Mechanism and Function of Signal Transduction by the Wnt/Β-Catenin
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THE GENOMIC STRUCTURE of the ZEBRAFISH Wnt8b GE NE
THE GENOMIC STRUCTURE OF THE ZEBRAFISH wnt8b GENE by Yvonne Marie Beckham Department of Zoology Submitted in partial fulfilment of the requirements for the degree of Master of Science Faculty of Graduate Studies The University of Western Ontario London, Ontario December 1997 O Yvonne Marie Beckham, 1997 National Library Bibliothèque nationale du Canada Acquisitions and Acquisitions et Bibliographie Services seMces bibliographiques 395 Weüingtaci Street 395. Ne Wellington OttawaON K1AON4 OttawaON K1AW canada canada The author has granted a non- L'auteur a accordé une licence non exclusive licence allowing the exclusive permettant à la National Lhrary of Canada to Bibliothèque nationale du Canada de reproduce, loan, distribute or sell reproduire, prêter, districbuer ou copies of this thesis in microform, vendre des copies de cette thèse sous paper or electronic formats. la forme de microfiche/nlm, de reproduction sur papier ou sur fonnat électronique. The author retains ownership of the L'auteur conserve la propriété du copyright in this thesis. Neither the droit d'auteur qui protège cette thèse. thesis nor substantial extracts fiom it Ni la thèse ni des extraits substantiels may be printed or otherwise de celle-ci ne doivent être imprimés reproduced without the author's ou autrement reproduits sans son permission. autorisation. ABSTRACT Screening of a zebrafish genomic library to identify the prornoter elements of the zebrafish ivnr8b gene resulted in the isolation of two clones. p8b-3H and p8b-7A. Southem blot analysis demonstrated that clone p8b- 3H contained the 3' portion of the cDNA. p8b-7A showed only weak hybridization to the wnr8b cDNA used to initially isolate this clone. -
Regulation of Dishevelled DEP Domain Swapping by Conserved Phosphorylation Sites
Regulation of Dishevelled DEP domain swapping by conserved phosphorylation sites Gonzalo J. Beitiaa,1, Trevor J. Rutherforda,1, Stefan M. V. Freunda, Hugh R. Pelhama, Mariann Bienza, and Melissa V. Gammonsa,2 aMedical Research Council Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge, CB2 0QH, United Kingdom Edited by Roeland Nusse, Stanford University School of Medicine, Stanford, CA, and approved May 13, 2021 (received for review February 20, 2021) Wnt signals bind to Frizzled receptors to trigger canonical and with these effectors even if present at a low cellular concentra- noncanonical signaling responses that control cell fates during tion (1, 3, 12). animal development and tissue homeostasis. All Wnt signals are The DEP domain is a small globular domain composed of three relayed by the hub protein Dishevelled. During canonical (β-catenin– α-helices and a flexible hinge loop between the first (H1) and sec- dependent) signaling, Dishevelled assembles signalosomes via dy- ond helix (H2), which, in the monomeric configuration, folds back namic head-to-tail polymerization of its Dishevelled and Axin (DIX) on itself to form a prominent “DEP finger” that is responsible domain, which are cross-linked by its Dishevelled, Egl-10, and Pleck- for binding to Frizzled (Fig. 1A) (13). DEP dimerization involves strin (DEP) domain through a conformational switch from monomer a highly unusual mechanism called “domain swapping” (14). During to domain-swapped dimer. The domain-swapped conformation of this process, H1 of one DEP monomer is exchanged with H1 from a DEP masks the site through which Dishevelled binds to Frizzled, im- reciprocal one through outward motions of the hinge loops, replacing plying that DEP domain swapping results in the detachment of Dish- intra- with intermolecular contacts. -
A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated. -
EGFR Confers Exquisite Specificity of Wnt9a-Fzd9b Signaling in Hematopoietic Stem Cell Development
bioRxiv preprint doi: https://doi.org/10.1101/387043; this version posted August 7, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Grainger, et al, 2018 EGFR confers exquisite specificity of Wnt9a-Fzd9b signaling in hematopoietic stem cell development Stephanie Grainger1, Nicole Nguyen1, Jenna Richter1,2, Jordan Setayesh1, Brianna Lonquich1, Chet Huan Oon1, Jacob M. Wozniak2,3,4, Rocio Barahona1, Caramai N. Kamei5, Jack Houston1,2, Marvic Carrillo-Terrazas3,4, Iain A. Drummond5,6, David Gonzalez3.4, Karl Willert#,¥,1, and David Traver¥,1,7. ¥co-corresponding authors: [email protected]; [email protected] #Lead contact 1Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California, 92037, USA. 2Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, California, 92037, USA. 3Skaggs School of Pharmacy and Pharmaceutical Science, University of California, San Diego, La Jolla, California, 92093, USA. 4Department of Pharmacology, University of California, San Diego, La Jolla, California, 92092 5Massachusetts General Hospital Nephrology Division, Charlestown, Massachusetts, 02129, USA. 6Harvard Medical School, Department of Genetics, Boston MA 02115 7Section of Cell and Developmental Biology, University of California, San Diego, La Jolla, California, 92037, USA. Running title: A mechanism for Wnt-Fzd specificity in hematopoietic stem cells Keywords: hematopoietic stem cell (HSC), Wnt, Wnt9a, human, zebrafish, Fzd, Fzd9b, FZD9, EGFR, APEX2 1 bioRxiv preprint doi: https://doi.org/10.1101/387043; this version posted August 7, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. -
Role of the Wnt/ B-Catenin Pathway in Liver Development and Zonation
University of Bath PHD Role of the Wnt/ -catenin Pathway in Liver Development and Zonation Shen Wen, Yeh Award date: 2012 Awarding institution: University of Bath Link to publication Alternative formats If you require this document in an alternative format, please contact: [email protected] General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal ? Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Download date: 10. Oct. 2021 Role of the Wnt/ -catenin Pathway in Liver Development and Zonation YEH, SHENG-WEN A thesis submitted for the degree of Doctor of Philosophy University of Bath Department of Biology and Biochemistry September, 2012 COPYRIGHT Attention is drawn to the fact that copyright of this thesis rests with the author. A copy of this thesis has been supplied on condition that anyone who consults it is understood to recognise that its copyright rests with the author and that they must not copy it or use material from it except as permitted by law or with the consent of the author. -
Recruitment of Adenomatous Polyposis Coli and B-Catenin to Axin-Puncta
Oncogene (2008) 27, 5808–5820 & 2008 Macmillan Publishers Limited All rights reserved 0950-9232/08 $32.00 www.nature.com/onc ORIGINAL ARTICLE Recruitment of adenomatous polyposis coli and b-catenin to axin-puncta MC Faux, JL Coates, B Catimel, S Cody, AHA Clayton, MJ Layton and AW Burgess Ludwig Institute for Cancer Research, Melbourne Tumour Biology Branch, Parkville, Victoria, Australia The adenomatous polyposis coli (APC)tumour suppressor coli (APC) form a complex that promotes the phos- is a multifunctional protein involved in the regulation of phorylation of b-catenin by glycogen synthase kinase-3-b Wnt signalling and cytoskeletal dynamics. Little is known (GSK3-b), which consequently targets b-catenin for about how APC controls these disparate functions. In this ubiquitination by bTrCP and destruction by the study, we have used APC- and axin-fluorescent fusion proteasome (Aberle et al., 1997; Orford et al., 1997; proteins to examine the interactions between these Kitagawa et al., 1999). Wnt stimulation and APC proteins and show that the functionally distinct popula- mutations disrupt the APC/axin complex and result in tions of APC are also spatially separate. Axin-RFP forms increased levels of b-catenin in the nucleus and cytoplasmic punctate structures, similar to endogenous cytoplasm (Munemitsu et al., 1995). b-Catenin is known axin puncta. Axin-RFP recruits b-catenin destruction to interact with members of the Tcf family of transcrip- complex proteins, including APC, b-catenin, glycogen tion factors to activate transcription of genes involved in synthase kinase-3-b (GSK3-b)and casein kinase-1- a proliferation and cellular transformation (Korinek (CK1-a). -
Table SI. Characteristics of 9 Patients Chosen from 60 Patients with Hepatocellular Carcinoma
Table SI. Characteristics of 9 patients chosen from 60 patients with hepatocellular carcinoma. Characteristic No. of patients (%) Age, years <50 3 (33.3) ≥50 6 (66.7) Sex Female 4 (44.4) Male 5 (55.6) Albumin, g/l ≥35 8 (88.9) <35 1 (11.1) AFP, ng/ml ≤20 2 (22.2) >20 7 (77.8) Tumor diameter, cm ≤5 3 (33.3) >5 6 (66.7) Portal vein invasion Without 3 (33.3) With 6 (66.7) BCLC stage A 2 (22.2) B/C 7 (77.8) AFP, α-fetoprotein; BCLC, Barcelona Clinic Liver Cancer. Table SII. List of the gene symbol and relative expression of six significant clusters. Gene symbol SPOT Profile Day 0 Day 3 Day 7 Day 14 Day 21 ALCAM ID_10 16 0 -356.5 378.5 0.1 307.8 ANGPT2 ID_13 16 0 -45.7 197.2 96 60.2 CD80 ID_24 16 0 -177 362 -29 187 CTNNB1 ID_29 16 0 -58 294 83 49 BMP4 ID_37 16 0 -107 189 0 53 CCL28 ID_49 16 0 -307 856 491 347 CCR1 ID_50 16 0 -189 391 236 112 CCR4 ID_53 16 0 -101 361 89 240 CCR7 ID_56 16 0 -98 361 103 66 CLC ID_70 16 0 -147 274 0 188 CRIM1 ID_74 16 0 -642 229 -48 -112 CXCL14 ID_83 16 0 -434 1,154.00 778 376 CXCL16 ID_84 16 0 -128 800 477 180 DKK3 ID_97 16 0 -199 610 107 3 FGFBP1 ID_129 16 0 -224 484 -155 37 FGF20 ID_147 16 0 -113 264 -32 -4 WFIKKN1 ID_163 16 0 -195 544 262 41 GFRA1 ID_175 16 0 -536 443 29 280 GFRA4 ID_178 16 0 -211 208 -47 116 TNFSF18 ID_180 16 0 -14 246 89 68 GPC5 ID_187 16 0 -180 1,345.00 298 509 GH1 ID_194 16 0 -596 206 10 -9 CCHCR1 ID_198 16 0 -108 322 50 238 NRG1 ID_200 16 0 -81 378.5 170.5 187 ICAM1 ID_207 16 0 -136 98 -17 63 IFNB1 ID_213 16 0 -87 233 143 29 IGFBP3 ID_218 16 0 -1,311.00 609 -368 -178 IGFBP4 ID_219 16 0 -
Towards an Integrated View of Wnt Signaling in Development Renée Van Amerongen and Roel Nusse*
HYPOTHESIS 3205 Development 136, 3205-3214 (2009) doi:10.1242/dev.033910 Towards an integrated view of Wnt signaling in development Renée van Amerongen and Roel Nusse* Wnt signaling is crucial for embryonic development in all animal Notably, components at virtually every level of the Wnt signal species studied to date. The interaction between Wnt proteins transduction cascade have been shown to affect both β-catenin- and cell surface receptors can result in a variety of intracellular dependent and -independent responses, depending on the cellular responses. A key remaining question is how these specific context. As we discuss below, this holds true for the Wnt proteins responses take shape in the context of a complex, multicellular themselves, as well as for their receptors and some intracellular organism. Recent studies suggest that we have to revise some of messengers. Rather than concluding that these proteins are shared our most basic ideas about Wnt signal transduction. Rather than between pathways, we instead propose that it is the total net thinking about Wnt signaling in terms of distinct, linear, cellular balance of signals that ultimately determines the response of the signaling pathways, we propose a novel view that considers the receiving cell. In the context of an intact and developing integration of multiple, often simultaneous, inputs at the level organism, cells receive multiple, dynamic, often simultaneous and of both Wnt-receptor binding and the downstream, sometimes even conflicting inputs, all of which are integrated to intracellular response. elicit the appropriate cell behavior in response. As such, the different signaling pathways might thus be more intimately Introduction intertwined than previously envisioned. -
DIPPER, a Spatiotemporal Proteomics Atlas of Human Intervertebral Discs
TOOLS AND RESOURCES DIPPER, a spatiotemporal proteomics atlas of human intervertebral discs for exploring ageing and degeneration dynamics Vivian Tam1,2†, Peikai Chen1†‡, Anita Yee1, Nestor Solis3, Theo Klein3§, Mateusz Kudelko1, Rakesh Sharma4, Wilson CW Chan1,2,5, Christopher M Overall3, Lisbet Haglund6, Pak C Sham7, Kathryn Song Eng Cheah1, Danny Chan1,2* 1School of Biomedical Sciences, , The University of Hong Kong, Hong Kong; 2The University of Hong Kong Shenzhen of Research Institute and Innovation (HKU-SIRI), Shenzhen, China; 3Centre for Blood Research, Faculty of Dentistry, University of British Columbia, Vancouver, Canada; 4Proteomics and Metabolomics Core Facility, The University of Hong Kong, Hong Kong; 5Department of Orthopaedics Surgery and Traumatology, HKU-Shenzhen Hospital, Shenzhen, China; 6Department of Surgery, McGill University, Montreal, Canada; 7Centre for PanorOmic Sciences (CPOS), The University of Hong Kong, Hong Kong Abstract The spatiotemporal proteome of the intervertebral disc (IVD) underpins its integrity *For correspondence: and function. We present DIPPER, a deep and comprehensive IVD proteomic resource comprising [email protected] 94 genome-wide profiles from 17 individuals. To begin with, protein modules defining key †These authors contributed directional trends spanning the lateral and anteroposterior axes were derived from high-resolution equally to this work spatial proteomes of intact young cadaveric lumbar IVDs. They revealed novel region-specific Present address: ‡Department profiles of regulatory activities -
The Developmental Biology of Dishevelled: an Enigmatic Protein Governing Cell Fate and Cell Polarity John B
Review 4421 The developmental biology of Dishevelled: an enigmatic protein governing cell fate and cell polarity John B. Wallingford1 and Raymond Habas2,3 1Section of Molecular Cell and Developmental Biology, and Institute for Cellular and Molecular Biology, University of Texas, Austin, TX 78712, USA 2Department of Biochemistry, UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA 3Cancer Institute of New Jersey, UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA e-mail: [email protected] and [email protected] Development 132, 4421-4436 Published by The Company of Biologists 2005 doi:10.1242/dev.02068 Summary The Dishevelled protein regulates many developmental adult, ranging from cell-fate specification and cell polarity processes in animals ranging from Hydra to humans. Here, to social behavior. Dishevelled also has important roles in we discuss the various known signaling activities of this the governance of polarized cell divisions, in the directed enigmatic protein and focus on the biological processes that migration of individual cells, and in cardiac development Dishevelled controls. Through its many signaling activities, and neuronal structure and function. Dishevelled plays important roles in the embryo and the Introduction experiments demonstrated that dishevelled was also involved In its original definition, the word ‘dishevelled’ applied in the Frizzled-dependent signaling cascade governing PCP in specifically to one’s hair, its definition being ‘without a hat’ or, the wing, legs and abdomen (Krasnow et al., 1995; Theisen et more commonly, ‘un-coiffed’. Fittingly, the dishevelled gene al., 1994). The cloning of the Drosophila dsh gene unveiled a was first identified and so named because in flies bearing this novel protein (Klingensmith et al., 1994; Theisen et al., 1994), mutation the body and wing hairs fail to orient properly and additional experiments in the fly demonstrated that Development (Fahmy and Fahmy, 1959). -
Head Formation Requires Dishevelled Degradation That Is Mediated By
© 2018. Published by The Company of Biologists Ltd | Development (2018) 145, dev143107. doi:10.1242/dev.143107 RESEARCH ARTICLE Head formation requires Dishevelled degradation that is mediated by March2 in concert with Dapper1 Hyeyoon Lee*,**, Seong-Moon Cheong‡,**, Wonhee Han, Youngmu Koo, Saet-Byeol Jo, Gun-Sik Cho§, Jae-Seong Yang¶, Sanguk Kim and Jin-Kwan Han‡‡ ABSTRACT phosphorylate LRP6 (Bilic et al., 2007). Inhibition of GSK3β by Dishevelled (Dvl/Dsh) is a key scaffold protein that propagates Wnt the phospho-LRP6-containing activated receptor complex protects β signaling essential for embryogenesis and homeostasis. However, -catenin from proteasomal degradation (Logan and Nusse, 2004; β whether the antagonism of Wnt signaling that is necessary for MacDonald et al., 2009). Consequently, -catenin accumulates and vertebrate head formation can be achieved through regulation of Dsh interacts with T-cell factor/lymphoid-enhancer factor (TCF/LEF) in protein stability is unclear. Here, we show that membrane-associated the nucleus, thereby initiating transcription. RING-CH2 (March2), a RING-type E3 ubiquitin ligase, antagonizes During vertebrate development, the canonical Wnt pathway plays Wnt signaling by regulating the turnover of Dsh protein via ubiquitin- a crucial role in head formation (Glinka et al., 1997; Kiecker and mediated lysosomal degradation in the prospective head region of Niehrs, 2001; Yamaguchi, 2001). Proper head formation requires Xenopus. We further found that March2 acquires regional and inhibition of the canonical -
Apical Membrane Localization of the Adenomatous Polyposis Coli Tumor
Apical Membrane Localization of the Adenomatous Polyposis Coli Tumor Suppressor Protein and Subcellular Distribution of the -Catenin Destruction Complex in Polarized Epithelial Cells Anke Reinacher-Schick and Barry M. Gumbiner Cellular Biochemistry and Biophysics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021 Abstract. The adenomatous polyposis coli (APC) pro- This apical membrane association is not dependent on tein is implicated in the majority of hereditary and spo- the mutational status of either APC or -catenin. An ad- radic colon cancers. APC is known to function as a tu- ditional pool of APC is cytosolic and fractionates into mor suppressor through downregulation of -catenin as two distinct high molecular weight complexes, 20S and part of a high molecular weight complex known as the 60S in size. Only the 20S fraction contains an apprecia- -catenin destruction complex. The molecular composi- ble portion of the cellular axin and small but detectable tion of the intact complex and its site of action in the cell amounts of glycogen synthase kinase 3 and -catenin. are still not well understood. Reports on the subcellular Therefore, it is likely to correspond to the previously localization of APC in various cell systems have differed characterized -catenin destruction complex. Dishev- significantly and have been consistent with an associa- elled is almost entirely cytosolic, but does not signifi- tion with a cytosolic complex, with microtubules, with cantly cofractionate with the 20S complex. The dispro-