Non Diaphanous Formin Delphilin Acts As a Barbed End Capping Protein
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Snapshot: Formins Christian Baarlink, Dominique Brandt, and Robert Grosse University of Marburg, Marburg 35032, Germany
SnapShot: Formins Christian Baarlink, Dominique Brandt, and Robert Grosse University of Marburg, Marburg 35032, Germany Formin Regulators Localization Cellular Function Disease Association DIAPH1/DIA1 RhoA, RhoC Cell cortex, Polarized cell migration, microtubule stabilization, Autosomal-dominant nonsyndromic deafness (DFNA1), myeloproliferative (mDia1) phagocytic cup, phagocytosis, axon elongation defects, defects in T lymphocyte traffi cking and proliferation, tumor cell mitotic spindle invasion, defects in natural killer lymphocyte function DIAPH2 Cdc42 Kinetochore Stable microtubule attachment to kinetochore for Premature ovarian failure (mDia3) chromosome alignment DIAPH3 Rif, Cdc42, Filopodia, Filopodia formation, removing the nucleus from Increased chromosomal deletion of gene locus in metastatic tumors (mDia2) Rac, RhoB, endosomes erythroblast, endosome motility, microtubule DIP* stabilization FMNL1 (FRLα) Cdc42 Cell cortex, Phagocytosis, T cell polarity Overexpression is linked to leukemia and non-Hodgkin lymphoma microtubule- organizing center FMNL2/FRL3/ RhoC ND Cell motility Upregulated in metastatic colorectal cancer, chromosomal deletion is FHOD2 associated with mental retardation FMNL3/FRL2 Constituently Stress fi bers ND ND active DAAM1 Dishevelled Cell cortex Planar cell polarity ND DAAM2 ND ND ND Overexpressed in schizophrenia patients Human (Mouse) FHOD1 ROCK Stress fi bers Cell motility FHOD3 ND Nestin, sarcomere Organizing sarcomeres in striated muscle cells Single-nucleotide polymorphisms associated with type 1 diabetes -
Identification of a WNT5A-Responsive Degradation Domain in the Kinesin
G C A T T A C G G C A T genes Article Identification of a WNT5A-Responsive Degradation Domain in the Kinesin Superfamily Protein KIF26B Edith P. Karuna ID , Shannon S. Choi, Michael K. Scales, Jennie Hum, Michael Cohen, Fernando A. Fierro and Hsin-Yi Henry Ho * ID Department of Cell Biology and Human Anatomy, School of Medicine, University of California, Davis, CA 95616, USA; [email protected] (E.P.K.); [email protected] (S.S.C.); [email protected] (M.K.S.); [email protected] (J.H.); [email protected] (M.C.); ffi[email protected] (F.A.F.) * Correspondence: [email protected]; Tel.: +1-530-752-8857 Received: 19 February 2018; Accepted: 26 March 2018; Published: 5 April 2018 Abstract: Noncanonical WNT pathways function independently of the β-catenin transcriptional co-activator to regulate diverse morphogenetic and pathogenic processes. Recent studies showed that noncanonical WNTs, such as WNT5A, can signal the degradation of several downstream effectors, thereby modulating these effectors’ cellular activities. The protein domain(s) that mediates the WNT5A-dependent degradation response, however, has not been identified. By coupling protein mutagenesis experiments with a flow cytometry-based degradation reporter assay, we have defined a protein domain in the kinesin superfamily protein KIF26B that is essential for WNT5A-dependent degradation. We found that a human disease-causing KIF26B mutation located at a conserved amino acid within this domain compromises the ability of WNT5A to induce KIF26B degradation. Using pharmacological perturbation, we further uncovered a role of glycogen synthase kinase 3 (GSK3) in WNT5A regulation of KIF26B degradation. -
How Models and Biological Experimentation Have Come Together to Reveal Mechanisms of Cytokinesis Daniel B
© 2018. Published by The Company of Biologists Ltd | Journal of Cell Science (2018) 131, jcs203570. doi:10.1242/jcs.203570 REVIEW Unite to divide – how models and biological experimentation have come together to reveal mechanisms of cytokinesis Daniel B. Cortes1, Adriana Dawes2, Jian Liu3, Masoud Nickaeen4, Wanda Strychalski5 and Amy Shaub Maddox1,* ABSTRACT these systems. Thus, cytokinesis can serve as a paradigm to Cytokinesis is the fundamental and ancient cellular process by which understand diverse behaviors of cellular motility. one cell physically divides into two. Cytokinesis in animal and fungal Mathematical modeling (see Glossary), combined with biological ‘ ’ cells is achieved by contraction of an actomyosin cytoskeletal ring experimentation (i.e. wet lab approaches including microscopy, assembled in the cell cortex, typically at the cell equator. Cytokinesis genetics, biochemistry and biophysics), has significantly advanced ‘ ’ is essential for the development of fertilized eggs into multicellular our understanding of cytokinesis. Herein, we use the word modeling organisms and for homeostatic replenishment of cells. Correct to collectively refer to diverse theoretical approaches, in which execution of cytokinesis is also necessary for genome stability and biological, biochemical and biophysical processes are described with the evasion of diseases including cancer. Cytokinesis has fascinated mathematical equations. These approaches, often historically rooted scientists for well over a century, but its speed and dynamics make in, and motivated by, problems in physics and chemistry, include experiments challenging to perform and interpret. The presence continuum mechanics modeling and agent-based modeling (see of redundant mechanisms is also a challenge to understand Glossary). The following references can serve as a starting point for cytokinesis, leaving many fundamental questions unresolved. -
A Global Transcriptional Network Connecting Noncoding Mutations to Changes in Tumor Gene Expression
HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Nat Genet Manuscript Author . Author manuscript; Manuscript Author available in PMC 2018 October 02. Published in final edited form as: Nat Genet. 2018 April ; 50(4): 613–620. doi:10.1038/s41588-018-0091-2. A global transcriptional network connecting noncoding mutations to changes in tumor gene expression Wei Zhang1,†,*, Ana Bojorquez-Gomez1,†, Daniel Ortiz Velez2, Guorong Xu3, Kyle S. Sanchez1, John Paul Shen1, Kevin Chen2, Katherine Licon1, Collin Melton4, Katrina M. Olson1,5, Michael Ku Yu1, Justin K. Huang1,6, Hannah Carter1, Emma K. Farley1,5, Michael Snyder4, Stephanie I. Fraley2, Jason F. Kreisberg1,*, and Trey Ideker1,2,6,* 1Department of Medicine, University of California, San Diego, La Jolla, California, USA 2Department of Bioengineering, University of California San Diego, La Jolla, CA, USA 3Center for Computational Biology and Bioinformatics, University of California, San Diego, La Jolla, California, USA 4Department of Genetics, Stanford University School of Medicine, Stanford, California, USA 5Division of Biological Sciences, University of California San Diego, La Jolla, CA, USA 6Bioinformatics and Systems Biology Program, UC San Diego, La Jolla, California, USA Abstract Although cancer genomes are replete with noncoding mutations, the effects of these mutations remain poorly characterized. Here we perform an integrative analysis of 930 tumor whole genomes and matched transcriptomes, identifying a network of 193 noncoding loci in which mutations disrupt target gene expression. These “somatic eQTLs” (expression Quantitative Trait Loci) are frequently mutated in specific cancer tissues, and the majority can be validated in an independent cohort of 3,382 tumors. Among these, we find that the effects of noncoding mutations on DAAM1, MTG2 and HYI transcription are recapitulated in multiple cancer cell lines, and that increasing DAAM1 expression leads to invasive cell migration. -
Daam2 Couples Translocation and Clustering of Wnt Receptor Signalosomes Through Rac1 Carlo D
© 2021. Published by The Company of Biologists Ltd | Journal of Cell Science (2021) 134, jcs251140. doi:10.1242/jcs.251140 RESEARCH ARTICLE Daam2 couples translocation and clustering of Wnt receptor signalosomes through Rac1 Carlo D. Cristobal1,QiYe2, Juyeon Jo2, Xiaoyun Ding3, Chih-Yen Wang2, Diego Cortes2, Zheng Chen4 and Hyun Kyoung Lee1,3,5,* ABSTRACT Dynamic polymerization of the Dishevelled proteins functions at Wnt signaling plays a critical role in development across species and the core of the Wnt signalosome by interacting with both the is dysregulated in a host of human diseases. A key step in signal Frizzled Wnt receptors and low-density lipoprotein receptor-related transduction is the formation of Wnt receptor signalosomes, during protein 5/6 (LRP5/6), leading to recruitment of Axin proteins β which a large number of components translocate to the membrane, from the -catenin destruction complex (MacDonald et al., 2009; cluster together and amplify downstream signaling. However, the Schwarz-Romond et al., 2007). However, the exact composition molecular processes that coordinate these events remain poorly and mechanisms of signalosome assembly at the plasma membrane defined. Here, we show that Daam2 regulates canonical Wnt remain unclear. signaling via the PIP –PIP5K axis through its association with Rac1. The hallmark of canonical Wnt signaling is the accumulation and 2 β Clustering of Daam2-mediated Wnt receptor complexes requires both translocation of -catenin into the nucleus for gene transcription, β Rac1 and PIP5K, and PIP5K promotes membrane localization of these whereas non-canonical Wnt signaling is -catenin independent and complexes in a Rac1-dependent manner. Importantly, the localization involves assembly/disassembly of the actin cytoskeleton, polarized of Daam2 complexes and Daam2-mediated canonical Wnt signaling is cell shape changes and cell migration (Niehrs, 2012; Schlessinger dependent upon actin polymerization. -
Profilin and Formin Constitute a Pacemaker System for Robust Actin
RESEARCH ARTICLE Profilin and formin constitute a pacemaker system for robust actin filament growth Johanna Funk1, Felipe Merino2, Larisa Venkova3, Lina Heydenreich4, Jan Kierfeld4, Pablo Vargas3, Stefan Raunser2, Matthieu Piel3, Peter Bieling1* 1Department of Systemic Cell Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany; 2Department of Structural Biochemistry, Max Planck Institute of Molecular Physiology, Dortmund, Germany; 3Institut Curie UMR144 CNRS, Paris, France; 4Physics Department, TU Dortmund University, Dortmund, Germany Abstract The actin cytoskeleton drives many essential biological processes, from cell morphogenesis to motility. Assembly of functional actin networks requires control over the speed at which actin filaments grow. How this can be achieved at the high and variable levels of soluble actin subunits found in cells is unclear. Here we reconstitute assembly of mammalian, non-muscle actin filaments from physiological concentrations of profilin-actin. We discover that under these conditions, filament growth is limited by profilin dissociating from the filament end and the speed of elongation becomes insensitive to the concentration of soluble subunits. Profilin release can be directly promoted by formin actin polymerases even at saturating profilin-actin concentrations. We demonstrate that mammalian cells indeed operate at the limit to actin filament growth imposed by profilin and formins. Our results reveal how synergy between profilin and formins generates robust filament growth rates that are resilient to changes in the soluble subunit concentration. DOI: https://doi.org/10.7554/eLife.50963.001 *For correspondence: peter.bieling@mpi-dortmund. mpg.de Introduction Competing interests: The Eukaryotic cells move, change their shape and organize their interior through dynamic actin net- authors declare that no works. -
Role of G-Protein Regulation of Formins During Gradient Tracking in Saccharomyces Cerevisiae
The University of Maine DigitalCommons@UMaine Honors College Spring 5-2017 Role of G-protein Regulation of Formins during Gradient Tracking in Saccharomyces cerevisiae Stephen Soohey University of Maine Follow this and additional works at: https://digitalcommons.library.umaine.edu/honors Recommended Citation Soohey, Stephen, "Role of G-protein Regulation of Formins during Gradient Tracking in Saccharomyces cerevisiae" (2017). Honors College. 261. https://digitalcommons.library.umaine.edu/honors/261 This Honors Thesis is brought to you for free and open access by DigitalCommons@UMaine. It has been accepted for inclusion in Honors College by an authorized administrator of DigitalCommons@UMaine. For more information, please contact [email protected]. ROLE OF G-PROTEIN REGULATION OF FORMINS DURING GRADIENT TRACKING IN SACCHAROMYCES CEREVISIAE by Stephen C. Soohey A Thesis Submitted in Partial Fulfillment of the Requirements for a Degree with Honors (Molecular and Cellular Biology) The Honors College University of Maine May 2017 Advisory Committee: Joshua Kelley, Assistant Professor of Biochemistry, Advisor Sally Molloy, Assistant Professor of Genomics Robert Gundersen, Chair of Molecular & Biomedical Sciences Edward Bernard, Laboratory Coordinator and Lecturer Sarah Harlan-Haughey, Assistant Professor of English and Honors ABSTRACT The yeast Saccharomyces cerevisiae uses a GPCR to direct the pheromone response pathway. Haploid yeast detect and respond to pheromone gradients produced by the opposite mating type to find a mating partner. At a high dose of pheromone, yeast will form a short, focused mating projection in order to mate with yeast that are close by. At lower doses of pheromone, the yeast form a broader projection which grows towards the source of pheromone. -
Role and Regulation of the P53-Homolog P73 in the Transformation of Normal Human Fibroblasts
Role and regulation of the p53-homolog p73 in the transformation of normal human fibroblasts Dissertation zur Erlangung des naturwissenschaftlichen Doktorgrades der Bayerischen Julius-Maximilians-Universität Würzburg vorgelegt von Lars Hofmann aus Aschaffenburg Würzburg 2007 Eingereicht am Mitglieder der Promotionskommission: Vorsitzender: Prof. Dr. Dr. Martin J. Müller Gutachter: Prof. Dr. Michael P. Schön Gutachter : Prof. Dr. Georg Krohne Tag des Promotionskolloquiums: Doktorurkunde ausgehändigt am Erklärung Hiermit erkläre ich, dass ich die vorliegende Arbeit selbständig angefertigt und keine anderen als die angegebenen Hilfsmittel und Quellen verwendet habe. Diese Arbeit wurde weder in gleicher noch in ähnlicher Form in einem anderen Prüfungsverfahren vorgelegt. Ich habe früher, außer den mit dem Zulassungsgesuch urkundlichen Graden, keine weiteren akademischen Grade erworben und zu erwerben gesucht. Würzburg, Lars Hofmann Content SUMMARY ................................................................................................................ IV ZUSAMMENFASSUNG ............................................................................................. V 1. INTRODUCTION ................................................................................................. 1 1.1. Molecular basics of cancer .......................................................................................... 1 1.2. Early research on tumorigenesis ................................................................................. 3 1.3. Developing -
Rho Activation of Mdia Formins Is Modulated by an Interaction with Inverted Formin 2 (INF2)
Rho activation of mDia formins is modulated by an interaction with inverted formin 2 (INF2) Hua Suna,b,c, Johannes S. Schlondorffb,c, Elizabeth J. Brownc,d, Henry N. Higgse, and Martin R. Pollakb,c,1 aNephrology Division, Department of Medicine, Shanghai Children’s Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China; bNephrology Division, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215; cDepartment of Medicine, Harvard Medical School, Boston, MA 02115; dDivision of Nephrology, Department of Medicine, Children’s Hospital, Boston, MA 02115; and eDepartment of Biochemistry, Dartmouth Medical School, Hanover, NH 03755 Edited by Christine E. Seidman, Harvard Medical School, Boston, MA, and approved December 30, 2010 (received for review November 12, 2010) Inverted formin 2 (INF2) encodes a member of the diaphanous glomerular slit diaphragm (11–13). The importance of the actin subfamily of formin proteins. Mutations in INF2 cause human cytoskeleton in maintaining the glomerular filtration barrier is kidney disease characterized by focal and segmental glomerulo- supported by the fact that mutations in α-actinin-4, an actin cross- sclerosis. Disease-causing mutations occur only in the diaphanous linking protein, cause a similar form of autosomal-dominant FSGS inhibitory domain (DID), suggesting specific roles for this domain in (14). Numerous lines of evidence support the notion that podo- the pathogenesis of disease. In a yeast two-hybrid screen, we cytes are highly sensitive to perturbations in their actin cytoskel- identified the diaphanous autoregulatory domains (DADs) of the eton (15). Consistent with this, FSGS-associated mutant forms of mammalian diaphanous-related formins (mDias) mDia1, mDia2, INF2 induce distinct patterns of actin polymerization in cultured and mDia 3 as INF2_DID-interacting partners. -
Role of Rho Family Gtpases in Epithelial Morphogenesis
Downloaded from genesdev.cshlp.org on October 1, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW Role of Rho family GTPases in epithelial morphogenesis Linda Van Aelst1,3 and Marc Symons2 1Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA; 2Center for Oncology and Cell Biology, North Shore-Long Island Jewish Research Institute and Department of Surgery, North Shore-Long Island Jewish Medical Center, Manhasset, New York 11030, USA Epithelial cell sheets line the organ and body surfaces will also discuss the participation of these GTPases in and the specialized barrier functions of these epithelia epithelial remodeling during wound-healing and epithe- regulate the exchange of substances with the outside en- lial-mesenchymal transitions. vironment and between different body compartments. As other members of the Ras superfamily, Rho Epithelia play a role in a wide range of physiological GTPases cycle between a GDP-bound (inactive) state processes such as digestion, excretion, and leukocyte and a GTP-bound (active) state. In the active state, these trafficking. In addition, during development, some epi- GTPases relay signals from growth factors, cytokines, thelia form transient primitive structures, including the and adhesion molecules to regulate a wide range of bio- neural tube and somites, which are essential for the de- logical processes, including actin cytoskeleton organiza- velopment of more complex organs. tion, transcriptional regulation, and vesicle trafficking The establishment and maintenance of epithelial cell (Van Aelst and D’Souza-Schorey 1997; Hall 1998). polarity is critical for the development and functioning The nucleotide state of Rho family proteins is con- of multicellular organisms (Nelson 2000). -
Cytoskeleton: Formins Induce Nuclear Actin Assembly
RESEARCH HIGHLIGHTS Nature Reviews Molecular Cell Biology | AOP, published online 24 April 2013; doi:10.1038/nrm3580 CYTOSKELETON nuclear export signal (NES-Dia1ct)) that formins drive actin assembly in the or constitutively active MAL. nucleus in response to serum. Moreover, they found that nuclear So, can MAL–SRF activity be induced Formins induce nuclear actin polymerization was required for upon nuclear mDia activation? Dia1ct-driven SRF activity, as Dia1ct To activate endogenous formins in actin assembly did not induce SRF activity when an the nucleus, the authors used an actin mutant that cannot polymerize optogenetic tool, whereby mDia Formins promote the assembly of actin was overexpressed in the nucleus. autoinhibition is released by the filaments in the cytoplasm. This leads Interestingly, only nuclear Dia1ct but not photoactivation of a diaphanous formins drive to the release of MAL (megakaryocytic cytoplasmic NES-Dia1ct could prevent autoregulatory domain. Indeed, acute leukaemia; also known as MRTF) the sequestration of MAL by nuclear repeated illumination of cells, and actin assembly from monomeric G-actin and the G-actin, which suggests that nuclear thus mDia activation, resulted in the in the nucleus accumulation of this cofactor, which actin polymerization releases MAL from reversible assembly of nuclear actin stimulates serum response factor G-actin. Moreover, cells expressing a filaments, MAL nuclear accumulation (SRF)-dependent expression of dominant-negative mDia mutant that and SRF activity. cytoskeletal target genes, in the localizes exclusively to the nucleus Together, these results show that nucleus. Although diaphanous-related exhibited decreased serum-induced the assembly of dynamic nuclear formins (mDia) have been detected in SRF activity compared with control cells, actin networks in response to serum is the nucleus, it was unclear whether they suggesting that nuclear mDia is required dependent on nuclear mDia activation. -
A DAAM1 3′-UTR SNP Mutation Regulates Breast Cancer Metastasis
Mei et al. Cancer Cell Int (2019) 19:55 https://doi.org/10.1186/s12935-019-0747-8 Cancer Cell International PRIMARY RESEARCH Open Access A DAAM1 3′-UTR SNP mutation regulates breast cancer metastasis through afecting miR-208a-5p-DAAM1-RhoA axis Jie Mei1†, Ting Yan2†, Yifu Huang1,3, Tiansong Xia4, Fei Chang1, Shuning Shen1, Leiyu Hao1, Yin Chen1, Zhongyuan Wang1, Xiaozheng Jiang1, Bujie Xu1 and Yichao Zhu1,5* Abstract Background: Dishevelled-associated activator of morphogenesis 1 (DAAM1) is a member of microflament-related formins and mediates cell motility in breast cancer (BrCa). However, the genetic mutation status of DAAM1 mRNA and its correlation with pathological characteristics are still unclearly. Methods: A patient cohort and BrCa cells were recruited to demonstrate the role of functional SNP in microRNA- 208a-5p binding site of DAAM1 3′-UTR and underlying mechanism in BrCa metastasis. Results: The expression and activation of DAAM1 increased markedly in lymphnode metastatic tissues. A genetic var- iant (rs79036859 A/G) was validated in the miR-208a-5p binding site of DAAM1 3′-UTR. The G genotype (AG/GG) was a risk genotype for the metastasis of BrCa by reducing binding afnity of miR-208a-5p for the DAAM1 3′-UTR. Further- more, the miR-208a-5p expression level was signifcantly suppressed in lymphnode metastatic tissues compared with that in non-lymphnode metastatic tissues. Overexpression of miR-208a-5p inhibited DAAM1/RhoA signaling pathway, thereby leading to the decrease of the migratory ability. Conclusion: Overall, the rs79036859 G variant of DAAM1 3′-UTR was identifed as a relevant role in BrCa metastasis via the diversity of miR-208a-5p binding afnity.