Cell Adhesion, Polarity & Cytoskeleton
- PTPRN2 and PLCβ1 promote metastatic breast cancer cell migration through PI(4,5)P2‐dependent actin remodeling
- ↵*Corresponding author. Tel: +1 212 327 208; Fax: +1 212 327 7209; E‐mail: stavazoie{at}rockefeller.edu
The phosphatidylinositol phosphatase activity harboring protein tyrosine phosphatase PTPRN2 and the phospholipase PLCβ1 are overexpressed in breast cancer. Both enzymes reduce plasma membrane PI(4,5)P2 levels, thereby enhancing cofilin‐mediated actin remodeling and breast cancer metastasis.
Synopsis
The phosphatidylinositol phosphatase activity harboring protein tyrosine phosphatase PTPRN2 and the phospholipase PLCβ1 are overexpressed in breast cancer. Both enzymes reduce plasma membrane PI(4,5)P2 levels, thereby enhancing cofilin‐mediated actin remodeling and breast cancer metastasis.
Increased expression of PTPRN2 and PLCβ1 clinically correlates with breast cancer metastasis.
PTPRN2 and PLCβ1 promote breast cancer cell migration.
PTPRN2 and PLCβ1 modulate plasma membrane PI(4,5)P2 levels to promote actin remodeling.
The EMBO Journal (2016) 35: 62–76
- Received May 6, 2015.
- Revision received October 16, 2015.
- Accepted October 19, 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.
- Formation of the transition zone by Mks5/Rpgrip1L establishes a ciliary zone of exclusion (CIZE) that compartmentalises ciliary signalling proteins and controls PIP2 ciliary abundance
- Victor L Jensen1,
- Chunmei Li1,
- Rachel V Bowie2,
- Lara Clarke2,
- Swetha Mohan1,
- Oliver E Blacque2 and
- Michel R Leroux*,1
- 1Department of Molecular Biology and Biochemistry and Centre for Cell Biology, Development and Disease, Simon Fraser University, Burnaby, BC, Canada
- 2School of Biomolecular and Biomedical Science, University College Dublin, Belfield, Dublin 4, Ireland
- ↵*Corresponding author. Tel: +1 778 782 6683; Fax: +1 778 782 5583; E‐mail: leroux{at}sfu.ca
Caenorhabditis elegans MKS‐5 (mammalian RPGRIP1L) is required for formation of the ciliary transition zone. MKS‐5 acts to exclude membrane‐associated signalling proteins from the TZ and limits PIP2 ciliary abundance.
Synopsis
Caenorhabditis elegans MKS‐5, the orthologue of mammalian RPGRIP1L and RPGRIP1, is required for formation of the ciliary transition zone (TZ), a subdomain at the base of the cilium that functions as a gate, or membrane diffusion barrier. MKS‐5 acts to exclude membrane‐associated signalling proteins from the TZ and limits PIP2 ciliary abundance, which together helps to create an optimal, discrete ciliary signalling compartment.
Disruption of MKS‐5 results in loss of all identified proteins from the TZ, and loss of TZ ultrastructure (including Y‐links).
MKS‐5 may act as an assembly factor, rather than a “scaffold” for the incorporation of MKS and NPHP module proteins within the TZ.
MKS and NPHP module components function redundantly within the basal body transition fibres and TZ Y‐links.
MKS‐5, and thus the TZ, creates a ciliary zone of exclusion (CIZE) that compartmentalises signalling proteins to the distal domains of the axoneme.
MKS‐5 is required for restricting PIP2 ciliary abundance, suggesting that the TZ acts as a lipid gate or barrier.
The EMBO Journal (2015) 34: 2537–2556
- Received January 27, 2014.
- Revision received August 22, 2015.
- Accepted August 26, 2015.
- © 2015 The Authors
- Cancer: leaping the E‐cadherin hurdle
Aberrant activation of the Wnt signaling pathway is a common cause of colon cancer and other tumor types, accomplishing many of the hallmarks of cancer including sustained proliferative signaling, replicative immortality, reprogrammed metabolism, angiogenesis, and invasion. Yet, the dominant mutation that leads to chronic Wnt signaling in colon cancer is quite different from the spectrum of mutations that activate Wnt signaling in other tumor types. In this issue of The EMBO Journal, Huels et al (2015) focus on the influential role E‐cadherin plays in shaping these differences.
See also: DJ Huels et al (September 2015)
E‐cadherin levels determine the barrier for aberrant β‐catenin activation in colon cancer, providing an explanation for the different spectrum of mutations in the Wnt pathway associated with colon cancer as compared to other tumor types.
- © 2015 The Authors
- Collaborative protein filaments
- 1MRC Laboratory of Molecular Biology, Cambridge, UK
- 2Division of Biology, California Institute of Technology, Pasadena, CA, USA
- ↵*Corresponding author. Tel: +1 626 3958848; E‐mail: dghosal{at}caltech.edu
Bacterial protein filaments can assemble on their own as part of the cytoskeleton, or alternatively may require an scaffolding matrix. The latter, now called collaborative filaments, are conserved and are known to be involved in critical cellular functions, such as cell division.
The EMBO Journal (2015) 34: 2312–2320
- Received April 9, 2015.
- Revision received May 28, 2015.
- Accepted July 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.
- The tumor suppressor FBW7 controls ciliary length
The primary cilium provides a hub for reception of extracellular chemical and mechanical cues that influence differentiation, proliferation, and polarity, and contributes to cell cycle control. Ciliary length impacts the cilium's ability to coordinate these processes, and length control defects are linked to a number of clinically important developmental disorders. An exciting new study identifies a new mechanism of ciliary regulation based on interactions of CDK5 and the FBW7 tumor suppressor in regulating the degradation of the centrosomal protein NDE1 (Maskey et al, 2015).
See also: D Maskey et al (October 2015)
New work reveals ubiquitin‐dependent degradation of NDE1 as a mechanism linking cell cycle stage to ciliogenesis.
- © 2015 The Authors
- 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
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