Handbook of Experimental Pharmacology Volume 10SIII Editorial Board G.V.R.Born,London P. Cuatrecasas, Ann Arbor, MI H. Herken, Berlin K. Melmon, Stanford, CA GTPases in Biology II Contributors M. Biel, L. Birnbaumer, KJ. Blumer, J. Bockaert, E. Bosse, J.L. Boyer, P. Brabet, M. Camps, M.G. Caron, P.J. Casey, J. Chen, K. Clark, D. Corda, S. Coulter, P.N. Devreotes, D. Donelly, T.D. DuBose, Jr., J.H. Exton, J.B.C. Findlay, R.A. Firtel, V. Flockerzi, M. Forte, C. Gaskins, P. Gierschik, R. Gundersen, R.W. Gurich, J.R. Hadcock, J.A. Hadwiger, T.K Harden, J.D. Hildebrandt, Y.-K. Ho, F. Hofmann, K.P. Hofmann, V. Homburger, M.D. Houslay, R. Hullin, D. Hyde, R. Iyengar, O. Jacobowitz, S. Jahangeer, KH. Jakobs, G.L. Johnson, R.L. Johnson, N. Kimura, S.D. Kroll, Y. Kurachi, R.H. Lee, R.J. Lefkowitz, Y. Li, C. Londos, C.C. Malbon, D.H. Maurice, KR. McLeish, G. Milligan, A.J. Morris, E.J. Neer, A.S. Otero, U. Panten, D. Park, G.S. Pitt, R.T. Premont, F. Quan, M. Rodbell, W. Rosenthal, M. Russell, P. Ruth, C. Schwanstecher, M. Schwanstecher, I.A. Simpson, E. Stefani, G. Szabo, J.A. Thissen, T.D. Ting, L. Toro, G.L. Waldo, A. Welling, T.G. Wensel, M. Whiteway, W. Wolfgang, L. Wu Editors Burton F. Dickey and Lutz Birnbaumer Springer-Verlag Berlin Heidelberg New York London Paris Tokyo Hong Kong Barcelona Budapest Professor BURTON F. DICKEY, M.D. Baylor College of Medicine Department of Medicine Cell Biology and Experimental Therapeutics, Room 3C-385 Houston V A Medical Center 2002 Holcombe Boulevard Houston, TX 77030, USA Professor LUTZ BIRNBAUMER, Ph.D. Baylor College of Medicine Department of Cell Biology, Molecular Physiology and Biophysics, Medicine and Neurosciences One Baylor Plaza Houston, TX 77030, USA With 144 Figures and 22 Tables Library of Congress Cataloging-in Publication Data. GTPases in biology. (Handbook of experimental pharmacology; v. 108) "Contributors. M. Biel" ... [et al.l, vol. 2-t.p. Includes bibliographical refer ences and index. I. Guanosine triphosphatase. I. Aktories, K. II. Dickey, Burton F., 1953- . III. Birnbaumer, Lutz. IV. Series. QP905.H3 vol. 108 615'11 s 93-21636 lQP609.G83] [574.19'253] ISBN-I3 : 978-3-642-78347-0 e-ISBN-I3 : 978-3-642-78345-6 DOl: 10.1007/978-3-642-78345-6 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer-Verlag. 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Typesetting: Best-set Typesetter Ltd., Hong Kong 27/3130/SPS - 5 4 3 210 - Printcd on acid-free paper List of Contributors BIEL, M., Institut fUr Pharmakologie und Toxikologie der Technischen UniversiHit, Biedersteiner StraBe 29, D-80802 Munchen, Germany BIRNBAUMER, L., Departments of Cell Biology, Molecular Physiology and Biophysics, and Medicine (Endocrinology) and Division of Neuro sciences, Baylor College of Medicine, Texas Medical Center, One Baylor Plaza, Houston, TX 77030, USA BLUMER, K.J., Department of Cell Biology and Physiology, Box 8228, Washington University School of Medicine, 660 South Euclid Avenue, Saint Louis, MO 63110, USA BOCKAERT, J., UPR 9023 Centre CNRS-INSERM de Pharmacologie-Endo crinologie, Rue de la Cardonille, F-34094 Montpellier Cedex 5, France BOSSE, E., Institut fUr Pharmakologie und Toxikologie der Technischen Universitat, Biedersteiner StraBe 29, D-80802 Munchen Germany BOYER, J.L., Department of Pharmacology, School of Medicine, CB#7365, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7365, USA BRABET, P., UPR 9023 Centre CNRS-INSERM de Pharmacologie-Endo crinologie, Rue de la Carodonille, F-34094 Montpellier Cedex 5, France CAMPS, M., Molecular Pharmacology Division, German Cancer Research Center, 1m Neuenheimer Feld 280/111, D-69120 Heidelberg, Germany CARON, M.G., Departments of Medicine (Cardiology), Biochemistry and Cell Biology, Howard Hughes Medical Institute, Duke University Medical Center, P.O. Box 3821, Durham, NC 27710 CASEY, P.J., Section of Cell Growth, Regulation and Oncogenesis and Department of Biochemistry, Duke University Medical Center, P.O. Box 3686, Durham, NC 27710, USA CHEN, J., Department of Pharmacology, Mount Sinai School of Medicine of the City University of New York, P.O. Box 1215, One Gustave Levy Place, New York, NY 10029, USA VI List of Contributors CLARK, K., Eukaryotic Genetics Group, Biotechnology Research Institute, National Research Council of Canada, 6100 Royalmount Avenue, Montreal, Quebec, Canada H4P, 2R2 CORDA, D., Laboratory of Cellular and Molecular Endocrinology, Istituto di Ricerche Farmacologiche "Mario Negri", Consorzio Mario Negri Sud, Via Nazionale, 1-66030 S. Maria Imbaro (Chieti), Italy COULTER, S., Signal Transduction Section, Laboratory of Cellular and Molecular Pharmacology, Building 7-737, Research Triangle Park, NC 27709, USA DEVREOTES, P.N., Department of Biological Chemistry, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA DONNELLY, D., Department of Biochemistry and Molecular Biology, The University of Leeds, Leeds LS2 9JT, Great Britain DuBoSE, T.D., JR., University of Texas Health Science Center at Houston, Division of Nephrology, 6431 Fannin, P.O. Box 20708, Houston, TX 77025, USA EXTON, J.H., Howard Hughes Medical Institute and Department of Molecular Physiology and Biophysics, Vanderbilt University, School of Medicine, 802 Light Hall, Nashville, TN 37232, USA FINDLAY, J.B.C., Department of Biochemistry and Molecular Biology, The University of Leeds, Leeds LS2 9JT, Great Britain FIRTEL, R.A., Department of Biology, Center for Molecular Genetics, University of California, San Diego, La Jolla, CA 92093-0634, USA FLOCKERZI, V., Institut fUr Pharmakologie und Toxikologie der Technischen Universitat, Biedersteiner StraBe 29, D-80802 Miinchen Germany FORTE, M., Vollum Institute for Advanced Biomedical Research, Oregon Health Sciences University, 3181 S.W. Sam Jackson Park Rd., Portland, OR 97201, USA GASKINS, c., Department of Biology, Center for Molecular Genetics, University of California, San Diego, La Jolla, CA 92093-0634, USA GIERSCHIK, P., Molecular Pharmacology Division, German Cancer Research Center, 1m Neuenheimer Feld 280/III, D-69120 Heidelberg, Germany GUNDERSEN, R., Department of Biological Chemistry, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA GURICH, R.W., University of Texas Medical Branch, Division of Nephrology, 4.200 Old John Sealy, Galveston, TX 77550, USA List of Contributors VII HAD COCK , J.R., American Cyanamid Company, Agricultural Research Division, Molecular and Cellular Biology Group, P.O. Box 400, Princeton, NJ 08543-0400, USA HADWIGER, J.A., Department of Biology, Center for Molecular Genetics, University of California, San Diego, La Jolla, CA 92093-0634, USA HARDEN, T.K, Department of Pharmacology, School of Medicine, CB#7365, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7365, USA HILDEBRANDT, J.D., Department of Cell and Molecular Pharmacology, Medical University of South Carolina, 171 Ashley Avenue, Charleston, SC 29425-2251, USA Ho, Y.-K, Departments of Biochemistry and Ophthamology, University of Illinois at Chicago, Health Sciences Center, mlc 536, 1853 West Polk Street, Chicago, IL 60612, USA HOFMANN, F., Institut fur Pharmakologie und Toxikologie der Technischen Universitat, Biedersteiner StraBe 29, D-80802 Munchen Germany HOFMANN, KP., Institut fUr Biophysik und Strahlenbiologie, Albert Ludwigs-Universitat, AlbertstraBe 23, D-79104 Freiburg, Germany HOMBURGER, V., UPR 9023 Centre CNRS-INSERM de Pharmacologie Endocrinologie, Rue de la Cardonille, F-34094 Montpellier Cedex 5, France HOUSLAY, M.D., Molecular Pharmacology Group, Department of Biochemistry, University of Glasgow, Glasgow G12 8QQ, Great Britain HULLIN, R., Institut fur Pharmakologie und Toxikologie der Technischen Universitat, Biedersteiner StraBe 29, D-80802 Munchen, Germany HYDE, D., Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556, USA IYENGAR, R., Department of Pharmacology, Mount Sinai School of Medicine of the City of New York, P.O. Box 1215, One Gustave Levy Place, New York, NY 10029, USA JACOBOWITZ, 0., Department of Pharmacology, Mount Sinai School of Medicine of the City of New York, P.O. Box 1215, One Gustave Levy Place, New York, NY 10029, USA JAHANGEER, S., Signal Transduction Section, Laboratory of Cellular and Molecular Pharmacology, Building 7-733, Research Triangle Park, NC 27709, USA JAKOBS, KH., Institut fur Pharmakologie, Universitatsklinikum Essen, Hufelandstr. 55, D-45122 Essen, Germany VIII List of Contributors JOHNSON, G.L., Division of Basic Sciences, National Jewish Center for Immunology and Respiratory Medicine, 1400 Jackson Street, Denver, CO 80206, USA JOHNSON, R.L., Department of Biological Chemistry, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA KIMURA, N., Department of Molecular Biology, Tokyo Metropolitan Institute of Gerontology, 35-2, Sakaecho, Itabashi-ku, Tokyo-l73, Japan KROLL, S.D., Department of Pharmacology, Mount Sinai School of Medicine, City University of New York, P.O. Box 1215, One Gustave Levy Place, New York, NY 10029, USA KURACHI, Y., Division of Cardiovascular Diseases, Department of Internal Medicine, and Department of Pharmacology, Mayo Clinic, Mayo Foundation, Rochester, MN 55905, USA LEE, R.H., Department of Anatomy and Cell Biology, UCLA School of Medicine and Developmental Neurology Laboratory, Veteran Administration Medical Center, Sepulveda, CA 91343, USA LEFKOWITZ, R.J., Department of Medicine (Cardiology), Biochemistry and Cell Biology, Howard Hughes Medical Institute, Duke University Medical Center, P.O. Box 3821, Durham, NC 27710 LI, Y., Department of Molecular Physiology and Biological Physics, Jordan Hall, Box 449, University of Virginia, Charlottesville, VA 22908, USA LONDOS, c., Membrane Regulation Section, Laboratory of Cellular and Developmental Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bldg. 6, Rm. Bl-15, Bethesda, MD 20892, USA MALBON, C. C., Department of Pharmacology, Diabetes and Metabolic Diseases Research Program, School of Medicine, Health Sciences Center, University Stony Brook, Stony Brook, NY 11794-8651, USA MAURICE, D.H., Department of Pharmacology, School of Medicine, CB#7365, The University of north Carolina at Chapel Hill, Chapel Hill, NC 27599-7365, USA McLEISH, K.R., Kidney Disease Program, Departments of Biochemistry and Medicine, University of Louisville and the Veterans Administration Medical Center, 500 South Floyd Street, Louisville, KY 40292, USA MILLIGAN, G., Molecular Pharmacology Group, Department of Biochemistry, University of Glasgow, Glasgow G12 8QQ, Scotland, Great Britain List of Contributors IX MORRIS, A.J., Department of Pharmacology, School of Medicine, CB#7365, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7365, USA NEER, E.J., Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA OTERO, A.S., Department of Molecular Physiology and Biological Physics, Jordan Hall, Box 449, University of Virginia, Charlottesville, VA 22908, USA PANTEN, U., Institut fUr Pharmakologie und Toxikologie der Universitat Gottingen, Robert-Koch-StraBe 40, D-37075 Gottingen, Germany PARK, D., Laboratory of Biochemistry, National Heart, Lung and Blood Institute, National Institutes of Health, 9000 Rockville Pike, Building 3, Room 125, Bethesda, MD 20892, USA PITT, G.S., Department of Biological Chemistry, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA PREMONT, R.T., Department of Pharmacology, Mount Sinai School of Medicine of the City University of New York, P.O. Box 1215, One Gustave Levy Place, New York, NY 10029, USA Present address: Department of Medicine, Box 3821, Duke University Medical Center, Durham, NC 27710, USA QUAN, F., Vollum Institute for Advanced Biomedical Research, Oregon Health Sciences University, 3181 S.W. Sam Jackson Park Rd., Portland, OR 97201, USA RODBELL, M., Signal Transduction Section, Laboratory of Cellular and molecular Pharmacology, Building 18-01, Research Triangle Park, NC 27709, USA ROSENTHAL, W., Rudolf-Buchheim-Institut fur Pharmakologie der Justus Liebig-Universitat GieBen, Frankfurter StraBe 107, D-35392 GieBen, Germany RUSSELL, M., Division of Basic Sciences, National Jewish Center, for Immunology and Respiratory Medicine, 1400 Jackson Street, Denver, CO 80206, USA RUTH, P., Institut fUr Pharmakologie und Toxikologie der Technischen Universitat, Biedersteiner StraBe 29, D-80802 Munchen, Germany SCHWANSTECHER, C., Institut fUr Pharmakologie und Toxikologie der Universitat Gottingen, Robert-Koch-StraBe 40, D-37075 Gottingen, Germany x List of Contributors SCHWANSTECHER, M., Institut fUr Pharmakologie und Toxikologie der Universitat Gottingen, Robert-Koch-StraBe 40, D-37075 Gottingen, Germany SIMPSON, LA., Experimental Diabetes, Metabolism and Nutrition Section, Diabetes Branch, National Institute of Diabetes and Digestive Disease and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA STEFANI, E., Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Texas Medical Center, One Baylor Plaza, Houston, TX 77030, USA SZABO, G., Department of Molecular Physiology and Biological Physics, Jordan Hall, Box 449, University of Virginia, Charlottesville, VA 22908, USA THISSEN, J.A., Section of Cell Growth, Regulation and Oncogenesis and Department of Biochemistry, Duke University Medical Center, P.O. Box 3686, Durham, NC 27710, USA TING, T.D., Department of Biochemistry, University of Illinois at Chicago, Health Sciences Center, 1853 West Polk Street, Chicago, IL 60612, USA TORO, L., Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Texas Medical Center, One Baylor Plaza, Houston, TX 77030, USA WALDO, G.L., Department of Pharmacology, School of Medicine, CB#7365 , The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7365, USA WELLING, A., Institut fUr Pharmakologie und Toxikologie der Technischen Universitat, Biedersteiner StraBe 29, D-80802 Munchen, Germany WENSEL, T.G., Verna and Marrs McLean Department of Biochemistry, Baylor College of Medicine, Medical Center, One Baylor Plaza, Houston, TX 77030, USA WHITEWAY, M., Eukaryotic Genetics Group, Biotechnology Research Institute, National Research Council of Canada, 6100 Royalmount Avenue, Montreal, Quebec, Canada H4P 2R2 WOLFGANG, W., Vollum Institute for Advanced Biomedical Research, Oregon Health Sciences University, 3181 S.W. Sam Jackson Park Rd., Portland, OR 97201, USA Wu L., Department of Biological Chemistry, Johns Hopkins University, School of Medicine, 725 N. Wolfe St., Baltimore, MD 21205, USA Preface The question that may be raised is why a book on GTPases, especially as so much has been written lately in so many primary journals and review publications. Moreover, I received Pedro Cuatrecasas' invitation to edit this book after having just completed the editing, with Ravi Iyengar, of G Proteins for Academic Press. Understandably, my initial reaction was negative. Prodded by Pedro, and witnessing the breakneck pace at which new information was appearing in journals, I finally agreed. But even so, I decided to delay until I could better define how to organize and focus the book. A review of G Proteins by Peter Gierschik, which he titled "Balanced but unpackaged," proved helpful for the selection of topics and details of execution. G Proteins had been on trimeric G proteins only. Gierschik asked for "something on the small GTPases" and also more about structure. He also suggested more cross referencing, more serious editing by the editors, and faster publication. The arrival in Houston, from Boston, of my co-editor Burt Dickey, with his interest in small GTPases and GTPase structure, and his willingness to aid me, gave me - us - the impetus of requesting chapters. It soon proved that Burt was doing all the work, as some of the authors know. Burt would not take a "no" for an answer, and insisted, again and again. The consequence of the broadened scope was that a 30-40 chapter book became what it is now - a two volume compendium. The original dead line for receipt of the manuscripts was July 1992. The last chapters arrived around New Year. The original manuscripts represented the state-of-the-art in mid-late 1992, but thankfully many of the authors have taken advantage of an opportunity to add remarks on important recent developments. I am not sure that we have been able to cope with all of Peter Gierschik's (valid) criticisms. We hope that errors have been kept to a minimum. But he also wished that authors would not contradict each other, or at least that the editors would edit out the contradictions. Yet, for the most part contradic tions are based on the working hypotheses of the individual investigators and represent their legitimate points of view. They are, in fact, an exposition of the evolution of thoughts and arise because the experiments are not yet clear. We have thus left them, as far as they exist. Authors also change their mind. For example, I am sure that if one looked carefully, Henry Bourne