Signaling Function of Α-Catenin in Microtubule Regulation
Total Page:16
File Type:pdf, Size:1020Kb
Load more
Recommended publications
-
Loss of At-Catenin Alters the Hybrid Adhering Junctions in the Heart and Leads to Dilated Cardiomyopathy and Ventricular Arrhythmia Following Acute Ischemia
1058 Research Article Loss of aT-catenin alters the hybrid adhering junctions in the heart and leads to dilated cardiomyopathy and ventricular arrhythmia following acute ischemia Jifen Li1,*, Steven Goossens2,3,`, Jolanda van Hengel2,3,`, Erhe Gao1, Lan Cheng1, Koen Tyberghein2,3, Xiying Shang1, Riet De Rycke2, Frans van Roy2,3,* and Glenn L. Radice1 1Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, PA, USA 2Department for Molecular Biomedical Research, Flanders Institute for Biotechnology (VIB), B-9052 Ghent, Belgium 3Department of Biomedical Molecular Biology, Ghent University, B-9052 Ghent, Belgium *Authors for correspondence ([email protected]; [email protected]) `These authors contributed equally to this work Accepted 4 October 2011 Journal of Cell Science 125, 1058–1067 ß 2012. Published by The Company of Biologists Ltd doi: 10.1242/jcs.098640 Summary It is generally accepted that the intercalated disc (ICD) required for mechano-electrical coupling in the heart consists of three distinct junctional complexes: adherens junctions, desmosomes and gap junctions. However, recent morphological and molecular data indicate a mixing of adherens junctional and desmosomal components, resulting in a ‘hybrid adhering junction’ or ‘area composita’. The a-catenin family member aT-catenin, part of the N-cadherin–catenin adhesion complex in the heart, is the only a-catenin that interacts with the desmosomal protein plakophilin-2 (PKP2). Thus, it has been postulated that aT-catenin might serve as a molecular integrator of the two adhesion complexes in the area composita. To investigate the role of aT-catenin in the heart, gene targeting technology was used to delete the Ctnna3 gene, encoding aT-catenin, in the mouse. -
Conserved Microtubule–Actin Interactions in Cell Movement and Morphogenesis
REVIEW Conserved microtubule–actin interactions in cell movement and morphogenesis Olga C. Rodriguez, Andrew W. Schaefer, Craig A. Mandato, Paul Forscher, William M. Bement and Clare M. Waterman-Storer Interactions between microtubules and actin are a basic phenomenon that underlies many fundamental processes in which dynamic cellular asymmetries need to be established and maintained. These are processes as diverse as cell motility, neuronal pathfinding, cellular wound healing, cell division and cortical flow. Microtubules and actin exhibit two mechanistic classes of interactions — regulatory and structural. These interactions comprise at least three conserved ‘mechanochemical activity modules’ that perform similar roles in these diverse cell functions. Over the past 35 years, great progress has been made towards under- crosstalk occurs in processes that require dynamic cellular asymme- standing the roles of the microtubule and actin cytoskeletal filament tries to be established or maintained to allow rapid intracellular reor- systems in mechanical cellular processes such as dynamic shape ganization or changes in shape or direction in response to stimuli. change, shape maintenance and intracellular organelle movement. Furthermore, the widespread occurrence of these interactions under- These functions are attributed to the ability of polarized cytoskeletal scores their importance for life, as they occur in diverse cell types polymers to assemble and disassemble rapidly, and to interact with including epithelia, neurons, fibroblasts, oocytes and early embryos, binding proteins and molecular motors that mediate their regulated and across species from yeast to humans. Thus, defining the mecha- movement and/or assembly into higher order structures, such as radial nisms by which actin and microtubules interact is key to understand- arrays or bundles. -
Absence of NEFL in Patient-Specific Neurons in Early-Onset Charcot-Marie-Tooth Neuropathy Markus T
ARTICLE OPEN ACCESS Absence of NEFL in patient-specific neurons in early-onset Charcot-Marie-Tooth neuropathy Markus T. Sainio, MSc, Emil Ylikallio, MD, PhD, Laura M¨aenp¨a¨a, MSc, Jenni Lahtela, PhD, Pirkko Mattila, PhD, Correspondence Mari Auranen, MD, PhD, Johanna Palmio, MD, PhD, and Henna Tyynismaa, PhD Dr. Tyynismaa [email protected] Neurol Genet 2018;4:e244. doi:10.1212/NXG.0000000000000244 Abstract Objective We used patient-specific neuronal cultures to characterize the molecular genetic mechanism of recessive nonsense mutations in neurofilament light (NEFL) underlying early-onset Charcot- Marie-Tooth (CMT) disease. Methods Motor neurons were differentiated from induced pluripotent stem cells of a patient with early- onset CMT carrying a novel homozygous nonsense mutation in NEFL. Quantitative PCR, protein analytics, immunocytochemistry, electron microscopy, and single-cell transcriptomics were used to investigate patient and control neurons. Results We show that the recessive nonsense mutation causes a nearly total loss of NEFL messenger RNA (mRNA), leading to the complete absence of NEFL protein in patient’s cultured neurons. Yet the cultured neurons were able to differentiate and form neuronal networks and neuro- filaments. Single-neuron gene expression fingerprinting pinpointed NEFL as the most down- regulated gene in the patient neurons and provided data of intermediate filament transcript abundancy and dynamics in cultured neurons. Blocking of nonsense-mediated decay partially rescued the loss of NEFL mRNA. Conclusions The strict neuronal specificity of neurofilament has hindered the mechanistic studies of re- cessive NEFL nonsense mutations. Here, we show that such mutation leads to the absence of NEFL, causing childhood-onset neuropathy through a loss-of-function mechanism. -
Conditional Ablation of P130cas/BCAR1 Adaptor Protein
Camacho Leal et al. Cell Communication and Signaling (2018) 16:73 https://doi.org/10.1186/s12964-018-0289-z RESEARCH Open Access Conditional ablation of p130Cas/BCAR1 adaptor protein impairs epidermal homeostasis by altering cell adhesion and differentiation Maria del Pilar Camacho Leal†, Andrea Costamagna†, Beatrice Tassone, Stefania Saoncella, Matilde Simoni, Dora Natalini, Aurora Dadone, Marianna Sciortino, Emilia Turco, Paola Defilippi, Enzo Calautti‡ and Sara Cabodi*‡ Abstract Background: p130 Crk-associated substrate (p130CAS; also known as BCAR1) is a scaffold protein that modulates many essential cellular processes such as cell adhesion, proliferation, survival, cell migration, and intracellular signaling. p130Cas has been shown to be highly expressed in a variety of human cancers of epithelial origin. However, few data are available regarding the role of p130Cas during normal epithelial development and homeostasis. Methods: To this end, we have generated a genetically modified mouse in which p130Cas protein was specifically ablated in the epidermal tissue. Results: By using this murine model, we show that p130Cas loss results in increased cell proliferation and reduction of cell adhesion to extracellular matrix. In addition, epidermal deletion of p130Cas protein leads to premature expression of “late” epidermal differentiation markers, altered membrane E-cadherin/catenin proteins localization and aberrant tyrosine phosphorylation of E-cadherin/catenin complexes. Interestingly, these alterations in adhesive properties in absence -
Catenin Controls Vinculin Binding
ARTICLE Received 4 Feb 2014 | Accepted 25 Jun 2014 | Published 31 Jul 2014 DOI: 10.1038/ncomms5525 Force-dependent conformational switch of a-catenin controls vinculin binding Mingxi Yao1,*, Wu Qiu2,3,*, Ruchuan Liu2,3, Artem K. Efremov1, Peiwen Cong1,4, Rima Seddiki5, Manon Payre5, Chwee Teck Lim1,6, Benoit Ladoux1,5,Rene´-Marc Me`ge5 & Jie Yan1,3,6,7 Force sensing at cadherin-mediated adhesions is critical for their proper function. a-Catenin, which links cadherins to actomyosin, has a crucial role in this mechanosensing process. It has been hypothesized that force promotes vinculin binding, although this has never been demonstrated. X-ray structure further suggests that a-catenin adopts a stable auto-inhibitory conformation that makes the vinculin-binding site inaccessible. Here, by stretching single a- catenin molecules using magnetic tweezers, we show that the subdomains MI vinculin- binding domain (VBD) to MIII unfold in three characteristic steps: a reversible step at B5pN and two non-equilibrium steps at 10–15 pN. 5 pN unfolding forces trigger vinculin binding to the MI domain in a 1:1 ratio with nanomolar affinity, preventing MI domain refolding after force is released. Our findings demonstrate that physiologically relevant forces reversibly unfurl a- catenin, activating vinculin binding, which then stabilizes a-catenin in its open conformation, transforming force into a sustainable biochemical signal. 1 Mechanobiology Institute, National University of Singapore, Singapore 117411, Singapore. 2 Department of Physics, National University of Singapore, Singapore 117542, Singapore. 3 College of Physics, Chongqing University, No. 55 Daxuecheng South Road, Chongqing 401331, China. 4 Singapore-MIT Alliance for Research and Technology, National University of Singapore, Singapore 117543, Singapore. -
Microtubule-Associated Protein Tau (Molecular Pathology/Neurodegenerative Disease/Neurofibriliary Tangles) M
Proc. Nati. Acad. Sci. USA Vol. 85, pp. 4051-4055, June 1988 Medical Sciences Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: Identification as the microtubule-associated protein tau (molecular pathology/neurodegenerative disease/neurofibriliary tangles) M. GOEDERT*, C. M. WISCHIK*t, R. A. CROWTHER*, J. E. WALKER*, AND A. KLUG* *Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, United Kingdom; and tDepartment of Psychiatry, University of Cambridge Clinical School, Hills Road, Cambridge CB2 2QQ, United Kingdom Contributed by A. Klug, March 1, 1988 ABSTRACT Screening of cDNA libraries prepared from (21). This task is made all the more difficult because there is the frontal cortex ofan zheimer disease patient and from fetal no functional or physiological assay for the protein(s) of the human brain has led to isolation of the cDNA for a core protein PHF. The only identification so far possible is the morphol- of the paired helical fiament of Alzheimer disease. The partial ogy of the PHFs at the electron microscope level, and here amino acid sequence of this core protein was used to design we would accept only experiments on isolated individual synthetic oligonucleotide probes. The cDNA encodes a protein of filaments, not on neurofibrillary tangles (in which other 352 amino acids that contains a characteristic amino acid repeat material might be occluded). One thus needs a label or marker in its carboxyl-terminal half. This protein is highly homologous for the PHF itself, which can at the same time be used to to the sequence ofthe mouse microtubule-assoiated protein tau follow the steps of the biochemical purification. -
A Unique and Specific Interaction Between Αt-Catenin and Plakophilin
2126 Research Article A unique and specific interaction between ␣T-catenin and plakophilin-2 in the area composita, the mixed-type junctional structure of cardiac intercalated discs Steven Goossens1,2,*, Barbara Janssens1,2,*,‡, Stefan Bonné1,2,§, Riet De Rycke1,2, Filip Braet1,2,¶, Jolanda van Hengel1,2 and Frans van Roy1,2,** 1Department for Molecular Biomedical Research, VIB and 2Department of Molecular Biology, Ghent University, B-9052 Ghent, Belgium *These authors contributed equally to this work ‡Present address: Wiley-VCH, Boschstrasse 12, D-69469 Weinheim, Germany §Present address: Diabetes Research Center, Brussels Free University (VUB), Laarbeeklaan 103, B-1090 Brussels, Belgium ¶Present address: Australian Key Centre for Microscopy and Microanalysis, The University of Sydney, NSW 2006, Australia **Author for correspondence (e-mail: [email protected]) Accepted 24 April 2007 Journal of Cell Science 120, 2126-2136 Published by The Company of Biologists 2007 doi:10.1242/jcs.004713 Summary Alpha-catenins play key functional roles in cadherin- desmosomal proteins in the heart localize not only to the catenin cell-cell adhesion complexes. We previously desmosomes in the intercalated discs but also at adhering reported on ␣T-catenin, a novel member of the ␣-catenin junctions with hybrid composition. We found that in the protein family. ␣T-catenin is expressed predominantly in latter junctions, endogenous plakophilin-2 colocalizes with cardiomyocytes, where it colocalizes with ␣E-catenin at the ␣T-catenin. By providing an extra link between the intercalated discs. Whether ␣T- and ␣E-catenin have cadherin-catenin complex and intermediate filaments, the specific or synergistic functions remains unknown. In this binding of ␣T-catenin to plakophilin-2 is proposed to be a study we used the yeast two-hybrid approach to identify means of modulating and strengthening cell-cell adhesion specific functions of ␣T-catenin. -
Neurofilaments: Neurobiological Foundations for Biomarker Applications
Neurofilaments: neurobiological foundations for biomarker applications Arie R. Gafson1, Nicolas R. Barthelmy2*, Pascale Bomont3*, Roxana O. Carare4*, Heather D. Durham5*, Jean-Pierre Julien6,7*, Jens Kuhle8*, David Leppert8*, Ralph A. Nixon9,10,11,12*, Roy Weller4*, Henrik Zetterberg13,14,15,16*, Paul M. Matthews1,17 1 Department of Brain Sciences, Imperial College, London, UK 2 Department of Neurology, Washington University School of Medicine, St Louis, MO, USA 3 a ATIP-Avenir team, INM, INSERM , Montpellier university , Montpellier , France. 4 Clinical Neurosciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, United Kingdom 5 Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Québec, Canada 6 Department of Psychiatry and Neuroscience, Laval University, Quebec, Canada. 7 CERVO Brain Research Center, 2601 Chemin de la Canardière, Québec, QC, G1J 2G3, Canada 8 Neurologic Clinic and Policlinic, Departments of Medicine, Biomedicine and Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland. 9 Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY, 10962, USA. 10Departments of Psychiatry, New York University School of Medicine, New York, NY, 10016, 11 Neuroscience Institute, New York University School of Medicine, New York, NY, 10016, USA. 12Department of Cell Biology, New York University School of Medicine, New York, NY, 10016, USA 13 University College London Queen Square Institute of Neurology, London, UK 14 UK Dementia Research Institute at University College London 15 Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden 16 Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden 17 UK Dementia Research Institute at Imperial College, London * Co-authors ordered alphabetically Address for correspondence: Prof. -
Altered Distribution of ß-Catenin, and Its Binding Proteins E-Cadherin And
Altered Distribution of -Catenin, and Its Binding Proteins E-Cadherin and APC, in Ulcerative Colitis–Related Colorectal Cancers Daniela E. Aust, M.D., Jonathan P. Terdiman, M.D., Robert F. Willenbucher, M.D., Karen Chew, C.T. (A.S.C.P.), Linda Ferrell, M.D., Carmina Florendo, B.S., Annette Molinaro-Clark, M.A., Gustavo B. Baretton, M.D., Ph.D, Udo Löhrs, M.D., Ph.D, Frederic M. Waldman, M.D., Ph.D Cancer Center (DA, KC, CF, AC, FW) and Departments of Laboratory Medicine (FW), Medicine (RW, JT), and Pathology (LF), University of California San Francisco, San Francisco, California; and Pathologisches Institut der Ludwig-Maximilians-Universität, München, Germany (GB, UL) related and sporadic colorectal cancers suggest that The -catenin pathway plays a central role in tran- the specific alterations in this pathway may differ in scriptional signaling and cell–cell interactions in these two cancer groups. colonic epithelium. Alterations of the expression of -catenin, and its binding partners E-cadherin and KEY WORDS: APC, -catenin, Colorectal cancer, the adenomatous polyposis coli protein (APC), are E-cadherin, Immunohistochemistry, Ulcerative frequent events in sporadic colorectal cancer. Ulcer- colitis. ative colitis (UC)–related cancers originate in a field Mod Pathol 2001;14(1):29–39 of chronic inflammation and therefore may have  different alterations in the -catenin pathway than -catenin is a multifunctional protein that is involved sporadic cancers. To test this hypothesis, expres- in cell–cell interaction and transcriptional signaling  sion and subcellular localization of -catenin, (1–5). -catenin expression is largely regulated by its E-cadherin, and APC were detected by immunohis- two major binding partners, E-cadherin on the mem- tochemistry in paraffin sections from 33 UC-related brane and the adenomatous polyposis coli (APC) and 42 sporadic colorectal cancers. -
The Role of the Actin Cytoskeleton During Muscle Development In
THE ROLE OF THE ACTIN CYTOSKELETON DURING MUSCLE DEVELOPMENT IN DROSOPHILA AND MOUSE by Shannon Faye Yu A Dissertation Presented to the Faculty of the Louis V. Gerstner, Jr. Graduate School of the Biomedical Sciences in Partial Fulfillment of the Requirements of the Degree of Doctor of Philosophy New York, NY Oct, 2013 Mary K. Baylies, PhD! Date Dissertation Mentor Copyright by Shannon F. Yu 2013 ABSTRACT The actin cytoskeleton is essential for many processes within a developing organism. Unsurprisingly, actin and its regulators underpin many of the critical steps in the formation and function of muscle tissue. These include cell division during the specification of muscle progenitors, myoblast fusion, muscle elongation and attachment, and muscle maturation, including sarcomere assembly. Analysis in Drosophila has focused on regulators of actin polymerization particularly during myoblast fusion, and the conservation of many of the actin regulators required for muscle development has not yet been tested. In addition, dynamic actin processes also require the depolymerization of existing actin fibers to replenish the pool of actin monomers available for polymerization. Despite this, the role of actin depolymerization has not been described in depth in Drosophila or mammalian muscle development. ! Here, we first examine the role of the actin depolymerization factor Twinstar (Tsr) in muscle development in Drosophila. We show that Twinstar, the sole Drosophila member of the ADF/cofilin family of actin depolymerization proteins, is expressed in muscle where it is essential for development. tsr mutant embryos displayed a number of muscle defects, including muscle loss and muscle misattachment. Further, regulators of Tsr, including a Tsr-inactivating kinase, Center divider, a Tsr-activating phosphatase, Slingshot and a synergistic partner in depolymerization, Flare, are also required for embryonic muscle development. -
The Relationship Between Intermediate Filaments and Microfilaments Before and During the Formation of Desmosomes and Adherens-Ty
Published May 1, 1987 The Relationship between Intermediate Filaments and Microfilaments before and during the Formation of Desmosomes and Adherens-type Junctions in Mouse Epidermal Keratinocytes Kathleen J. Green, Benjamin Geiger,* Jonathan C. R. Jones, John C. Talian, and Robert D. Goldman Department of Cell Biology and Anatomy, Northwestern University Medical School, Chicago, Illinois 60611; and * Department of Chemical Immunology, The Weizmann Institute of Science, Rehovot, Israel Abstract. Actin, keratin, vinculin and desmoplakin ermost of the concentric MFB. Individual IF often organization were studied in primary mouse keratino- splay out, becoming interwoven into these MFB in the cytes before and during Ca2+-induced cell contact forma- region of cell-substrate contact. In the first 30 min af- tion. Double-label fluorescence shows that in cells cul- ter the Ca 2+ switch, areas of submembranous dense Downloaded from tured in low Ca 2÷ medium, keratin-containing inter- material (identified as adherens junctions), which are mediate filament bundles (IFB) and desmoplakin- associated with the perpendicular MFB, can be seen at containing spots are both concentrated towards the cell newly formed cell-ceU contact sites. By 1-2 h, IFB- center in a region bounded by a series of concentric desmosomal component complexes are aligned with microfilament bundles (MFB). Within 5-30 min after the perpendicular MFB as the complexes become jcb.rupress.org raising Ca 2+ levels, a discontinuous actin/vinculin-rich, redistributed to cell-cell interfaces. Cytochalasin D submembranous zone of fluorescence appears at cell- treatment causes the redistribution of actin into numer- cell interfaces. This zone is usually associated with ous patches; keratin-containing Lr:B undergo a con- short, perpendicular MFB, which become wider and comitant redistribution, forming foci that coincide with longer with time. -
Nuclear Expression of E-Cadherin in Solid Pseudopapillary Tumors of the Pancreas
JOP. J Pancreas (Online) 2007; 8(3):296-303. ORIGINAL ARTICLE Nuclear Expression of E-Cadherin in Solid Pseudopapillary Tumors of the Pancreas Stefano Serra1, Sima Salahshor2, Mosa Fagih1, Firouzeh Niakosari1, Jasim M Radhi3, Runjan Chetty1 1Department of Pathology, University Health Network/Toronto Medical Laboratories. Toronto, Canada. 2Samuel Lunenfeld Research Institute, Centre for Systems Biology, University of Toronto. Toronto, Canada. 3Department of Pathology and Molecular Medicine, McMaster University. Hamilton, Canada ABSTRACT trypsin diffusely positive (50% or more of the tumor cells staining) and CD56 showed focal Context Solid pseudopapillary tumors of the positivity in all cases with 5-10% of tumor pancreas are rare and have recently been cells displaying immunolabeling. All cases shown to harbor mutations of the beta-catenin were negative for chromogranin and gene with resultant nuclear localization of synaptophysin. All 18 cases displayed beta-catenin protein to the nucleus. Moreover, cytoplasmic and nuclear localization of beta- there is a close relationship between beta- catenin protein. Similarly, E-cadherin protein catenin and E-cadherin. was localized to the nucleus in all 18 cases, Objective To explore the protein expression with loss of the characteristic membranous of E-cadherin in a series of solid pseudo- decoration of cells. papillary tumors of the pancreas. Conclusion This study is the first Participants Eighteen cases of solid demonstration of aberrant nuclear localization pseudopapillary tumors of the pancreas. of E-cadherin protein in solid pseudopapillary tumors of the pancreas. Whilst the exact Design The cases were studied using a tissue mechanism is not know and nuclear E- microarray that was constructed as follows: cadherin is not related to tumor aggression, for each case, 4 to 14 cores measuring 1.0 mm this staining pattern may be of diagnostic each were drilled from the blocks.