Vitamins and hormones, volume 99

Cover photo credit: Mulloy, B., Rider, C.C The Bone Morphogenetic Proteins and Their Antagonists Vitamins and Hormones (2015) 99, pp 63–90 Academic Press is an imprint of Elsevier 225 Wyman Street, Waltham, MA 02451, USA 525 B Street, Suite 1800, San Diego, CA 92101-4495, USA 125 London Wall, London, EC2Y 5AS, UK The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, UK First edition 2015 Copyright © 2015 Elsevier Inc All rights reserved No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions This book and the individual 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contained in the material herein ISBN: 978-0-12-802442-3 ISSN: 0083-6729 For information on all Academic Press publications visit our website at store.elsevier.com Former Editors ROBERT S HARRIS KENNETH V THIMANN Newton, Massachusetts University of California Santa Cruz, California JOHN A LORRAINE University of Edinburgh Edinburgh, Scotland PAUL L MUNSON University of North Carolina Chapel Hill, North Carolina JOHN GLOVER University of Liverpool Liverpool, England GERALD D AURBACH Metabolic Diseases Branch National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health Bethesda, Maryland IRA G WOOL University of Chicago Chicago, Illinois EGON DICZFALUSY Karolinska Sjukhuset Stockholm, Sweden ROBERT OLSEN School of Medicine State University of New York at Stony Brook Stony Brook, New York DONALD B MCCORMICK Department of Biochemistry Emory University School of Medicine, Atlanta, Georgia CONTRIBUTORS Paul F Austin Department of Surgery, Division of Urology, Washington University School of Medicine, St Louis Children’s Hospital, St Louis, Missouri, USA Ana Claudia Oliveira Carreira NUCEL-NETCEM (Cell and Molecular Therapy Center), Internal Medicine Department, School of Medicine, University of Sa˜o Paulo, Sa˜o Paulo, Brazil Suvro Chatterjee Vascular Biology Lab, AU-KBC Research Centre, MIT Campus, and Department of Biotechnology, Anna University, Chennai, India Jian Q Feng Department of Biomedical Sciences, Texas A&M Baylor College of Dentistry, Dallas, Texas, USA Renato Astorino Filho NUCEL-NETCEM (Cell and Molecular Therapy Center), Internal Medicine Department, School of Medicine, University of Sa˜o Paulo, Sa˜o Paulo, Brazil Jose´ Mauro Granjeiro Bioengineering Division, National Institute of Metrology, Quality, and Technology, Duque de Caxias, and Department of Dental Materials, Dental School, Fluminense Federal University, Niteroi, Brazil Judith B Grinspan Children’s Hospital of Philadelphia, and Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA Qiusha Guo Department of Surgery, Division of Urology, Washington University School of Medicine, St Louis Children’s Hospital, St Louis, Missouri, USA Robert J Hinton Department of Biomedical Sciences, Texas A&M Baylor College of Dentistry, Dallas, Texas, USA Eijiro Jimi Division of Molecular Signaling and Biochemistry, Department of Health Promotion, Center for Oral Biological Research, Kyushu Dental University, Kitakyushu, Fukuoka, Japan Junjun Jing State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China Piotr Kraj Department of Biological Sciences, Old Dominion University, Norfolk, Virginia, USA xi xii Contributors Michal Kuczma Cancer Center, Georgia Regents University, Augusta, Georgia, USA Isabel La Rosa Laboratory of Animal Biotechnology, Agriculture Faculty, University of Buenos Aires (UBA), Buenos Aires, Argentina Scott R Manson Department of Surgery, Division of Urology, Washington University School of Medicine, St Louis Children’s Hospital, St Louis, Missouri, USA Katelynn H Moore Department of Surgery, Division of Urology, Washington University School of Medicine, St Louis Children’s Hospital, St Louis, Missouri, USA Thomas D Mueller Department Plant Physiology and Biophysics, Julius-von-Sachs Institute of the University Wuerzburg, Wuerzburg, Germany Barbara Mulloy Centre for Biomedical Sciences, School of Biological Sciences, Royal Holloway, University of London, Egham, Surrey, United Kingdom Saranya Rajendran Vascular Biology Lab, AU-KBC Research Centre, Anna University, MIT Campus, Chennai, India Chris C Rider Centre for Biomedical Sciences, School of Biological Sciences, Royal Holloway, University of London, Egham, Surrey, United Kingdom Mariana Correa Rossi Department of Chemistry and Biochemistry, Biosciences Institute, UNESP, Universidade Estadual Paulista, Botucatu, Brazil Jamila H Siamwala Department of Orthopaedic Surgery, University of California, San Diego, California, USA Mari Cleide Sogayar NUCEL-NETCEM (Cell and Molecular Therapy Center), Internal Medicine Department, School of Medicine, University of Sa˜o Paulo, and Chemistry Institute, Biochemistry Department, Sa˜o Paulo, Brazil Willian Fernando Zambuzzi Department of Chemistry and Biochemistry, Biosciences Institute, UNESP, Universidade Estadual Paulista, Botucatu, Brazil PREFACE Bone morphogenic (or morphogenetic) proteins (BMPs) represent a subfamily in the transforming growth factor beta superfamily About 20 BMPs are already known First discovered in connection with their activities on bone, they play key roles in bone formation and skeletal development and in the differentiation of cartilage and chondrocytes BMPs are considered as potential treatments for bone healing and for the loss of bone during space flight, especially in flights of extended duration Additionally, it is now recognized that BMPs are involved in the development of several tissues including limb buds, kidney, heart, eye, and skin In kidney disease, for example, BMP levels fall, opening the possibility that BMP treatment might offer a beneficial therapeutic effect The basic information on the interaction of BMPs triggering activation of their receptors as well as the antagonists of this interaction is known Features of BMP signaling also are now being studied The signaling processes involve nuclear factor kappa B in some cases and also are known to affect the process of myelination The chapters in this volume are arranged by first considering the basic information in the mechanism of BMP action Accordingly, the first chapters deal with BMP–receptor interaction T.D Mueller describes the “Mechanisms of BMP–Receptor Interaction and Activation.” In addition, B Mulloy and C.C Rider report on “The Bone Morphogenetic Proteins and Their Antagonists.” Both of these chapters demonstrate the use of threedimensional crystal structures S.R Manson, P.F Austin, Q Guo, and K.H Moore report on “BMP-7 Signaling and Its Critical Roles in Kidney Development, the Responses to Renal Injury, and Chronic Kidney Disease.” E Jimi reports on “The Role of BMP Signaling and NF-κB Signaling on Osteoblastic Differentiation, Cancer Development, and Vascular Diseases—Is the Activation of NF-κB a Friend or Foe of BMP Function?” Additionally, in this vein, M Kuczma and P Kraj review “Bone Morphogenic Protein Signaling Regulates Development and Activation of CD4+ T Cells.” J Grinspan writes on “Bone Morphogenetic Proteins: Inhibitors of Myelination in Development and Disease.” Continuing on the topic of development, I La Rosa describes “Bone Morphogenetic Proteins in Preimplantation Embryos.” xiii xiv Preface The following chapters refer to the effects on bone and cartilage J.H Siamwala, S Rajendran, and S Chatterjee introduce “Strategies of Manipulating BMP Signaling in Microgravity to Prevent Bone Loss.” J Jing, R.J Hinton, and J.Q Feng review “Bmpr1a Signaling in Cartilage Development and Endochondral Bone Formation.” The final chapter covers “Bone Morphogenetic Proteins: Promising Molecules for Bone Healing, Bioengineering, and Regenerative Medicine” authored by A.C.O Carreira, W.F Zambuzzi, M.C Rossi, R.A Filho, M.C Sogayar, and J.M Granjeiro The illustration on the cover is Figure of Chapter by B Mulloy and C.C Rider entitled “The Bone Morphogenetic Proteins and Their Antagonists.” It presents the crystal structure of the BMP antagonist noggin complexed with the BMP-7 dimer (magenta) at the top Noggin dimer is a ribbon in red below while at the very bottom is the heparin-binding site in yellow Final processing of this volume was facilitated by Helene Kabes (Oxford, UK) and Vignesh Tamilselvvan (Chennai, India) GERALD LITWACK North Hollywood, CA June 17, 2015 CHAPTER ONE Mechanisms of BMP–Receptor Interaction and Activation Thomas D Mueller1 Department Plant Physiology and Biophysics, Julius-von-Sachs Institute of the University Wuerzburg, Wuerzburg, Germany Corresponding author: e-mail address: mueller@biozentrum.uni-wuerzburg.de Contents Evolutionary Expansion and Diversification of the Transforming Growth Factor β Superfamily Phylogenetic Analysis Reveals Four Functional Subfamilies for TGFβ Ligands Expression as Protease-Activated Proproteins and a Cystine-Knot Motif in the C-Terminal Mature Region as Key Features of TGFβ Ligand Members TGFβ Receptor Activation and Its Downstream Signaling Cascade Too Few Receptors for Too Many Ligands Lead to Promiscuity Molecular Mechanisms to Ensure Ligand–Receptor Promiscuity and Specificity: The Concept of Multiple Hot Spots of Binding Molecular Mechanisms to Ensure Ligand–Receptor Promiscuity and Specificity: The Concept of Structural Adaptability Consequences of Promiscuity and Specificity in the TGFβ Superfamily: Conclusions References 12 18 22 25 32 37 41 Abstract Bone morphogenetic proteins (BMPs), together with the eponymous transforming growth factor (TGF) β and the Activins form the TGFβ superfamily of ligands This protein family comprises more than 30 structurally highly related proteins, which determine formation, maintenance, and regeneration of tissues and organs Their importance for the development of multicellular organisms is evident from their existence in all vertebrates as well as nonvertebrate animals From their highly specific functions in vivo either a strict relation between a particular ligand and its cognate cellular receptor and/or a stringent regulation to define a distinct temperospatial expression pattern for the various ligands and receptor is expected However, only a limited number of receptors are found to serve a large number of ligands thus implicating highly promiscuous ligand– receptor interactions instead Since in tissues a multitude of ligands are often found, which signal via a highly overlapping set of receptors, this raises the question how such promiscuous interactions between different ligands and their receptors can generate concerted and highly specific cellular signals required during embryonic development and tissue homeostasis Vitamins and Hormones, Volume 99 ISSN 0083-6729 http://dx.doi.org/10.1016/bs.vh.2015.06.003 # 2015 Elsevier Inc All rights reserved Thomas D Mueller EVOLUTIONARY EXPANSION AND DIVERSIFICATION OF THE TRANSFORMING GROWTH FACTOR β SUPERFAMILY Multicellular organisms require continuous intercellular communication not only during their development but also for homeostasis and survival Processes such as cell differentiation, proliferation, migration or apoptosis depend on endocrine, paracrine or possibly autocrine stimuli, which at their heart are often, but not exclusively exerted by protein–protein interactions at the cell surface involving a secreted (sometimes also membraneassociated) growth factor, and a transmembrane receptor During evolution, nature has “recycled” successful examples of above combinations thereby forming larger protein families, in which further homologous growth factors plus their respective receptors were formed possibly by gene duplication and acquired additional functionalities necessary to cope with the increasing complexity of the evolving organisms The transforming growth factor β (TGFβ) superfamily comprising TGFβs, Activins, and bone morphogenetic proteins (BMPs) as well as growth and differentiation factors (GDFs) presents a prime example of such a protein family with a few growth factors in simple organisms like worms (five TGFβ ligands, for review: SavageDunn, 2005) and a large number of ligands in mammals (>30 TGFβ factors in human, for review: Feng & Derynck, 2005; Hinck, 2012; Mueller & Nickel, 2012; Fig 1A) An evolutionary expansion in the TGFβ superfamily can be also noted from the observation that homologs of BMPs—in contrast to senso strictu TGFβs and Activins—are already found in worms, whereas homologs of Activins appear for the first time in flies and senso strictu TGFβs emerge in fish and amphibian (Newfeld, Wisotzkey, & Kumar, 1999) This suggests that BMPs are likely the founding members of this growth factor family, which then diverged into Activins and TGFβ Thus, TGFβs seem to be the evolutionary youngest members despite serving as eponym of the whole superfamily The later emergence of Activins and TGFβs is also consistent with their encoded functionalities Activins modulate the reproductive axis (Bilezikjian, Blount, Donaldson, & Vale, 2006) and exert regulatory roles in inflammation and immunity (for reviews: AlemanMuench & Soldevila, 2012; Hedger, Winnall, Phillips, & de Kretser, 2011), and TGFβs being implicated in the control of immunity (for review: Yoshimura & Muto, 2011) and wound healing (for review: Leask & Abraham, 2004), functions that are not or differently implemented in Mechanisms of BMP–Receptor Interaction and Activation Figure (A) Phylogenetic analysis of the TGFβ ligand superfamily The TGFβs can be classified into four subgroups indicated on the left: (I) sensu stricto TGFβs, (II) Activin/ Inhibins, (III) BMPs/GDFs, and (IV) others Type I and type II receptor recruitment is indicated, the activation of either the SMAD1/5/8 or SMAD2/3 pathway is marked by light or dark gray-shaded boxes, respectively (B) Phylogenetic analysis of the TGFβ receptors showing the classification into type I and type II receptors Light and dark gray boxes indicate the activation of either SMAD1/5/8 or SMAD2/3 (C) TGFβ proteins are expressed as pre-proproteins containing a signal peptide (SP), a prodomain, which in TGFβs is covalently dimerized by disulfide bonds (marked by asterisks), a proteolytic processing site (RXXR) and a mature region containing the characteristic cystine-knot motif comprising six conserved cysteine residues (marked by bars) Some TGFβs lack a seventh cysteine residue (marked by two asterisks) involved in covalent dimer formation (D) Architecture of the TGFβ receptors comprising a signal peptide (SP), an extracellular ligand-binding domain (ECD), a single-span transmembrane element, and an intracellular kinase domain Type I receptors differ by an additional membrane-proximal glycine/serine-rich motif (GS-box) Furthermore, BMPRII has a unique C-terminal domain (marked by an asterisks), which recruits additional signaling proteins Thomas D Mueller simpler organisms such as worms or insects But not only TGFβs and Activin additionally appeared later in evolution, but also the number of BMP homologs expanded dramatically In Caenorhabditis elegans, four of the five TGFβ members, dbl1, daf7, tig2, and tig3, could be mapped to the mammalian BMP orthologs, BMP5, GDF8/11, BMP8, and BMP2 (for review: Gumienny & Savage-Dunn, 2013); however, the functional similarities seem limited For instance, dbl1 and daf7, which are involved in the regulation of body size in the so-called Dauer larval development pathway, possibly exert a similar growth-limiting function as found for GDF8/11 in vertebrates Despite their limited homology with BMP8 and BMP2, no functions have yet been described for the C elegans orthologs tig-2 and tig-3, but both members might be involved in patterning Unc129, whose mature region exhibits limited sequence homology to mammalian BMP8 and GDF6, seems to be involved in axon guidance and signals via a non-TGFβ related noncanonical signaling pathway (Gumienny & Savage-Dunn, 2013) In flies, seven TGFβ members have been identified of which the ligands dpp, gbb, and screw can be mapped to the mammalian BMP2/4 and BMP5/6/7 (Newfeld et al., 1999), myoglianin likely presents an ortholog of GDF8/11 (Lo & Frasch, 1999), and dActivinβ, Dawdle and Maverick are fly Activin-like ligands (Kutty et al., 1998; Nguyen, Parker, & Arora, 2000; Parker, Ellis, Nguyen, & Arora, 2006; Serpe & O’Connor, 2006) Possibly due to the evolutionary smaller distance, the fly BMP orthologs dpp, gbb, and screw exert in vivo function more closely related to their vertebrate/mammalian counterparts Dpp, the fly ortholog of BMP2 and BMP4, is essential for correct dorsoventral patterning in fly (Irish & Gelbart, 1987), a function it shares with BMP2/swirl in fish (Kishimoto, Lee, Zon, Hammerschmidt, & Schulte-Merker, 1997) and BMP4 in mouse (Winnier, Blessing, Labosky, & Hogan, 1995) Drosophila gbb is involved in the development of the fly’s intestinal tract or the eyes similarly as found for BMP6/7 in vertebrates (Helder et al., 1995; Luo et al., 1995; Perr, Ye, & Gitelman, 1999; Wharton et al., 1999) On the contrary, the functions encoded by dActivinβ and the further distant Activin-like members Dawdle and Maverick seem to be more limited to neuronal morphogenesis compared to their vertebrate homologs (Kutty et al., 1998; Nguyen et al., 2000; Ting et al., 2007; Zhu et al., 2008) With the emergence of vertebrates, the number of TGFβ members not only doubled as evident from the 14 and 19 TGFβ ligands in fish (two Activin orthologs; Thisse, Wright, & Thisse, 2000) of Danio rerio are not listed in Massague (2000) and amphibian (Xenopus laevis), but their encoded ... different ligands and their receptors can generate concerted and highly specific cellular signals required during embryonic development and tissue homeostasis Vitamins and Hormones, Volume 99 ISSN... which the ligands dpp, gbb, and screw can be mapped to the mammalian BMP2/4 and BMP5/6/7 (Newfeld et al., 1999 ), myoglianin likely presents an ortholog of GDF8/11 (Lo & Frasch, 1999 ), and dActivinβ,... et al., 1995 ; Luo et al., 1995 ; Perr, Ye, & Gitelman, 1999 ; Wharton et al., 1999 ) On the contrary, the functions encoded by dActivinβ and the further distant Activin-like members Dawdle and Maverick