: +44 207 269 3353; E‐mail: barry.thompson{at}cancer.org.uk
-
↵† These authors contributed equally to this work
In Drosophila, both the apical and the basolateral Spectrin cytoskeleton are able to activate the Hippo signaling pathway in a tissue‐dependent manner. In cultured human cells this depends on cell density, suggesting a role for Spectrins in mechanosensing.
Synopsis
In Drosophila, both the apical and the basolateral Spectrin cytoskeleton are able to activate the Hippo signaling pathway in a tissue‐dependent manner. In cultured human cells this depends on cell density, suggesting a role for Spectrins in mechanosensing.
The Spectrin cytoskeleton is required for Hippo signalling in Drosophila.
Loss of Spectrins causes mild tissue overgrowth.
Apical Spectrins bind to Expanded, Merlin and Kibra.
Spectrins are potential mechanosensors.
The EMBO Journal (2015) 34: 940–954
- Received July 29, 2014.
- Revision received January 15, 2015.
- Accepted January 21, 2015.
- © 2015 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.
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