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Dissecting Signaling and Functions of Adhesion G Proteincoupled Receptors

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Dissecting Signaling and Functions of Adhesion G Proteincoupled Receptors Ann. N.Y. Acad. Sci. ISSN 0077-8923 ANNALS OF THE NEW YORK ACADEMY OF SCIENCES Issue: Annals Meeting Reports Dissecting signaling and functions of adhesion G protein–coupled receptors Demet Arac¸,1 Gabriela Aust,2 Davide Calebiro,3 Felix B. Engel,4 Caroline Formstone,5 Andre´ Goffinet,6 Jorg¨ Hamann,7 Robert J. Kittel,8 Ines Liebscher,9 Hsi-Hsien Lin,10 Kelly R. Monk,11 Alexander Petrenko,12 Xianhua Piao,13 Simone Promel,¨ 9 HelgiB.Schioth,¨ 14 Thue W. Schwartz,15 Martin Stacey,16 Yuri A. Ushkaryov,17 Manja Wobus,18 Uwe Wolfrum,19 Lei Xu,20 and Tobias Langenhan8 1Stanford University, Stanford, California. 2Department of Surgery, Research Laboratories, University of Leipzig, Leipzig, Germany. 3Institute of Pharmacology and Rudolf Virchow Center, DFG-Research Center for Experimental Biomedicine, University of Wurzburg,¨ Wurzburg,¨ Germany. 4Department of Cardiac Development and Remodelling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany, and Laboratory of Experimental Renal and Cardiovascular Research, Department of Nephropathology, Institute of Pathology, University of Erlangen-Nurnberg,¨ Erlangen, Germany. 5MRC Centre for Developmental Neurobiology, King’s College London, New Hunts House, London, United Kingdom. 6Universite´ Catholique de Louvain, Institute of Neuroscience, Developmental Neurobiology, Brussels, Belgium. 7Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. 8Institute of Physiology, Department of Neurophysiology, University of Wurzburg,¨ Wurzburg,¨ Germany. 9Institute of Biochemistry, Molecular Biochemistry, Medical Faculty, University of Leipzig, Leipzig, Germany. 10Department of Microbiology and Immunology, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan. 11Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri. 12Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia. 13Division of Newborn Medicine, Department of Medicine, Boston Children’s Hospital and Harvard Medical School, Boston, Massachusetts. 14Department of Neuroscience, Functional Pharmacology, Uppsala University, Uppsala, Sweden. 15Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, and the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark. 16Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom. 17Division of Cell and Molecular Biology, Imperial College London, London, United Kingdom, and Medway School of Pharmacy, University of Kent, Chatham, United Kingdom. 18Medical Clinic and Policlinic I, University Hospital Carl Gustav Carus, Dresden, Germany. 19Cell and Matrix Biology, Institute of Zoology, Johannes Gutenberg University of Mainz, Mainz, Germany. 20University of Rochester Medical Center, Rochester, New York Address for correspondence: Tobias Langenhan, Institute of Physiology, Department of Neurophysiology, University of Wurzburg,¨ Rontgenring¨ 9, 97070 Wurzburg,¨ Germany. [email protected]. G protein–coupled receptors (GPCRs) comprise an expanded superfamily of receptors in the human genome. Adhesion class G protein–coupled receptors (adhesion-GPCRs) form the second largest class of GPCRs. Despite the abundance, size, molecular structure, and functions in facilitating cell and matrix contacts in a variety of organ systems, adhesion-GPCRs are by far the most poorly understood GPCR class. Adhesion-GPCRs possess a unique molecular structure, with extended N-termini containing various adhesion domains. In addition, many adhesion-GPCRs are autoproteolytically cleaved into an N-terminal fragment (NTF, NT, ␣-subunit) and C-terminal fragment (CTF, CT, ␤-subunit) at a conserved GPCR autoproteolysis–inducing (GAIN) domain that contains a GPCR proteolysis site (GPS). These two features distinguish adhesion-GPCRs from other GPCR classes. Though active research on adhesion-GPCRs in diverse areas, such as immunity, neuroscience, and development and tumor biology has been intensified in the recent years, the general biological and pharmacological properties of adhesion- GPCRs are not well known, and they have not yet been used for biomedical purposes. The “6th International Adhesion-GPCR Workshop,” held at the Institute of Physiology of the University of Wurzburg¨ on September 6–8, 2012, assembled a majority of the investigators currently actively pursuing research on adhesion-GPCRs, including scientists from laboratories in Europe, the United States, and Asia. The meeting featured the nascent mechanistic understanding of the molecular events driving the signal transduction of adhesion-GPCRs, novel models to evaluate their functions, and evidence for their involvement in human disease. Keywords: G protein–coupled receptors; GPS motif; autoproteolysis; molecular and genetic analysis doi: 10.1111/j.1749-6632.2012.06820.x Ann. N.Y. Acad. Sci. xxxx (2012) 1–25 c 2012 New York Academy of Sciences. 1 Adhesion G protein–coupled receptors Arac¸ et al. Introduction specific. There are at least 21 adhesion-GPCRs in C. intestinalis that possess just the GPCR proteoly- The biennial adhesion-GPCR workshops evolved sis site (GPS) proteolytic domain in the N-termini, from a European grassroots initiative that be- while in the sea urchin there are 40 adhesion-GPCRs gan in 2002 and have been fostering informal containing multiple leucine-rich repeats (LRRs) but communication on topics concerning adhesion- , lacking GPS sites.5 6 Furthermore, comprehensive GPCR research. The workshops slowly evolved from analysis of the entire set of adhesion and related se- gatherings of a group of immunologists working cretin, and Methuselah groups of GPCRs provided on the founding adhesion-GPCR class members, the first evolutionary hierarchy among the five main F4/80 and CD97, to the only international meet- classes of vertebrate GPCRs. Schioth’s¨ group pro- ing solely dedicated to adhesion-GPCR research. vided convincing evidence that the secretin GPCRs This year the tenth anniversary workshop gave descended from the family of adhesion-GPCRs, more than 20 laboratories a platform on which probably from group V of the adhesion-GPCRs.7 to exchange their latest insights into the biology Moreover, they clarified the origin of the adhesion- of this poorly understood receptor class. At the GPCRs by providing the first evidence for the pres- same occasion, the Adhesion-GPCR Consortium ence of adhesion-GPCR homologues in fungi.8 This (AGC) was formed by the constituting member study estimated that the adhesion-GPCRs evolved assembly (http://www.adhesiongpcr.org). The AGC from Dictyostelium cAMP receptors before the split will represent and disseminate adhesion-GPCR re- of unikonts from a common ancestor of all ma- search and coordinate concerted funding initiatives jor eukaryotic lineages.8 In addition, they mined on the topic. The workshop program was divided the close unicellular relatives of the metazoan lin- into (1) evolutionary aspects of adhesion-GPCRs, eage Salpingoeca rosetta and Capsaspora owczarzaki. (2) signaling of adhesion-GPCRs, (3) adhesion- These species have a rich group of the adhesion- GPCRs in development, (4) adhesion-GPCRs GPCRs that provided additional insight into the first in neurobiology, and (5) adhesion-GPCRs in emergence of the N-terminal domains of the ad- disease. hesion family.8 Prime examples are the emergence of the characteristic adhesion-family domains, GPS The origin of the adhesion-GPCR family and the Calx-␤ domain in C. owczarzaki, and the Helgi Schioth¨ (Uppsala University) introduced his EGF-CA domain in S. rosetta.8 Further, Schioth¨ studies on the origin of the adhesion-GPCR class of analyzed the hemichordate Saccoglossus kowalevskii seven-span transmembrane (7TM) receptors. The (acorn worm), which serves as an important model adhesion G protein–coupled receptors (GPCRs) are organism for developmental biologists to under- the second largest family of GPCRs, with genes con- stand the evolution of the central nervous system taining multiple exons that are presumed to have (CNS). Unlike vertebrates that have a centralized arisen through several mechanisms.1,2 Adhesion- nervous system, the acorn worm has a diffuse nerve GPCRs are of ancient origin and are found in several net. Despite this, the acorn worm contains well- eukaryotes that include most of the vertebrates, the conserved orthologues for several of the adhesion closest relatives to the vertebrates (Ciona intestinalis family members with a similar N-terminal domain and Branchiostoma floridae), and the most primi- architecture. This is particularly apparent for those tive animals (Nematostella vectensis and Trichoplax genes responsible for CNS development and regula- adhaerens;Fig.1).3 Intriguingly, gene mining in tion in vertebrates (Krishnan, A., et al. unpublished amphioxus B. floridae has revealed several novel data). Overall, adhesion-GPCRs have a remarkably adhesion-GPCR domains such as somatomedin B, long and complex evolutionary history that can be kringle, lectin C-type, SRCR, LDLa, immunoglobu- traced down to the common ancestors of metazoa lin I-set, CUB, and TNFR, typically not found in the and fungi (Fig. 1). Knowledge of the origin and mammalian receptors.4 Further, unique adhesion- evolution of the unique N-terminal domain archi- GPCRs have been identified in urochordates (C. in- tectures of these genes may offer opportunities to testinalis) and in the Strongylocentrotus purpuratus better understand their
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