COLD SPRING HARBOR SYMPOSIA ON QUANTITATIVE BIOLOGY

VOLUME LIII COLD SPRING HARBOR SYMPOSIA ON QUANTITATIVE BIOLOGY

VOLUME LIII

Molecular Biology of Signal Transduction

COLD SPRING HARBOR LABORATORY 1988 COLD SPRING HARBOR SYMPOSIA ON QUANTITATIVE BIOLOGY VOLUME LIII 1988 by The Cold Spring Harbor Laboratory International Standard Book Number 0-87969-056-9 International Standard Serial Number 0091-7451 Library of Congress Catalog Card Number 34-8174

Printed in the United States of America All rights reserved

COLD SPRING HARBOR SYMPOSIA ON QUANTITATIVE BIOLOGY

Founded in 1933 by REGINALD G. HARRIS Director of the Biological Laboratory 1924 to 1936

Previous Symposia Volumes

I (1933) Surface Phenomena XXV (1960) Biological Clocks II (1934) Aspects of Growth XXVI (1961) Cellular Regulatory Mechanisms III (1935) Photochemical Reactions XXVII (1962) Basic Mechanisms in Animal Virus Biology IV (1936) Excitation Phenomena XXVIII (1963) Synthesis and Structure of Macromolecules V (1937) Internal Secretions XXIX (1964) Human Genetics VI (1938) Protein Chemistry XXX (1965) Sensory Receptors VII (1939) Biological Oxidations XXXI (1966) The Genetic Code VIII (1940) Permeability and the Nature of Cell Membranes XXXII (1967) Antibodies IX (1941) Genes and Chromosomes: Structure and Organi- XXXIII (1968) Replication of DNA in Microorganisms zation XXXIV (1969) The Mechanism of Protein Synthesis X (1942) The Relation of Hormones to Development XXXV (1970) Transcription of Genetic Material XI (1946) Heredity and Variation in Microorganisms XXXVI (1971) Structure and Function of Proteins at the XII (1947) Nucleic Acids and Nucleoproteins Three-dimensional Level XIII (1948) Biological Applications of Tracer Elements XXXVII (1972) The Mechanism of Muscle Contraction XIV (1949) Amino Acids and Proteins XXXVIII (1973) Chromosome Structure and Function XV (1950) Origin and Evolution of Man XXXIX (1974) Tumor Viruses XVI (1951) Genes and Mutations XL (1975) The Synapse XVII (1952) The Neuron XLI (1976) Origins of Lymphocyte Diversity XVIII (1953) Viruses XLII (1977) Chromatin XIX (1954) The Mammalian Fetus: Physiological Aspects of XLIII (1978) DNA: Replication and Recombination Development XLIV (1979) Viral Oncogenes XX (1955) Population Genetics: The Nature and Causes of XLV (1980) Movable Genetic Elements Genetic Variability in Population XLVI (1981) Organization of the Cytoplasm XXI (1956) Genetic Mechanisms: Structure and Function XLVII (1982) Structures of DNA XXII (1957) Population Studies: Animal Ecology and De- XLVIII (1983) Molecular Neurobiology mography XLIX (1984) Recombination at the DNA Level XXIII (1958) Exchange of Genetic Material: Mechanism and L (1985) Molecular Biology of Development Consequences LI (1986) Molecular Biology of Homo sapiens XXIV (1959) Genetics and Twentieth Century Darwinism LII (1987) Evolution of Catalytic Function

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ABRAHAM,IRENE, Dept. of Cell Biology, Upjohn tion, Karolinska Institute, Huddings Univer- Company, Kalamazoo, Michigan sity Hospital, Sweden ADAMS, DOLPH, Dept. of Pathology, Duke Uni- BERNINGER, MARK, Life Technologies Inc., Gaith- versity Medical Center, Durham, North ersburg, Maryland Carolina BERRIDGE, MICHAEL, Dept. of Zoology, Agricul- ADARI, HEDY, Cetus Corporation, Emeryville, tural and Food Research Council, Cam- California bridge, England ADEREM, ALAN, Dept. of Cellular Physiologyand BILLINGSLEY, MELVIN, Dept. of Pharmacology, Immunology, Rockefeller University, New Milton S. Hershey Medical Center, Pennsyl- York, New York vania ADLER, JULIUS, Dept. of Biochemistry, Universi- BIRNRAUMER, LUTZ, Dept. of Cell Biology, ty of Wisconsin, Madison Baylor College of Medicine, Houston, AHN, NATALIE,University of Washington, Seattle Texas ALCORTA,DAVID, Dept. of Cellular and Develop- BIRNBAUMER, MARIEL, Dept. of Cell Biology, mental Biology, Harvard University, Cam- Baylor College of Medicine, Houston, Texas bridge, Massachusetts BITENSKY, MARK, Los Alamos National Labora- ALLENDE, CATHERINE,Dept. of Biology, Univer- tory, New Mexico sidad de Chile, Santiago BLENIS, JOAN, Dept. of Molecular Biology, ALLENDE, JORGE, Dept. of Biochemistry, Univer- Northwestern University Medical School, sidad de Chile, Santiago Chicago, Illinois APPLEBURY, MEREDITHE, University of Chicago, BLOCH, DONALD, Dept. of Genetics, Harvard Eye Research Laboratories, Illinois Medical School, Boston, Massachusetts AXEL, RICHARD, Columbia University, Howard BLUMER, KEN, Dept. of Biochemistry, University Hughes Medical Institute, New York, New of California, Berkeley York BOBBITr, JESSE, Dept. of Biochemical Research, BACKER, JOSPEH, American Cyanamid, Pearl Lilly Research Laboratories, Indianapolis, River, New York Indiana BAEUERLE, PATRICK, Whitehead Institute, Cam- BOCCKINO,STEPHEN, Vanderbilt University, How- bridge, Massachusetts ard Hughes Medical Institute, Nash- BALLOU, LISA, Friedrich Miescher Institut, Basel, ville, Tennessee Switzerland BORASIO, GIAN DOMENICO, Dept. of Neuro- BARRETT, RONALD, Dept. of Neuroscience, Ab- chemistry, Max-Planck Institute for Psy- bott Laboratories, Abbott Park, Illinois chiatry, Martinsried, Federal Republic of BAYLOR,DENIS, Dept. of Neurobiology, Stanford Germany University School of Medicine, Califor- BORST, JANNIE, Dept. of Immunology, Nether- nia lands Cancer Institute, Amsterdam, The BELL, JOHN, Dept. of Biochemistry, McGill Uni- Netherlands versity, Montreal, Canada Bos, TIMOTHY, Dept. of Microbiology, University BELL, ROBERT, Dept. of Biochemistry, Duke Uni- of Southern California, Los Angeles versity Medical Center, Durham, North BOTELHO, LYNNE, Sandoz Research Institute, Carolina East Hanover, New Jersey BENOVIC, JEFFREY, Duke University, Durham, BOTSTEIN, DAVID, Genentech Inc., South San North Carolina Francisco, California BERG, HOWARD,Dept. of Cellular and Develop- BOURNE, HENRY, Dept. of Pharmacology, Uni- mental Biology, Harvard University Biologi- versity of California, San Franciso cal Laboratories, Cambridge, Massachu- BOYLE, WILLIAM, Dept. of Molecular Biology and setts Virology, Salk Institute, San Diego, Cali- BERKENSTAM, ANDERS, Dept. of Medical Nutri- fornia vi SYMPOSIUM PARTICIPANTS

BOWTELL, DAVID, University of California, Ber- Anatomy, Cornell University Medical Col- keley lege, New York, New York BRADSHAW, SUZANNE, Dept. of Cell Biology, CHARDIN, PIERRE, INSERM, Facult6 de Baylor College of Medicine, Houston, Texas Medecine Laboratory, St. Louis, Paris, BRASS, LAWRENCE, Hematology-Oncology Sec- France tion, University of Pennsylvania Phila- CHEN, WILLIAMS S., University of California, delphia Howard Hughes Medical Institute, San BRAVO, RODRIGO, European Molecular Biology Diego Laboratory, Heidelberg, Federal Republic of CLAPHAM, DAVID, Dept. of Pharmacology, Mayo Germany Clinic, Rochester, Minnesota BROWN, ARTHUR, Dept. of Physiology and CLARK, KAREN, University of Oregon Institute of Molecular Biophysics, Baylor College of Molecular Biology, Eugene Medicine, Houston, Texas COFFEY, ROBERT, Dept. of Medicine, Division of BROWN, DAVID, Dept. of Pharmacology, Univer- Gastroenterology, Vanderbilt University, sity College London, England Nashville, Tennessee BROWN, KENNETH, Institute of Animal Physiolo- CONNEELY, ORLA, Dept. of Cell Biology, Baylor gy, Cambridge, England College of Medicine, Houston, Texas BROWN, MICHAEL, Center for Genetic Disease, COOPER, J.A., Fred Hutchinson Cancer Center, University of Texas Health Science Center, Seattle, Washington Dallas COTE, TOM, Uniformed Services University, BucHou, THIERRY, INSERM, H6pital St. An- Bethesda, Maryland toine, Paris, France COURTNEIDGE, SARA, European Molecular Biolo- BUELL, GARY, Pharmacia Genetic Engineering gy Laboratory, Heidelberg, Federal Repub- Inc., La Jolla, California lic of Germany BURNS, DAVID, Dept. of Biochemistry, Duke CURRAN, THOMAS, Dept. of Molecular Oncology, University, Durham, North Carolina Roche Institute of Molecular Biology, Nut- BUTEL, JANET, Dept. of Virology, Baylor College ley, New Jersey of Medicine, Houston, Texas DAHLQUIST, FREDERICK, Institute of Molecular BUTT, TAUSEEE, Smith Kline & French Lab- Biology, University of Oregon, Eugene oratories, King of Prussia, Pennsylvania DALE, TREVOR, Imperial Cancer Research Fund, CADD, GARY, Dept. of Pharmacology, University London, England of Washington, Seattle DANIEL, TOM, Vanderbilt University, Nashville, CAPON, DAN, Dept. of Molecular Biology, Tennessee Genentech Inc., South San Francisco, Cali- DARNELL, JAMES, Dept. of Molecular Biology, fornia Rockefeller University, New York, New CARON, MARC, Duke University Medical Center, York Durham, North Carolina DAS MANJUSRI, Dept. of Biochemistry and Bio- CARROLL, DENNIS, Cold Spring Harbor Labora- physics, University of Pennsylvania, Phila- tory, New York delphia CARTER, ANTHONY, National Institutes of Health, DASH, PRAMOD, Dept. of Neurobiology and Be- Bethesda, Maryland havior, Columbia University, New York, CASSATELLA, MARCO, Wistar Institute, Philadel- New York phia, Pennsylvania DETERRE, PHILIPPE, Centre d'Etudes Nucleaires, CATELLI, MARIA-GRAZIA, INSERM, Laboratoire Laboratory Biophysique Moleculaire, Greno- Hormones, Montrouge, France ble, France CATO-BIRO, LAURA, Dept. of Biochemistry, DEVREOTES, PETER, Dept. of Biological Chemis- McGill University, Montreal, Canada try, Johns Hopkins University, Baltimore, CHABRE, MARC, Centre d'Etudes Nucleaires, Maryland Laboratoire Biologie Moleculaire et Cel- DIAMOND, IVAN, University of California, San lulaire, Grenoble, France Francisco General Hospital CHALEEF, DEBORAH, American Cyanamid Com- DICKEY, BURTON, Pulmonary Center, Boston pany, Princeton, New Jersey University School of Medicine, Massachu- CHAMBON, PIERRE, Institut de Chimie, setts Biologique, Strasbourg Faculty of Medicine, DIDSBURY, JOHN, Dept. of Inflammation Re- France search, Genentech Inc., South San Francis- CHAO, MOSES, Dept. of Cell Biology and co, California SYMPOSIUM PARTICIPANTS vii

DILIBERTO, EMANUEL,Dept. of Medical Biochem- FLANAGAN, JOHN, Dept. of Genetics, Harvard istry, Burroughs Wellcome Company, Re- Medical School, Boston, Massachusetts search Triangle Park, North Carolina FLAVELL, RICHARD, Biogen Research Corpora- DIXON, RICHARD, Merck Sharp & Dohme Re- tion, Cambridge, Massachusetts search Laboratories, West Point, Pennsyl- FLINT, ANDREW, Dept. of Biochemistry, Univer- vania sity of California, Berkeley DOSTMANN, WOLFGANG,Dept. of Chemistry, Uni- FLiP,I, ANTON, Dept. of Medicinal Chemistry, versity of California, San Diego, La Julia Pfizer Central Research, Groton, Connecti- DOWNWARD, JULIAN, Whitehead Institute, Cam- cut bridge, Massachusetts FOLDES, ROBERT, Dept. of Cancer and Cell Biolo- DUDLEY, DAVID, Park-Davis Research Division, gy, Mt. Sinai Hospital Research Institute, Ann Arbor, Michigan Toronto, Canada EATOCK, RUTH ANN, Dept. of Physiology, Uni- FOSTER, DAVID, Dept. of Biological Sciences, versity of Rochester, New York Hunter College New York, New York EDWARDS, AL, Dept. of Biochemistry, McGill FOULKES, GORDON, Oncogene Science Inc., Man- University, Montreal, Canada hasset, New York ENDEMANN, GERDA, Dept. of Cell Biology, Stan- FOWLKES, DANA, University of North Carolina, ford University, California Chapel Hill ERIKSON, RAYMOND, Dept. of Cellular and De- FRANZA, ROBERT, Cold Spring Harbor Labora- velopmental Biology, Harvard University tory, New York Biological Laboratories, Cambridge, Massa- KWOK-KEUN~ FUNG, BERNARD, Jules Stein Eye chusetts Institute, University of California School of ERNST, JOEL, University of California, San Fran- Medicine, Los Angeles cisco FURTH, MARK, Oncogene Science Inc., Manhas- ERTL, ADRIENNE, Dept. of Medicine, University set, New York of California, San Diego, La Julia GALIONE, ANTHONY,Dept. of Zoology, Universi- ERUSALIMSKY,JORGE, Imperial Cancer Research ty of Cambridge, England Fund, London, England GARBERS, DAVID, Vanderbilt University, Howard ERCH, KEITH R., Dept. of Molecular Genetics, Hughes Medical Institute, Nashville, Ten- University of California, San Diego, La Jolla nessee ESPINO, PEARL, Dept. of Cellular Regulation, GAROFALO, ROBERT, Dept. of Molecular Biology, Integrated Genetics, Framingham, Massa- Memorial Sloan Kettering Institute, New chusetts York, New York EVANS, RUN, Salk Institute, Howard Hughes GARPaSON, JAMES, Dept. of Pharmacology, Uni- Medical Institute Research Laboratories, La versity of Virginia, Charlottesville Jolla, California GATELL, SUSAN, Elsevier Publications, Trends in EVANS, TONY, Dept. of Pharmacological Sci- Neurosciences, Cambridge, England ences, Genentech Inc., South San Francisco, GEORGOPAPADAKOU,NAFSIKA, Dept. of Chemo- California therapy, Hoffmann-La Roche, Nutley, New FABBRO, DORIANO, University Clinic Medical York School Laboratories, Basel, Switzerland GIBBS, JAY, Dept. of Molecular Biology, Merck FANG, KATHY,Dept. of Biochemical Endocrinol- Sharp & Dohme Research Laboratories, ogy, Rockefeller University, New York, New West Point, Pennsylvania York GILL, GORDON, Dept. of Medicine, University of FARBER, JOSHUA, Dept. of Medicine, Johns Hop- California, San Diego, La Jolla kins University, Baltimore, Maryland GILMAN, ALFRED, Dept. of Pharmacology, Uni- FERAMISCO, JAMES, Cold Spring Harbor Labora- versity of Texas Health Science Center, tory, New York Dallas FERRO, ARI, Dept. of Biology, University of GILMAN, MICHAEL, Cold Spring Harbor Labora- Utah, Salt Lake City tory, New York FIRTEL, RICHARD, Center for Molecular Gen- GINSBERG, MARK, Dept. of Immunology, Scripps etics, University of California, San Diego, La Clinic and Research Foundation, La Jolla, Jolla California FISCHER, J.A., University of Zurich, Klinik Bal- GLASS, CHRISTOPHER, Dept. of Medicine, Univer- grist, Switzerland sity of California, San Diego, La Julia FISCHER, SIEGMUND,INSERM, Paris, France GOLDSTEIN, JOSEPH, Dept. of Molecular Gen- viii SYMPOSIUM PARTICIPANTS

etics, University of Texas Health ScienceCen- HENNER, DENNIS, Dept. of Cell Genetics, Genen- ter, Dallas tech Inc., South San Francisco, California GOMPERTS, BASTIEN, Dept. of Experimental HERSKOWITZ, IRA, Dept. of Biochemistry and Pathology, University College London, Eng- Biophysics, University of California, San land Francisco GONZATH-HACES, MARY, NCI-Frederick Cancer HEss, J. FRED, Dept. of Biology, California Insti- Research Facility, Frederick, Maryland tute of Technology, Pasadena GORDON, ADRIENNE, San Francisco General Hos- HIGASHIDA, H., Dept. of Biophysics, Kanazawa pital, University of California University School of Medicine, Japan GOSSE, MARILYN, Dept. of Pharmacology, Uni- HILL, DAVID, Genetics Institute, Cambridge, formed Services University, Bethesda, Massachusetts Maryland HIRSCH, JEANNE, Dept. of Biology, Yale Univer- GRAHAM, ROBERT, Cardiac Unit, Massachusetts sity, New Haven, Connecticut General Hospital, Boston HODGINS,M.B., Dept. of Dermatology, Glasgow GROPPI, VINCENT, Dept. of Cell Biology, Upjohn University, Scotland Company, Kalamazoo, Michigan HOMCY, CHARLES, Harvard Medical School, GUTKIND, SILVIO, LOPB, NIDR, National Insti- Massachusetts General Hospital, Boston tutes of Health, Bethesda, Maryland HUGANIR, RICHARD, Dept. of Neuroscience, HAIECH, JACQUES, CNRS, INSERM, Montpel- Johns Hopkins University, Baltimore, Mary- lier, France land HALL, ALAN, Institute of Cancer Research, Lon- HUNTER, TONY, Tumor Virus Laboratory, Salk don, Chester Beatty Laboratories, England Institute, La Jolla, California HALL, DAVID, Dana-Farber Cancer Institute, HUTCHCROFT, JILL, Dept. of Biological Sciences, Boston, Massachusetts Purdue University, West Lafayette, Indiana HAMM, HEIDI, Dept. of Physiology and Bio- IMBRA, RICK, Dept. of Environmental Medicine, physics, University of Illinois, Chicago New York University School of Medicine, HAMPTON, RANDOLPH, Dept. of Biochemistry, Tuxedo, New York University of Wisconsin, Madison INGHAM, COLIN, Dept. of Biochemistry, Universi- HANAFUSA, HIDESABURO, Rockefeller University, ty of Wisconsin Madison New York, New York IVES, HARLAN, Dept. of Medicine and Nephrolo- HANCOCK, JOHN, Institute of Cancer Research, gy, University of California, San Francisco London, Chester Beatty Laboratories, IWASHITA, SHINTARO, Mitsubishi-kasei Institute, England Tokyo, Japan HANLEY, MICHAEL, University of Cambridge, IYENGAR,RAVI, Dept. of Pharmacology, Mt. Sinai MRC Molecular Neurobiology Unit, Eng- School of Medicine, New York, New York land IZUMO, SEIGO, Dept. of Cardiology, Harvard HANSBURG, DANIEL, Fox Chase Cancer Center, Medical School, Children's Hospital, Philadelphia, Pennsylvania Boston, Massachusetts HASLAM, R., Dept. of Pathology, McMaster Uni- JACKOWSKI, SUZANNE, Dept. of Biochemistry, St. versity, Hamilton, Canada Jude Children's Research Hospital, Mem- HASSELL, JOHN, Dept. of Microbiology and Im- phis, Tennessee munology, McGill University, Montreal, JACKSON, STEPHEN, Dept. of Biochemistry, Uni- Canada versity of California, Berkeley HAUBRUCK,HEINZ, Dept. of Molecular Genetics, JACQUET, MICHEL, Laboratoire d'Information Max-Planck Institute, Gottingen, Federal Genetique et Development, Universit6 de Republic of Germany Paris-Sud, Orsay, France HE, XI, Dept. of Biology, University of Califor- JAMaOU, ROBERT,Dept. of Pathology, University nia, San Diego, La Jolla of North Carolina, Chapel Hill, North HEINRICH, JULIA, Dept. of Molecular Biology, Carolina Memorial Sloan Kettering Institute, New JASNY, BARBARA,Science, AAAS, Washington, York, New York D.C. HEMMINGS, BRIAN, Friedrich Miescher Institute, JAZIN, ELENA, New York State Department of Basel, Switzerland Health, Wadsworth Center for Research, Al- HEN, RENE, Columbia University, Howard bany, New York Hughes Medical Institute, New York, New JENNESS, DUANE, Dept. of Molecular Genetics York and Microbiology, University of Massa- SYMPOSIUM PARTICIPANTS ix

chusetts Medical School, Worcester, Massa- Institute of Technology, Cambridge, Massa- chusetts chusetts JOHNSON, DOUGLAS,Dept. of Biology, University KOBILKA, BRIAN, Duke University Medical Cen- of Michigan, Ann Arbor, Michigan ter, Durham, North Carolina JOHNSTON, ROGER, Dept. of Physiology and Bio- KOSHLAND, DANIEL, Dept, of Biochemistry, Uni- physics, State University of New York, Stony versity of California, Berkeley Brook KRAL, LEOS, Dept. of Biochemistry, Wayne State JONES, DAVID, Dept. of Molecular Biology and University, Detroit, Michigan Genetics, Johns Hopkins University, Balti- KREBS, EDWIN, University of Washington, How- more, Maryland ard Hughes Medical Institute, Seattle JOSHI, LATA, Sandoz Research Institute, East KUNG, CHING, Dept. of Molecular Biology, Uni- Hanover, New Jersey versity of Wisconsin, Madison JULIUS, DAVID, Columbia University College of KURJAN, JANET, Dept. of Biological Sciences, Physicians and Surgeons, Institute of Cancer Columbia University, New York, New York Research, New York, New York LACAL, JUAN CARLOS, National Cancer Institute, JURIVICH, DONALD, Duke University, Durham, NIH, Bethesda, Maryland North Carolina LACOMBE, M.L., Institut. Pasteur, Unit6 de Bio- KAHN, RICHARD,National Cancer Institute, NIH, chimie Cellulaire, Paris, France Laboratory of Biological Chemistry, Bethes- LAI, CHUN-YEN, Dept. of Protein Biochemistry, da, Maryland Hoffmann-La Roche, Nutley, New Jersey KAJIJI, SHAMA, Pfizer Central Research, Neuro- LANCET, DORON, Dept. of Membrane Research, sciences and Cancer, Groton, Connecti- Weizmann Institute of Science, Rehovot, cut Israel KANDEL, ERIC, Columbia University College of LANCHO, TERESA, Laboratory of Molecular Mi- Physicians and Surgeons, Center for Neuro- crobiology, National Institutes of Health, biology and Behavior, New York, New York Bethesda, Maryland KATAN, MATILDA, Ludwig Institute for Cancer LANDIS, CLAUDIA, Dept. of Pharmacology, Uni- Research, London, England versity of California, San Francisco KAUPP, BENJAMIN, Dept. of Biologie and Chemie, EARNER,JOSEPH, Dept. of Pharmacology, Univer- Universitfit Osnabruck, Federal Republic of sity of Virginia, Charlottesville Germany LEAR, JAMES, E.I. DuPont de Nemours & Com- KAZIRO, YOSHITO, Institute of Medical Sciences, pany, Central Research & Development Ex- University of Tokyo, Japan perimental Station, Wilmington, Delaware KHACHATRIAN,LEILI, Dept. of Pathology, Boston LEE, ANGEL, NHLBI, Clinical Hematology University School of Medicine, Massa- Branch, National Institutes of Health, chusetts Bethesda, Maryland KHORANA, H. GORIND, Dept. of Biology and LEEKOWlTZ, ROBERT, Duke University Medical Chemistry, Massachusetts Institute of Tech- Center, Durham, North Carolina nology, Cambridge LEICHTLING, BEN, Dept. of Pediatrics, National KIBERSTIS, PAULA, Cell Editorial Office, Cam- Jewish Center for Immunology, Denver, bridge, Massachusetts Colorado gaM, SUNG-Hou, Dept. of Chemistry, University LEVY, DAVID, Rockefeller University, New York, of California, Berkeley New York KIRSCn, DONALD, Dept. of Molecular Biology, LI, CONGYI, Dept. of Biochemistry, University of E.R. Squibb Princeton, New Jersey Wisconsin, Madison KLEIN, PETER, Dept. of Biological Chemistry, LIMBIRD,LEE, Dept. of Pharmacology, Vanderbitt Johns Hopkins University, Baltimore, University, Nashville, Tennessee Maryland LIN, CHUN WEE, Abbott Laboratories, Abbott KLEMENZ,, ROMAN, Ludwig Institute for Cancer Park, Illinois Research, Bern, Switzerland LrroscrI, IRENE, Dept. of Pharmacology, Univer- KMIECIK, THOMAS, NCI-Frederick Cancer Re- sity of Miami, Florida search Facility, Basic Research Program, LLOYD, ALISON, Institute of Cancer Research, Frederick, Maryland London, Chester Beatty Laboratories, Eng- Kr~OPF, JOHN, Genetics Institute, Cambridge, land Massachusetts Low, MART/N, Dept. of Physiology and Cellular KNOX, BARRY,Dept. of Chemistry, Massachusetts Biophysics, Columbia University College of x SYMPOSIUM PARTICIPANTS

Physicians and Surgeons, New York, New MCROBBIE, STUART, Saunders Scientific Publica- York tions, The Workshop, London, England LOWE, DAVID, Dept. of Molecular Biology, MEHMET, HUSEYIN, Imperial Cancer Research Genentech Inc., South San Francisco, Cali- Fund, London, England fornia MERCKEN, LUC, Genetica, Paris, France LUKAS, THOMAS, Dept. of Pharmacology, Van- MEYER, TOBIAS, Dept. of Cell Biology, Stanford derbilt University, Nashville, Tennessee University, California MACKENZIE, ROBERT, Abbott Laboratories, Ab- MEYERHOF, WOLFGANG, Universitiits Kranken- bott Park, Illinois haus Eppendorf, Institut fur Zellbio- MACNAB, ROBERT, Dept. of Molecular Biophysics chemie, Hamburg, Federal Republic of and Biochemistry, Yale University, New Germany Haven, Connecticut MICHELL, BOB, Dept. of Biochemistry, University MAGEE, TONY, MRC National Institute for Medi- of Birmingham, England cal Research, London, England MICHITSCH, RICHARD, Oncogene Science Inc., MAGGI, ADRIANA, University of Milan, Milano Manhasset, New York Molecular Pharmacology Laboratory, Italy MIKI, TORU, Dept. of Cellular and Molecular MAGUN, BRUCE, Dept. of Cell Biology and Biology, National Cancer Institute, Bethes- Anatomy, Oregon Health Sciences Universi- da, Maryland ty, Portland MILLER, R. TYLER, Dept. of Pharmacology, Uni- MARBACH, IRIT, Dept. of Biological Chemistry, versity of California, San Francisco Hebrew University of Jerusalem, Israel MISKO, THOMAS, Dept. of Molecular Genetics MARRION, NEIL, Dept. of Neurobiology and Be- and Mammalian Biology, Monsanto Com- havior, State University of New York, Stony pany, St. Louis, Missouri Brook, Howard Hughes Medical Research MISRA, RAVI, Dept. of Microbiology and Molecu- Laboratory, New York lar Genetics, Harvard Medical School, Bos- MARSH, LORRAINE, Dept. of Biochemistry and ton, Massachusetts Biophysics, University of California, San MOCHLY-ROSEN, MARIA, San Francisco General Francisco Hospital, University of California MARSHAK, DANIEL, Cold Spring Harbor Labora- MOE, GREG, Dept. of Biochemistry, University of tory, New York California, Berkeley MARSHALL, MARK, Dept. of Molecular Biology, MOELLING, KARIN, Max-Planck Institute of Merck Sharp & Dohme Research Labora- Molecular Genetics, Berlin, Federal Repub- tories, West Point, Pennsylvania lic of Germany MARTIN-ZANCA, DIONISIO, NCI-Frederick Cancer MOLLER, WIM, Dept. of Medical Biochemistry, Research Facility, Basic Research Program, Sylvius Laboratoria, Leiden, The Nether- Frederick, Maryland lands MATSUI, HIROAKI,Dept. of Medicine, Division of MOOLENAAR, WOUTER, Netherlands Cancer Insti- Cardiology, Duke University Medical Cen- tute, Amsterdam, The Netherlands ter, Durham, North Carolina MOORE, DAVID, Dept. of Molecular Biology, MATSUI, YASUSHI, Biosciences Laboratory Re- Massachusetts General Hospital, Boston search Center, Mitsubishi Chemical Ind., MORRISON, DEBORAH, Dana-Farber Cancer Insti- Yokohama, Japan tute, Boston, Massachusetts MATSUMOTO, KUNIHIRO, DNAX Research Insti- MOXHAM, CARY, Burroughs Wellcome, Research tute, PaiD Alto, California Triangle Park, North Carolina MATTER, ALEX, Ciba-Geigy, Basel, Switzerland MULHERKAR, RITA, NCI-Frederick Cancer Re- MAYER, BRUCE, Rockefeller University, New search Facility, Developmental Oncology York, New York Section, Frederick, Maryland MCCORMICK, FRANK, Dept. of Molecular Biology, MURAD, FERID, Dept. of Medicine, Stanford Uni- Cetus Corporation, Emeryville, California versity Medical Center, PaiD Alto, California McKAY, IAN, Amersham International plc New MYERS, ALAN, Dept. of Biochemistry, Iowa State Technologies, Buckinghamshire, United University, Ames Kingdom NAKAYAMA, NAOKI, Dept. of Molecular Biology, MCKNIGHT, STANLEY, G., Dept. of Pharmacol- DNAX Research Institute, PaiD Alto, Cali- ogy, University of Washington, Seattle fornia SYMPOSIUM PARTICIPANTS xi

NATHANS, DANIEL, Dept. of Molecular Biology POUYSSEGUR, JACQUES, Dept. of Biochemistry, and Genetics, Johns Hopkins University, Division Research Center, CNRS, Nice, Baltimore, Maryland France NATHANSON,NEIL, Dept. of Pharmacology, Uni- PRENTKI, MARC, Dept. of Medicine, Institut versity of Washington, Seattle de Biochimie Clinique, Geneva, Switzer- NEER, EVA, Dept. of Medicine, Brigham and land Women's Hospital, Boston, Massachusetts PRUSS, REBECCA, Dept. of Biochemical Sciences, NELKIN, BARRY,Oncology Center, Johns Hopkins Merrell Dow Research Institute, Cincinnati, University, Baltimore, Maryland Ohio NIMAN, HENRY, PROGENX INc., San Diego, PRYWES, RON, Dept. of Biochemistry and California Molecular Biology, Rockefeller, New York, NISHIZUr~A, YASUTOMI, Dept. of Biochemistry, New York Kobe University School of Medicine, Japan PTASHNE, MARK, Dept. of Biochemistry and NORTHUP, JOHN, Dept. of Pharmacology, Yale Molecular Biology, Harvard University, University, New Haven, Connecticut Cambridge, Massachusetts NOVICK, PETER, Dept. of Cell Biology, Yale Uni- RABEN, DANIEL,Dept. of Physiology,Johns Hop- versity School of Medicine, New Haven, kins University School of Medicine, Balti- Connecticut more, Maryland NUMA, SHOSAI~U, Dept. of Medical Chemistry, RACKER, EFRAIM,Dept. of Biochemistry, Cornell Kyoto University, Japan University, Ithaca, New York O'MALLEY, BERT, Dept. of Cell Biology, Baylor RAETZ, CHRISTIAN,Dept. of Biochemistry, Uni- College of Medicine, Houston, Texas versity of Wisconsin, Madison OESTREICHER, A. BEATE, Institute of Molecular RAJPUT, BHANA, Friedrich-Meischer Institute, Biology, University of Utrecht, The Nether- Basel, Switzerland lands RAKOWICZ-SZULCZYNSKA,EVA, The Wistar Insti- OOSAWA, KENJI, Dept. of Neurochemistry and tute, Philadelphia, Pennsylvania Neuropharmacology, Osaka University RAPP, ULF, National Cancer Institute, Labora- Medical School, Japan tory of Viral Carcinogenesis,Frederick, Mary- OTTO, HENNING, Dept. of Neurochemie, Free land University Berlin, Federal Republic of Ger- RAYTER, SYDONIA,Oncogene Science Inc., Man- many hasset, New York PARK, MORAG, NCI-Frederick Cancer Research REDDY, PRASAD, Center for Chemical Physics, Facility, Basic Research Program, Freder- National Bureau of Standards, Gaithers- ick, Maryland burg, Maryland PARKER, CARL, Dept. of Chemistry, California In- REDISKE, JOHN, Dept. of Inflammation, CIBA- stitute of Technology, Pasadena GEIGY Corporation, Summit, New Jersey PARKINSON,JOHN, Dept. of Biology, University of REED, RANDALL,Dept. of Molecular Biology and Utah, Salt Lake City Genetics, Johns Hopkins University Medical PARSONS,SARAH, Dept. of Microbiology, Univer- School, Baltimore, Maryland sity of Virginia Medical School, Charlottes- REED, STEVEN, Dept. of Molecular Biology, ville Scripps Clinic and Research Foundation, La PAWSON, TONY, Dept. of Molecular and Develop- Jolla, California mental Biology, Mt. Sinai Hospital Research REGAN, JOHN, Duke University Medical School, Institute, Toronto, Canada Durham, North Carolina PENN, LINDA, J.Z., Imperial Cancer Research RENEKE, JOHANNA,Dept. of Genetics, University Fund, London, England of California, Berkeley PIGGOIT,JAMES, Dept. of Cellular Pharmacology, RIABOWOL, KARL, Cold Spring Harbor Labora- Smith Kline & French Research Ltd., Hert- tory fordshire, England ROACH, ARTHUR, Dept. of Molecular Immunol- POGGIOLI,JOSIANE, Universit6 de Paris-Sud, Phy- ogy and Neurobiology, Mt. Sinai Hospital siologie et Pharmacolgie Cellulaire, IN- Research Institute, Toronto, Canada SERM, Orsay, France ROBERTS, BRUCE, Integrated Genetics, Framing- PONZETrO, CAROLA, Dept. of Medicine/Oncolo- ham, Massachusetts gy, University of Turin, Italy ROBERTS, THOMAS, Dept. of Pathology, Dana- xii SYMPOSIUM PARTICIPANTS

Farber Cancer Institute, Boston, Massa- crinology Laboratory, Rockefeller Universi- chusetts ty, New York, New York ROBERTSON, MIRANDA,Nature, London, England SASSONE-CORSI, PAOLO, Dept. of Molecular Biol- RODER, JOHN, Dept. of Molecular Immunology ogy and Virology Salk Institute, San Diego, and Neurobiology, Mt. Sinai Hospital Re- California search Institute, Toronto, Canada SAXE, CHARLES, NIDDK/NIH, Dept. of Cellular ROMERO, GUILLERMO, Dept. of Pharmacology, and Developmental Biology, National Insti- University of Virginia, Charlottesville tutes of Health, Bethesda, Maryland RONNETT, GABRIELE, Dept. of Neuroscience, SCI-ILESSINGER, JOSEPH, Rorer Biotechnology Inc., Johns Hopkins University School of Medi- RockviUe, Maryland cine, Baltimore, Maryland SCHLONDORFF, DETLEF, Albert Einstein College ROSEN, ANTONY, Dept. of Cellular Physiology of Medicine, Bronx, New York and Immunology, Rockefeller University, SCHONTHAL, AXEL, Kenforschungszentrum Karls- New York, New York ruhe, Institute fur Genetik und Toxikologie, ROSENBAUM, JAN, Procter & Gamble Company, Federal Republic of Germany Miami Valley Laboratories, Cincinnati, Ohio SCHULTZ, GUNTER, Dept. of Pharmacology, ROSENFELD, MICHAEL, University of California Freie University of Berlin, Federal Republic School of Medicine, San Diego, La Jolla of Germany ROSENTHAL,ARNON, Dept. of Molecular Biology, SCHULZ, JOHN, Dept. of Physiology, Tufts Uni- Genentech Inc., South San Francisco, Cali- versity, Boston, Massachusetts fornia SCHUTZ, GUNTHER, Institute of Cell and Tumor Ross, CHRISTOPHER, Dept. of Neuroscience, Biology, German Cancer Research Center, Johns Hopkins University, Baltimore, Mary- Heidelberg, Federal Republic of Germany land SCHWARTZ, JAMES, Columbia University, How- Ross, ELLIOTr, Dept. of Pharmacology, Universi- ard Hughes Medical Institute, New York, ty of Texas Health Science Center, Dallas New York ROTH, RICHARD, Dept. of Pharmacology, Stan- SEEDORF, KLAUS,Dept. of Developmental Biolo- ford University Medical School, California gy, Genentech Inc., South San Francisco, ROUSSEL, MARTINE, Dept. of Tumor Cell Biolo- California gy, St. Jude Children's Research Hospital, SEGEV, NAVA, Dept. of Biochemistry, Stanford Memphis, Tennessee University, California ROZENGURT, ENRIQUE,Imperial Cancer Research SERIGUCHI, KAZUO, Dept. of Biochemistry, Kobe Fund, London, England University School of Medicine, Japan RUBIN, GERALD, Dept. of Biochemistry, Univer- SELINCER, ZVI, Dept. of Biological Chemistry, sity of California, Berkeley Hebrew University of Jerusalem, Israel RUDKIN, BRIAN,Dept. of Growth Factor, Nation- SETH, PREM, Cancer Center, University of Roch- al Institutes of Health, NICHD, Bethesda, ester, New York Maryland SEUWEN, KLAUS, CNRS, Centre de Biochimie, RUGGIERI,ROSAMARIA, Dept. of Molecular Biolo- Nice, France gy, DNAX Research Institute, PaiD Alto, SHALABY, ISMAIL, Pfizer Central Research, California Groton, Connecticut RYAN, TIMOTHY, Dept. of Physics, Cornell Uni- SHAPIRO, ELI, Columbia University, Howard versity, Ithaca, New York Hughes Medical Institute, New York, New SADOWSKI,HENRY, Dept. of Biophysics and Med- York icine, University of Rochester, New York SHEARMAN,MARK, Dept. of Biochemistry, Kobe SAIMI, YOSHIRO, Dept. of Molecular Biology, University School of Medicine, Japan University of Wisconsin, Madison SHERMAN-GOLD, RIVKA, BioGrowth Inc., Rich- SAKMAR, THOMAS, Dept. of Chemistry, Massa- mond, California chusetts Institute of Technology, Cambridge, SHERR, CHARLES, Dept. of Tumor Cell Biology, Massachusetts St. Jude Children's Research Hospital, SALOMON, YORAM,Dept. of Hormone Research, Memphis, Tennessee Weizmann Institute of Science, Rehovot, SHI, WENYUAN,Dept. of Biochemistry, Universi- Israel ty of Wisconsin, Madison SALTIEL,ALAN, Dept. of Biochemistry and Endo- SHIMIZU, YOSHIKO, Dept. of Molecular and Cell- SYMPOSIUM PARTICIPANTS xiii

ular Biology, University of Arizona, Tuc- SULLIVAN, MARK, Eastman Kodak, Rochester, son New York SHOWELL, HENRY, Dept. of Immunology and SULTZMAN, LISA, Genetics Institute, Cambridge, Infectious Disease, Pfizer Central Research, Massachusetts Groton, Connecticut SWEATT, J. DAVID, Columbia University College SHUTrLEWORTH, TREVOR, Dept. of Physiology, of Physicians and Surgeons, Center for University of Rochester, New York Neurobiology Behavior, New York, New SIGAL, IRVING, Merck Sharp & Dohme Research York Laboratories, West Point, Pennsylvania TAYLOR, COLIN, Dept. of Zoology, University of SIMON, MELVIN, Dept. of Biology, California Cambridge, England Institute of Technology, Pasadena TAYLOR, SUSAN, Dept. of Chemistry, University SIMON, MICHAEL, Dept. of Biochemistry, Uni- of California, San Diego, La Jolla California versity of California, Berkeley TELERMAN, ADAM, Universit6 Libre de Brux- SKINNER, RICHARD,Dept. of Molecular Sciences, elles, Faculte de Medecine, Belgium Wellcome Foundation, Kent, England THEIBERT, ANNE, Dept. of Neuroscience, Johns SMART, JOHN, Dept. of Biological Chemistry, Hopkins University School of Medicine, Hoffmann-La Roche, Nutley, New Jersey Baltimore, Maryland SORBARA-CAZAN, Rockefeller University, New THOMAS, PAUL, Dept. of Protein Biochemistry, York, New York Hoffmann-La Roche, Nutley, New Jer- SPRAGUE, GEORGE, University of Oregon, Insti- sey tute of Molecular Biology, Eugene THORNER, JEREMY, Dept. of Biochemistry, Uni- STACEY, DENNIS, Dept. of Cell Biology, Roche versity of California, Berkeley Institute of Molecular Biology, Nutley, New TIPPER, DONALD, Dept. of Molecular Genetics Jersey and Microbiology, University of Massa- STADEL, JEFFREY, Dept. of Molecular Pharmacol- chusetts Medical School, Worcester ogy, Smith Kline & French Laboratories, TJIAN, ROBERT, Dept. of Biochemistry, Universi- King of Prussia, Pennsylvania ty of California, Berkley STEARNS, TIM, Dept. of Biology, Massachusetts TREISMAN, RICHARD, MRC Laboratory of Institute of Technology, Cambridge, Massa- Molecular Biology, Cambridge, England chusetts TSAI, MEN-HWEI, Dept. of Molecular Biology, STEPHENSON, JOHN, Oncogene Science Inc., Cleveland Clinic Foundation, Ohio Manhasset, New York TSAI, SOPHIA, Dept. of Cell Biology, Baylor STERNWEIS, PAUL, Dept. of Pharmacology, Uni- College of Medicine, Houston, Texas versity of Texas, Dallas TSIEN, ROGER, Dept. of Physiology and STEWART, RICHARD, University of Oregon, Insti- Anatomy, University of California, Ber- tute of Molecular Biology, Eugene keley STILES, CHARLES, Dana-Farber Cancer Institute, UI, MICHIO, Dept. of Physiological Chemistry, Harvard Medical School, Boston, Massa- University of Tokyo, Japan chusetts VAN DER VOORN, LOESJE, Netherlands Cancer STOCK, ANN, Dept. of Molecular Biology, Institute, Amsterdam, The Netherlands Princeton University, New Jersey VANKESSEL, GEURTS A., Dept. of Cell Biology, STOCK, JEFFRY, Dept. of Biochemical Sciences, Erasmus University, Rotterdam, The Nether- Princeton University, New Jersey lands STRASSER, RUTH, Dept. of Cardiology, Universi- VANNUCCI, SUSAN, Dept. of Physiology, Milton ty of Heidelberg, Federal Republic of Ger- S. Hershey Medical Center, Pennsylvania many VANONI, MARCO, Sezione Biochimica Com- STRUHL, KEVIN, Dept. of Biological Chemistry, parata, Fisiologia et Biochimica Generali, Harvard Medical School, Boston, Massa- Milano, Italy chusetts VERMA, INDER, Tumor Virology Laboratory, Salk STRULOVICI,BERTA, Syntex Research, Cancer and Institute, San Diego, California Developmental Biology, PaiD Alto, Cali- VICENTINI, LUCIA, Dept. of Pharmacology, Uni- fornia versity of Milan, Italy STRYER, LUBERT, Dept. of Cell Biology, Stanford VOGT, PETER, Dept. of Microbiology, University University Medical School, California of Southern California, Los Angeles xiv SYMPOSIUM PARTICIPANTS

WALTON, PAUL, University of California, San WILLIAMS, MEGAN, Dept. of Pathology, Brigham Diego, Theodore Gildred Cancer Facility, and Women's Hospital, Boston, Massa- La Jolla chusetts WANG, YUHUAN, University of Washington, WISHART, WILLIAM, Dept. of Biotechnology, Seattle Sandoz Ltd., Basel, Switzerland WARTMANN, MARKUS, University Clinic Medical WITTERS, LEE, Dept. of Medicine and Biochem- School Laboratories, Basel, Switzerland istry, Dartmouth Medical School, Hanover, WATERFIELD, MICHAEL, Imperial Cancer Re- New Hamshire search Fund, Ludwig Institute for Cancer WODNAR-FILIPOWICZ, WODNAR, Friedrich Mies- Research, London, England cher Institute, Basel, Switzerland WATSON, JAMES, Cold Spring Harbor Labora- WOLFF, HENRIK, Dept. of Pathology, University tory, New York of Helsinki, Finland WATTERSON, MARTIN, Dept. of Pharmacology, WOLITZKY, BARRY, Dept. of Molecular Genetics, Vanderbilt University, Nashville, Tennessee Hoffmann-La Roche, Nutley, New Jersey WEIEL, JAMES,Dept. of Pharmacology, Universi- WONG, STEPHEN, Dept. of Pharmacology, Uni- ty of Washington, Seattle versity of Texas Southwestern Medical Cen- WEINBERG, ROBERT, Whitehead Institute Center ter, Dallas, Texas for Cancer Research, Cambridge, Massa- Wooo, JOHN, Sandoz Institute for Medical Re- chusetts search, London, England WEINBERGER, OFRA, Dept. of Physiology, Col- WRIGHT, TIMOTHY, Dept. of Medicine, Johns umbia University, New York, New York Hopkins University School of Medicine, WEISS, ARTHUR, University of California, San Baltimore, Maryland Francisco, California YAMAMOTO, KEITH, Dept. of Biochemistry and WELCH, MARY, Boehringer Mannheim Corpora- Biophysics, University of California, San tion, Indianapolis, Indiana Francisco WESTHEAD, EDWARD, Dept. of Biochemistry, YANG, YU-CHUNG, Genetics Institute, Cam- University of Massachusetts, Amherst bridge, Massachusetts WHITEWAY, MALCOLM,National Research, Coun- YU, VICTOR, Neurex Corporation, Menlo Park, cil, Biotechnology Research Institute, Mon- California treal, Canada ZABRECKY, JIM, Integrated Genetics, Framing- WIGLER, MICHAEL, Cold Spring Harbor Labora- ham, Massachusetts tory, New York ZIFF, EDWARD, Dept. of Biochemistry, New WILLIAMS, LEWIS, University of California, How- York University School of Medicine, New ard Hughes Medical Institute San Francisco York First row" I. Verma, J. Schlessinger; J. Feramisco, J. Marin, M. Wigler Second row: M. Berridge; E. Racker, E. Krebs; M. Brown Third row: E. Kandel, J.D. Watson; F. Dahlquist, J. Goldstein, D. Koshland ~ i ~ i I ~i!ii~:~

,~.b !~i i
84

First row: L. Stryer; M. Simon, I. Herskowitz; E. Neer Second row: Coffee break at Grace Auditorium; (right) W. Moiler; D. Ryan; J. Inglis First row: M. Gilman, R. Franza; Z. Selinger; E. Racker, M. Wigler Second row: Break on Blackford lawn Third row: D. Lancet; D. Botstein, J.D. Watson; K. Yamamoto Fourth row: D. Koshland, I. Herskowitz, G. Rubin; Picnic First row: L. Birnbaumer, H. Khorana; J. Witkowski, G. Temple; P. Chambon, J.D. Watson Second row: M. Wiglet, H. Hanafusa, S. Numa; J, Ernst, R. Miller, A. Weiss Third row: H. Berg, J. Stock; S. Bradshaw Fourth row: F. Murad, J. Larner; Y. Kaziro First row: S. Courtneidge; H. Bourne, A. Gilman; M. Bitensky Second row: T. Curran, J. Feramisco, R. Tijan; M. Ptashne, J. Goldstein Third row." D. Koshland, D. Nathans; M. Waterfield; M. Gilman and son Foreword

For many decades, it has been clear that cells have a multitude of ways of sensing their environment and converting a plethora of external signals into measured intracellular responses. Already by 1965 Earl Sutherland had made the distinction between the "first-messenger" role of hormone-like signals and the "second-messenger" role of cyclic AMP, whose concentration was somehow influenced by signals from first messengers. In Sutherland's scheme, the first messenger binds to cellular receptors, with such binding events somehow leading to control of the concentration of the second messenger. Now we realize that many first messengers do not act directly through second messengers, but instead work at the genetic level by binding to cytoplasmically located receptors, which can then bind to DNA and turn on or off the functioning of specific genes. Today, we refer to the way that external signals are passed through various cellular components as signal transduction processes, with receptors and their associated molecules known as biological transducers. Because most transducer molecules are present in very limited amounts, their study at the biochemical level until recently was at best difficult, and hypotheses as to how they functioned were almost impossible to test rigorously. Today, recombinant DNA techniques have dramatically changed the picture. Even very rare receptors are now open to analysis if their respective genes can be cloned, and virtually every month, the amino acid sequence of a new key biological transducer is established. The time was thus appropriate last June to hold a Cold Spring Harbor Symposium on the Molecular Biology of Signal Transduction. Our aim as always was to have the key players in the field present, and two members of our staff, Mike Wigler and Jim Feramisco, worked with me as the principal organizers. In so functioning, we contacted many outside advisors, and in particular we wish to thank Richard Axel, Howard Berg, Henry Bourne, Ron Evans, Alfred Gilman, Joe Goldstein, Ira Herskowitz, Tom Jessel, Eric Kandel, Dan Koshland, and Lubert Stryer for their help. The final program consisted of 119 speakers, who spoke before an audience of 439, the largest ever yet to attend a Cold Spring Harbor Symposium. The crowd overflowed the Grace Auditorium, and a large closed-circuit screen in Bush was provided for those who tired of standing long hours in the side aisles. The meeting opened with a series of five virtually electric presentations by Howard Berg, Alfred Gilman, Mark Ptashne, Lubert Stryer, and Keith Yamamoto. A mode of high excitement prevailed throughout the subsequent 14 long sessions, which were concluded by a graciously thoughtful summary by Henry Bourne. Super-large meetings like this require many major sources of financial backing, and we gratefully acknowledge our long-term Symposium backers, the National Cancer Institute of the National Institutes of Health, the National Science Foundation, and the Department of Energy. We are also indebted to the Lucille P. Markey Charitable Trust for major help provided for the third straight year. Essential funds from our Corporate Sponsors Program also provide key support for our meetings program: Abbott Laboratories; American Cyanamid Company; Amersham International plc; AMGen; Applied Biosystems; Becton Dickinson and Company; Boehringer Mannheim GmbH; Bristol Myers Company; Cetus Corporation; Ciba-Geigy Corporation; Diagnostic Products Corporation; E.I. du Pont de Nemours & Company; Eastman Kodak Company; Genentech, Inc.; Genetics Institute; Hoffmann-La Roche Inc.; Life Technologies, Inc.; Johnson & Johnson; Eli Lilly and Company; Millipore Corporation; Monsanto Company; Oncogene Science, Inc.; Pall Corporation; Pfizer Inc.; Pharmacia; Schering-Plough Corporation; Smith Kline & French Laboratories; Tambrands Inc.; The Upjohn Company; The Wellcome Research Laboratories; Burroughs Wellcome Co.; and Wyeth Laboratories. Again our Meetings Office staff--Maureen Berejka, Barbara Ward, Diane Tighe, Karen Otto, and Michela McBride--performed at high level, overseeing the registration and housing of the participants as well as making them feel welcomed and special. Herb Parsons again ran a very competent audiovisual department, and my secretary, Andrea Stephenson, smoothly handled the massive telephone and written correspondence needed xix xx FOREWORD

to put together a Symposium. The publication of these books was again ably overseen by Nancy Ford, Managing Director of our Publications Department, working with our Symposium editors Dorothy Brown, Patricia Barker, and Ralph Battey, assisted by Joan Ebert, Mary Cozza, and Inez Sialiano.

James D. Watson, Director October 13, 1988 Contents

Part 1

Symposium Participants V Foreword xix

Bacterial Chemotaxis A Physicist Looks at Bacterial Chemotaxis H.C. Berg Roles of Methylation and Phosphorylation in the Bacterial Sensing System D.E. Koshland, Jr., D.A. Sanders, and R.M. Weis 11 Osmotaxis in Escherichia coil J. Adler, C. Li, A.J. Boileau, Y. Qi, and C. Kung 19 Galvanotaxis in Bacteria J. Adler and W. Shi 23 Interaction of CheB with Chemotaxis Signal Transduction Components in Escherichia coil: Modulation of the Methylesterase Activity and Effects on Cell Swimming Behavior R.C. Stewart, C.B. Russell, A.F. Roth, and F.W. Dahlquist 27 Protein Phosphorylation and Bacterial Chemotaxis J.F. Hess, R.B. Bourret, K. Oosawa, P. Matsumura, and M.L Simon 41 Phosphoproteins Involved in Bacterial Signal Transduction A.M. Stock, D.C. Wylie, J.M. Mottonen, A.N. Lupas, E.G. Ninfa, A.F. Ninfa, C.E. Schutt, and J. B. Stock 49 Structure-Function Studies of Bacterial Chemosensors P. Ames, J. Chen, C. Wolff, and J.S. Parkinson 59 The End of the Line in Bacterial Sensing: The Flagellar Motor R.M. Macnab 67

Protein Phosphorylation Casein Kinase II as a Potentially Important Enzyme Concerned with Signal Transduc- tion E.G. Krebs, R.N. Eisenman, E.A. Kuenzel, D.W. Litchfield, F.J. Lozeman, B. Liischer, and J. Sommercorn 77 Microinjection of the Catalytic Subunit of cAMP-dependent Protein Kinase Induces Expression of the c-los Gene K. T. Riabowol, M.Z. Gilman, and J.R. Feramisco 85 Regulating Cell Growth: Casein-kinase-II-dependent Phosphorylation of Nuclear On- coproteins D. Carroll, N. Santoro, and D.R. Marshak 91 The Family of Protein Kinase C: Its Molecular Heterogeneity and Differential Expres- sion U. Kikkawa, K. Ogita, M.S. Shearman, K. Ase, K. Sekiguchi, Z. Naor, A. Kishimoto, Y. Nishizuka, N. Saito, C. Tanaka, Y. Ono, T. Fujii, and K. lgarashi 97 Protein Kinase C Regulation by Sphingosine/Lysosphingolipids R.M. Bell, C.R. Loomis, and Y.A. Hannun 103 Expression of Wild-type and Mutant Subunits of the cAMP-dependent Protein Kinase G.S. McKnight, G.G. Cadd, C.H. Clegg, A.D. Otten, and L.A. Correll 111 cAMP-dependent Protein Kinase: A Framework for a Diverse Family of Enzymes S.S. Taylor, J.A. Buechler, L.W. Slice, D.K. Knighton, S. Durgerian, G.E. Ringheim, J.J. Neitzel, W.M. Yonemoto, J.M. Sowadski, and W. Dospmann 121 Targets for Signal-transducing Protein Kinase T. Hunter, P. Angel, W.J. Boyle, R. Chiu, E. Freed, K.L. Gould, C.M. Isacke, M. Karin, R.A. Lindberg, and P. van der Geer 131 Molecular Analyses of Gene Products Associated with the Response of Cells to Mitogenic Stimulation R.L. Erikson, D. Alcorta, P.-A. Bedard, J. Blenis, H.-P. Biemann, E. Erikson, S.W. Jones, J.L. Mailer, T.J. Martins, and D.L. Simmons 143 Interactions between the Middle T Antigen of Polyomavirus and Host Cell Proteins S.A. Courtneidge, R.M. Kypta, and E.T. Ulug 153 xxi xxii CONTENTS

Tyrosine Phosphorylation in Signal Transduction T.M. Roberts, D. Kaplan, W Mor- gan, T. Keller, H. Maroon, H. Piwnica Worms, B. Druker, B. Cohen, B. Schaff- hausen, M. Whitman, L. Cantley, U. Rapp, and D. Morrison 161 raf Family Serine/Threonine Protein Kinases in Mitogen Signal Transduction U.R. Rapp, G. Heidecker, M. Huleihel, J.L. Cleveland, W.C. Choi, T. Pawson, J.N. Ihle, and W.B. Anderson 173 Calmodulin and Calmodulin-regulated Protein Kinases as Transducers of Intracellular Calcium Signals T.J. Lukas, J. Haiech, W. Lau, T.A. Craig, W.E. Zimmer, R. L. Shattuck, M.O. Shoemaker, and D.M. Watterson 185 Regulation of the Vertebrate Cell Cycle by the cdc2 Protein Kinase G. Draetta, L. Brizuela, B. Moran, and D. Beach 195

Mechanism of Action of G Proteins Role of G Proteins in Transmembrane Signaling P.J. Casey, M.P. Graziano, M. Freissmuth, and A.G. Gilman 203 Structure of the Genes Coding for G-protein a Subunits from Mammalian and Yeast Cells Y. Kaziro, H. Itoh, T. Kozasa, R. Toyama, T. Tsukamoto, M. Matsuoka, M. Nakafuku, T. Obara, T. Takagi, and R. Hernandez 209 Mutations Probe Structure and Function of G-protein a Chains H.R. Bourne, S.B. Masters, R.T. Miller, K.A. Sullivan, and W Heideman 221 Receptor-effector Coupling by G Proteins: Purification of Human Erythrocyte Gi-2 and Gi-3 and Analysis of Effector Regulation Using Recombinant a Subunits Synthe- sized in Escherichia coli L. Birnbaumer, J. Codina, R. Mattera, A. Yatani, R. Graf, J. Olate, J. Sanford, and A.M. Brown 229 Functions of G-protein Subunits E.J. Neer, S. -Y. Kim, S. -L. Ang, D.B. Bloch, K.D. Bloch, Y. Kawahara, C. Tolman, R. Lee, D. Logothetis, D. Kim, J.G. Seidman, and D.E. Clapham 241 Receptor- and G-Protein-mediated Modulations of Voltage-dependent Calcium Chan- nels W Rosenthal, J. Hescheler, W. Trautwein, and G. Schultz 247 Unique Properties of a New GTP-binding Protein with a Molecular Mass of 24,000 Daltons Purified from Porcine Brain Membranes T. Katada and M. Ui 255 Functional Role of Muscarinic Acetylcholine Receptor Subtype Diversity A. Ashken- azi, E.G. Peralta, J.W. Winslow, J. Ramachandran, and D.J. Capon 263 ras Oncogene Proteins: Three-dimensional Structures, Functional Implications, and a Model for Signal Transducer S.-H. Kim, A.M. de Vos, L. Tong, M.V. Milburn, P.M. Matias, J. Jancarik, E. Ohtsuka, and S. Nishimura 273

Mechanisms of Neurosensory Transduction Molecular Basis of Visual Excitation L. Stryer 283 Molecular Basis of the Functional Heterogeneity of the Muscarinic Acetylcholine Receptor S. Numa, K. Fukuda, T. Kubo, A. Maeda, L Akiba, H. Bujo, J. Nakai, M. Mishina, and H. Higashida 295 Life, Evolution, and the Pursuit of Single Photon Sensitivity M.W Bitensky, M.M. Whalen, and D.C. Torney 303 Visual Signal Transduction: The Cycle of Transducin Shuttling between Rhodopsin and cGMP Phosphodiesterase M. Chabre, J. Bigay, F. Bruckert, F. Bornancin, P. Deterre, C. Pfister, and T.M. Vuong 313 Molecular Mechanics of the Cyclic-GMP-activated Channel of Retinal Rods J.W. Karpen, A.L. Zimmerman, L. Stryer, and D.A. Baylor 325 Inositol Lipid Cascade of Vision Studied in Mutant Flies Z. Selinger and B. Minke 333 Molecular Transduction in Smell and Taste D. Lancet, D. Lazard, J. Heldman, M. Khen, and P. Nef 343 Expression of G-protein a Subunits in Rat Olfactory Neuroepithelium: Candidates for Olfactory Signal Transduction D.T. Jones, E. Barbosa, and R.R. Reed 349 CONTENTS xxiii

Studies on Light Transduction by Bacteriorhodopsin and Rhodopsin M. Braiman, J. Bubis, T. Doi, H.-B. Chen, S.L. Flitsch, R.R. Franke, M.A. Gilles-Gonzalez, R.M. Graham, S.S. Karnik, H.G. Khorana, B.E. Knox, M.P. Krebs, T. Marti, T. Mogi, T. Nakayama, D.D. Oprian, K.L. Puckett, T.P. Sakmar, L.J. Stern, S. Subramaniam, and D.A. Thompson 355 Direct Coupling of G Proteins to Ionic Channels A.M. Brown, A. Yatani, Y. Imoto, G. Kirsch, H. Hamm, J. Codina, R. Mattera, and L. Birnbaumer 365 Role of G-protein-coupled Phosphatidylinositol System in Signal Transduction in Ver- tebrate Neurons: Experiments on Neuroblastoma Hybrid Cells and Ganglion Cells D.A. Brown, H. Higashida, P.R. Adams, N.V. Marrion, and T.G. Smart 375 Functional Expression of the 5-HTlc Receptor in Neuronal and Nonneuronal Cells D. Julius, A.B. MacDermott, T.M. Jessell, K. Huang, S. Molineaux, L Schieren, and R. Axel 385 Molecular Convergence of Presynaptic Inhibition and Presynaptic Facilitation on Com- mon Substrate Proteins of Individual Sensory Neurons of Aplysia D. Sweatt, A. Volterra, S.A. Siegelbaum, and E.R. Kandel 395 Electrical and Biochemical Properties of the cGMP-gated Cation Channel from Rod Photoreceptors U.B. Kaupp, W. Hanke, R. Simmoteit, and H. Liihring 407 Sevenless, a Gene Encoding a Putative Receptor for Positional Information G.M. Rubin 417 The Role of Arachidonic Acid Metabolites in Signal Transduction in an Identified Neural Network Mediating Presynaptic Inhibition in Aplysia E. Shapiro, D. PiomeUi, S. Feinmark, S. Vogel, G. Chin, and J.H. Schwartz 425 Molecular Mechanisms of Phospholipid Signaling Pathways in Mammalian Nerve Cells M.R. Hanley, T.R. Jackson, W. T. Cheung, M. Dreher, A. Gatti, P. Haw- kins, S.L Patterson, M. Vallejo, A.P. Dawson, and O. Thastrup 435

Growth Factor and Hormone Receptors Purification and Characterization of Placental Membrane Phosphotyrosine Phos- phatases C.J. Pallen, L. Sahlin, G. Panayotou, and M.D. Waterfield 447 Signal Transduction by the Platelet-derived Growth Factor Receptor L.T. Williams, J.A. Escobedo, M.T. Keating, and S.R. Coughlin 455 Role of Intrinsic Protein Tyrosine Kinase in Function and Metabolism of the Epidermal Growth Factor Receptor G.N. Gill, W.S. Chen, C.S. Lazar, J.R. Glenney, Jr., H.S. Wiley, H.A. Ingraham, and M.G. Rosenfeld 467 Molecular Analysis of the Nerve Growth Factor Receptor B. Hempstead, N. Patil, K. Olson, and M. Chao 477 Structure-Function Analysis of the/3-Adrenergic Receptor R.A.F. Dixon, L S. Sigal, and C.D. Strader 487 Functional Domains in the/3-Adrenergic Receptor E.M. Ross, S.K.-F. Wong, R.C. Rubenstein, and T. Higashijima 499 Molecular Biology of Adrenergic Receptors R.J. Lefkowitz, B.K. Kobilka, J.L. Benovic, M. Bouvier, S. Cotecchia, W. Hausdorff, H.G. Dohlman, J.W. Regan, and M. G. Caron 507 Signal Transduction by Epidermal Growth Factor Receptor J. Schlessinger, A. UI- lrich, A.M. Honegger, and W.H. Moolenaar 515 Macrophage Colony-stimulating Factor, CSF-1, and Its Proto-oncogene-encoded Re- ceptor C.J. Sherr, C.W. Rettenmier, and M.F. Roussel 521 Platelet-derived Growth Factor Generates at Least Two Distinct Intracellular Signals That Modulate Gene Expression S.D. Jones, D.J. Hall, B.J. Rollins, and C.D. Stiles 531 Insulin and Insulin-like Growth Factor Receptors and Responses R.A. Roth, G. Steele-Perkins, J. Hari, C. Stover, S. Pierce, J. Turner, J.C. Edman, and W.J. Rutter 537 Response and Binding Elements for Ligand-dependent Positive Transcription Factors Integrate Positive and Negative Regulation of Gene Expression M.G. Rosenfeld, C.K. Glass, S. Adler, E.B. Crenshaw III, X. He, S.A. Lira, H.P. Elsholtz, H.J. Mangalam, J.M. Holloway, C. Nelson, V.R. Albert, and H.A. Ingraham 545 xxiv CONTENTS

Part 2

Signal Transduction in Unicellular Eukaryotes From Membrane to Nucleus: The Pathway of Signal Transduction in Yeast and Its Genetic Control L. Marsh and L Herskowitz 557 The Role of G Proteins in Yeast Signal Transduction K. Matsumoto, M. Nakafuku, N. Nakayama, I. Miyajima, K. Kaibuchi, A. Miyajima, C. Brenner, K. Arai, and Y. Kaziro 567 Analysis of the Role of SCG1, a G~ Homolog, and SST2 in Pheromone Response and Desensitization in Yeast J. Kurjan and C. Dietzel 577 Function of the STE4 and STE18 Genes in Mating Pheromone Signal Transduction in Saccharomyces cerevisiae M. Whiteway, L. Hougan, D. Dignard, L. Bell, G. Saari, F. Grant, P. O'Hara, V.L. MacKay, and D.Y. Thomas 585 Functional Domains of a Peptide Hormone Receptor: The a-Factor Receptor (STE2 Gene Product) of the Yeast Saccharomyces cerevisiae K.J. Blumer, J.E. Reneke, W.E. Courchesne, and J. Thorner 591 Recovery from Pheromone-induced Arrest of the Yeast Cell Cycle: a-Factor Binding and Mutants That Show Pheromone-independent Arrest of Cell Division D. Blinder, P. Spatrick, S. Bouvier, C. Sullivan, and D. Jenness 605 Response of Yeast a Cells to a-Factor Pheromone: Topology of the Receptor and Identification of a Component of the Response Pathway K.L. Clark, N.G. Davis, D.K. Wiest, J.-J. Hwang-Shum, and G.F. Sprague, Jr. 611 Isolation and Characterization of Two Genes Encoding Yeast Mating Pheromone Signaling Elements: CDC72 and CDC73 S.I. Reed, J. Ferguson, and K.-Y. Jahng 621 Diverse Biological Functions of Small GTP-binding Proteins in Yeast D. Botstein, N. Segev, T. Stearns, M.A. Hoyt, J. Holden, and R.A. Kahn 629 Regulation of Vesicular Traffic by a GTP-binding Protein on the Cytoplasmic Surface of Secretory Vesicles in Yeast P.J. Novick, B. Goud, A. Salminen, N. C. Walworth, J. Nair, and M. Potenza 637 Studies of RAS Function in the Yeast Saccharomyces cerevisiae M. Wigler, J. Field, S. Powers, D. Broek, T. Toda, S. Cameron, J. Nikawa, T. Michaeli, J. Colicelli, and K. Ferguson 649 cAMP Receptor and G-protein Interactions Control Development in Dictyo- stelium M. Pupillo, P. Klein, R. Vaughan, G. Pitt, P Lilly, T. Sun, P. Devreotes, A. Kumagai, and R. Firtel 657 Ion Channels in Paramecium, Yeast, and Escherichia coli Y. Saimi, B. Martinac, M.C. Gustin, M.R. Culbertson, J. Adler, and C. Kung 667 A Molecular Analysis of G Proteins and Control of Early Gene Expression by the Cell- surface cAMP Receptor in Dictyostelium A. Kumagai, S. K. O. Mann, M. Pupillo, G. Pitt, P.N. Devreotes, and R.A. Firtel 675

Signal Transduction in the Nucleus jun: Oncogene and Transcriptional Regulator A.R. Ball, Jr., T.J. Bos, C. L61iger, L.P. Nagata, T. Nishimura, H. Su, H. Tsuchie, and P.K. Vogt 687 Transcriptional Regulation by the AP-1 Family of Enhancer-binding Proteins: A Nu- clear Target for Signal Transduction D. Bohmann, A. Admon, D.R. Turner, and R. Tjian 695 Transcriptional Activation by Yeast GCN4, a Functional Homolog to the jun Onco- protein K. Struhl, C.J. Brandl, W. Chert, P.A.B. Harbury, I.A. Hope, and S. Mehadevan 701 YAP1 Encodes a Yeast Homolog of Mammalian Transcription Factor AP-1 W.S. Moye-Rowley, K.D. Harshman, and C.S. Parker 711 Analysis of Serum Response Element Function In Vitro C. Norman and R. Treisman 719 CONTENTS xxv

Gene Regulation by Growth Factors R. Metz, J. Gorham, Z. Siegfried, D. Leonard, E. Gizang-Ginsberg, M.A. Thompson, D. Lawe, T. Kouzarides, R. Vosatka, D. MacGregor, S. Jamal, M.E. Greenberg, and E.B. Ziff 727 Transcriptional Regulation of c-los R. Prywes, T.M. Fisch, and R.G. Roeder 739 Regulation of Proto-oncogene fos: A Paradigm for Early Response Genes P. Sassone- Corsi, W.W. Lamph, and 1.M. Verma 749 Intracellular Mediators of c-los Induction M.Z. Gilman, L.A. Berkowitz, J.R. Feramisco, B.R. Franza, Jr., R.M. Graham, K. T. Riabowol, and W.A. Ryan, Jr. 761 Beyond the Second Messenger: Oncogenes and Transcription Factors T. Curran, F.J. Rauscher III, D.R. Cohen, and B.R. Franza, Jr. 769 Nuclear Oncoproteins Determine the Genetic Program in Response to External Stimuli A. Schrnthal, S. Gebel, B. Stein, H. Ponta, H.J. Rahmsdorf, and P. Herrlich 779 Phorbol-ester-induced Activation of the NF-K B Transcription Factor Involves Dissocia- tion of an Apparently Cytoplasmic NF-KB/Inhibitor Complex P.A. Baeuerle, M. Lenardo, J.W. Pierce, and D. Baltimore 789 Transcriptional Regulation of Interferon-stimulated Genes: A DNA Response Element and Induced Proteins That Recognize It D. Levy, N. Reich, D. Kessler, R. Pine, and J. E. Darnell, Jr. 799

Steroid Hormone Receptors Ligand-regulated Nonspecific Inactivation of Receptor Function: A Versatile Mecha- nism for Signal Transduction K.R. Yamamoto, P.J. Godowski, and D. Picard 803 Cooperative and Positional Independent trans-Activation Domains of the Human Glucocorticoid Receptor R.M. Evans and S.M. Hollenberg 813 Expression and Function of the Human Estrogen Receptor in Yeast J.H. White, D. Metzger, and P. Chambon 819 Cooperative Interactions of Steroid Hormone Receptors with Their Cognate Response Elements M.-J. Tsai, S.Y. Tsai, L. Klein-Hitpass, M. Bagchi, J.F. Elliston, J. Carlstedt-Duke, J.K. Gustafsson, and B. W. O'Malley 829 Cooperative Action of the Glucocorticoid Receptor and Transcription Factors U. Striihle, A. Miinsterberg, R. Mestril, G. Klock, W. Ankenbauer, W. Schmid, and G. Schiitz 835

Growth Control in Mammalian Cells Anti-oncogenes and the Negative Regulation of Cell Growth J.M. Horowitz, S.H. Friend, R.A. Weinberg, P, Whyte, K. Buchkovich, and E. Harlow 843 Interaction of ras p21 Proteins with GTPase Activating Protein F. McCormick, H, Adari, M. Trahey, R. Halenbeck, K. Koths, G.A. Martin, W. Crosier, K. Watt, B. Rubinfeld and G. Wong 849 Analysis of Mammalian ras Effector Function A. Hall, C. Cal~s, J.F. Hancock, A. Lloyd, A. Self, S. Gardener, M.D. Houslay, M.J.O. Wakelam, and C.J. Marshall 855 Structure/Function Studies of the ras Protein I.S, Sigal, M.S. Marshall, M.D. Schaber, U.S. Vogel, E.M. Scolnick, and J.B. Gibbs 863 Critical Role of Cellular ras Proteins in Proliferative Signal Transduction D.W. Stacey, M.-H. Tsai, C.-L. Yu, and J.K. Smith 871 Influence of p21 "~s on Phosphatidylinositol Turnover J. Downward and R.A. Weinberg 883 Genomic Response to Growth Factors D. Nathans, L.F. Lau, B. Christy, S. HartzeU, Y. Nakabeppu, and K. Ryder 893 Identification of Growth-factor-inducible Genes in Mouse Fibroblasts R. Bravo, M. Zerial, L. Toschi, M. Schiirmann, R. MiiUer, S.I. Hirai, M. Yaniv, J.M. Almendral, and R.-P. Ryseck 901 Characterization of p47 gag-crk , a Novel Oncogene Product with Sequence Similarity to a Putative Modulatory Domain of Protein-Tyrosine Kinases and Phospholipase C B.J. Mayer, M.Hamaguchi, and H. Hanafusa 907 xxvi CONTENTS

Phospholipase C-148: Chromosomal Location and Deletion Mapping of Functional Domains A. Bristol, S.M. Hall, R.W. Kriz, M.L. Stahl, Y.S. Fan, M.G. Byers, R.L. Eddy, T.B. Shows, and J.L. Knopf 915 Primary Structure of PLC-154 M. Katan, R. W. Kriz, N. Totty, R. Philp, E. Meldrum, R.A. Aldape, J. Knopf, and P.J. Parker 921

Second Messenger Systems Inositol Trisphosphate and Calcium Signaling M.J. Berridge and C.W. Taylor 927 Agonist-induced Calcium Oscillations in Depolarized Fibroblasts and Their Manipula- tion by Photoreleased Ins(1,4,5)P3, Ca + +, and Ca §247Buffer A.T. Harootunian, J. P. Y. Kao, and R.Y. Tsien 935 Signal Transduction in Mitogenesis: Further Evidence for Multiple Pathways E. Rozengurt, J. Erusalimsky, H. Mehmet, C. Morris, E. Ndnberg, and J. Sinnett- Smith 945 Role of Glycosyl Phosphoinositides in Insulin Action A.R. Saltiel, D.G. Osterman, and J. C. Darnell 955 Insulin Mediators: Structure and Formation J. Lamer, L.C. Huang, G. Tang, S. Suzuki, C.F.W. Schwartz, G. Romero, Z. Roulidis, K. ZeUer, T.Y. Shen, A.S. Oswald, and L. Luttrell 965 Gram-negative Endotoxin: A Biologically Active Lipid C.R.H. Raetz, K.A. Brozek, T. Clementz, J. D. Coleman, S. M. Galloway, D. T. Golenbock, and R. Y. Hampton 973 GTP-binding Proteins in the Control of Exocytosis B.D. Gomperts and P.E.R. Tatham 983 The Membrane Form of Guanylate Cyclase D.L. Garbers, D. G. Lowe, L.J. Dangott, M. Chinkers, D.S. Thorpe, J.K. Bentley, C.S. Ramarao, D.V. Goeddel, and S. Singh 993 Effects of Nitrovasodilators, Endothelium-dependent Vasodilators, and Atrial Peptides on cGMP F. Murad, D. Leitman, S. Waldman, C. -H. Chang, M. Hirata, and K. Kohse 1005 Molecular Cloning of the Growth-factor-activatable Human Na§ § Antiporter C. Sardet, A. Franchi, and J. Pouyss~gur 1011

Summary Summary: Signals Past, Present, and Future H.R. Bourne 1019

Author Index 1033

Subject Index 1037