Handbook of Experimental Pharmacology

Volume 95///

Editorial Board

G.y' R. Born, London P. Cuatrecasas, Ann Arbor, MI H. Herken, Berlin

Peptide Growth Factors and Their Receptors IT Contributors

J.E Battey, B. Beutler, L. Bonewald, R.L. Cate, M.Y. Chao, P.K. Donahoe, K. EIgjo, J. Folkman, T. Graf, R. Grosse, M.E.Gurney, Y.K.M.Han, C.-H. Heldin, A. Hsueh, M.Klagsbrun, O.D.Laerum, P.Langen, A.-M.Lebacq-Verheyden, D.C.Lee, A.Leutz, L.A. Liotta, D.T.MacLaughlin, G.R.Martin, K.Miyazono, D.Monard, M.A.S.Moore, D.E.Mullins, G.R.Mundy, C.ENathan, W.R.Paukovits, W.E.Paul, J.Pfeilschifter, D.B.Rifkin, C.Rivier, A.C.Sank, E.A.Sausville, E.Schiffmann, M.L.Stracke, J. Trepel, WVale, J.Vilcek, E.S.Vitetta, S.M. Wahl, H.L. Wong, J. Yu

Editors

Michael B. Sporn and Anita B. Roberts

Springer-Verlag Berlin Heidelberg New York London Paris Tokyo Hong Kong

MICHAEL B. SPORN, M. D.

ANITA B. ROBERTS, Ph. D.

Laboratory of Chemoprevention National Cancer Institute Bethesda, MD 20892 USA

With 75 Figures

ISBN-13:978-3-642-74783-0 e-ISBN-13:978-3-642-74781-6 DOl: 10.1007/978-3-642-74781-6

Library of Congress Cataloging-in-Publication Data. Peptide growth factors and their recep­tors/contributors, K.-I. Arai ... let al.]; editors, Michael B. Sporn and Anita B. Roberts. p. em. - (Hand­book of experimental pharmacology; v. 95) Contributors for v. 2, J.F. Battey and others. Includes bibliographical references. ISBN-13:978-3-642-74783-0 1. Growth factors. 2. Growth factors - Receptors. I. Arai, Ken-Ichi. II. Sporn, Michael B. III. Roberts, Anita B. IV. Battey, James F. V. Series. [DNLM: 1. Cell Communication. 2. Growth Substances. 3. Pep­tides. 4. Receptors, Endogenous Substances. W1 HA51L v. 95/QU 68 P42404] QP905.H3 vol. 95 [QP552.G76] 615'.1 s - dc20 [574.87'6] DNLM/DLC for Library of Congress.

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List of Contributors

J. F. BATTEY, Laboratory of Neurochemistry, NINDS, NIH, Bldg. 36, Rm. 4D20, 9000 Rockville Pike, Bethesda, MD 20892, USA

B. BEUTLER, The Howard Hughes Medical Institute and The Department of Internal Medicine of the University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Room Y5-210, Dallas, TX 75235-9050, USA

L. BONEWALD, Division of Endocrinology and Metabolism, University of Texas, Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78284, USA

R. L. CATE, Department of Molecular Biology, Biogen Inc., 14 Cambridge Center, Cambridge, MA 02142, USA

M. V. CHAO, Department of Cell Biology and Anatomy Division of Hematol­ogy/Oncology, Cornell University Medical College, 1300 York Ave., New York, NY 10021, USA

P. K. DONAHOE, Pediatric Surgical Research Laboratory, Massachusetts General Hospital, and Department of Surgery, Harvard Medical School, Warren Building, 32 Fruit Street, Boston, MA 02114, USA

K. ELGJO, Institute of Pathology, Rikshospitalet, University of Oslo, 0027 Oslo 1, Norway

J. FOLKMAN, Departments of Surgery and Anatomy and Cellular Biology, Children's Hospital and Harvard Medical School, 300 Longwood Ave., Boston, MA02115, USA

T. GRAF, European Molecular Biology Laboratory, Postfach 102209, Meyer­hofstr. 1,6900 Heidelberg, FRG

R. GROSSE, Central Institute of Molecular Biology, Academy of Sciences of the German Democratic Republic, Robert-Rossle-Str. 10, DDR-1115 Ber­lin

M. E. GURNEY, Department of Microbiology-Immunology and Department of Cell, Molecular and Structural Biology, Northwestern University, 303 East Chicago Ave., Chicago, IL 60611, USA

VI List of Contributors

V. K. M. HAN, The Lawson Research Institute, St. Joseph's Health Centre, 268 Grosvenor Street, London, Ontario, Canada N6A 4V2

C.-H. HELDIN, Ludwig Institute for Cancer Research, Biomedical Center, Uppsala Branch, Box 595, 75123 Uppsala, Sweden

A. HSUEH, Department of Reproductive Medicine, University of California, La Jolla, CA 92093, USA

M. KLAGSBRUN, Enders 10, Departments of Biological Chemistry and Surgery, Children's Hospital and Harvard Medical School, 300 Longwood Ave., Boston, MA 02115, USA

O. D. LAERUM, Department of Pathology, University of Bergen, The Gade In­stitute, Haukeland Hospital, 5016 Bergen, Norway

P. LANGEN, Central Institute of Molecular Biology, Academy of Sciences of the German Democratic Republic, Robert-Rossle-Str. 10, DDR-1115 Ber­lin

A-M. LEBACQ-VERHEYDEN, Unite de Genetique Cellulaire, UCL-74.59, Institute of Cellular and Molecular Pathology, 74 ave Hippocrate, 1200 Brussels, Belgium

D. C. LEE, Department of Microbiology and Immunology, and the Line­berger Cancer Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA

A. LEUTz, European Molecular Biology Laboratory, Postfach 102209, Meyerhofstr. 1,6900 Heidelberg, FRG

L. A LIOTTA, Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Building 10, Room 2A33, Bethesda, MD 20892, USA

D. T. MACLAUGHLIN, Pediatric Surgical Research Laboratory, Mas­sachusetts General Hospital, and Department of Surgery, Warren Build­ing, Room 1133,32 Fruit Street, Boston, MA 02114, USA

G. R. MARTIN, National Institute on Aging, Gerontology Research Center, Francis Scott Key Medical Center, Baltimore, MD 21224, USA

K. MIYAZONO, Ludwig Institute for Cancer Research, Box 595, Biomedical Center, 75123 Uppsala, Sweden

D. MONARD, Friedrich Miescher-Institut, Postfach 2543, 4002 Basel, Switzer­land

M. A S. MOORE, James Ewing Laboratory of Developmental Hematopoiesis, Section #6136, RM 717 C Rockefeller Bldg. Memorial Sloan Kettering Cancer Center, 1275 Y ork Avenue, New York, NY 10021, USA

D. E. MULLINS, Department of Pharmacology, Schering-Plough Research, Bloomfield, NJ 07003, USA

List of Contributors VII

G. R. MUNDY, Division of Endocrinology and Metabolism, University of Texas, Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78284, USA

C. F. NATHAN, Beatrice and Samuel A. Seaver Laboratory, Division of Hematology-Oncology, Department of Medicine, Cornell University Medical College, Box 57, 1300 Y ork Avenue, New York, NY 10021, USA

W. R. PAUKOVITS, Department of Growth Regulation, Institute of Tumor Biology, University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria

W. E. PAUL, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 10, Room 11 N311, Bethesda, MD 20892, USA

J. PFEILSCHIFTER, Universitatsklinik Heidelberg, Abteilung fUr Endokrino­logie, 6900 Heidelberg, FRG

D. B. RIFKIN, Department of Cell Biology and Kaplan Cancer Center, New York University Medical Center and the Raymond and Beverly Sackler Foundation, 550 First Avenue, New York, NY 10016, USA

C. RIVIER, The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, P.O. Box 85800, San Diego, CA 92138, USA

A. C. SANK, Laboratory of Developmental Biology and Anomalies, National Institute of Dental Research, National Institutes of Health, Building 30, Room 416, Bethesda, MD 20892, USA

E. A. SAUSVILLE, Departments of Medicine and Pharmacology, Georgetown University School of Medicine, Washington, DC 20007, USA

E. SCHIFFMANN, Department of Health & Human Services, Public Health Ser­vices, National Institutes of Health, Building 10, Room 2A33, Bethesda, MD 20892, USA

M. L. STRACKE, Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Building 10, Room 2A33, Bethesda, MD 20892, USA

J. TREPEL, Medicine Branch, National Cancer Institute, National Institutes of Health, Building 10, Room 12N230, 9000 Rockville Pike, Bethesda, MD 20892, USA

W. VALE, The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, P.O. Box 85800, San Diego, CA 92138, USA

J. VIL(;EK, Department of Microbiology, New York University Medical Center, 550 First Avenue, New York, NY 10016, USA

VIII List of Contributors

E. S. VITETTA, Department of Microbiology, University of Texas South­western Medical Center at Dallas, 5323 Harry Hines Blvd., Dallas, TX 75235, USA

S. M. WAHL, Laboratory of Immunology, National Institute of Dental Research, National Institutes of Health, Building 30, Room 326, Bethesda, MD 20892, USA

H. L. WONG, Laboratory of Immunology, National Institute of Dental Research, National Institutes of Health, Building 30, Room 334, Bethesda, MD 20892, USA

J. Yu, Department of Basic and Clinical Research, Scripps Clinic and Research Foundation, La Jolla, CA 92037, USA

Preface

This two-volume treatise, the collected effort of more than 50 authors, represents the first comprehensive survey of the chemistry and biology of the set of molecules known as peptide growth factors. Although there have been many symposia on this topic, and numerous publications of reviews dealing with selected subsets of growth factors, the entired field has never been covered in a single treatise. It is essential to do this at the present time, as the number of journal articles on peptide growth factors now makes it almost im­possible for anyone person to stay informed on this subject by reading the primary literature. At the same time it is becoming increasingly apparent that these substances are of universal importance in biology and medicine and that the original classification of these molecules, based on the laboratory setting of their discovery, as "growth factors," "lymphokines," "cytokines," or "colony-stimulating factors," was quite artifactual; they are in fact the basis of a common language for intercellular communication. As a set they affect es­sentially every cell in the body, and in this regard they provide the basis to develop a unified science of cell biology, germane to all of biomedical research.

This treatise is divided into four main sections. After three introductory chapters, its principal focus is the detailed description of each of the major peptide growth factors in 26 individual chapters. These chapters provide es­sential information on the primary structure, gene structure, gene regulation, cell surface receptors, biological activity, and potential therapeutic applica­tions of each growth factor (to the extent that these are known). The last two sections of these volumes deal with the coordinate actions of sets of growth factors, since it is clear that to understand their physiology, one must consider the interactions between these peptides. There are six chapters on specific cells and tissues, including bone marrow, brain, bone and cartilage, lymphocytes, macrophages, and connective tissue. The final six chapters consider the role of growth factors in controlling fundamental processes that pertain to many dif­ferent cells and tissues, such as proteolysis, inflammation and repair, angiogenesis, and embryogenesis.

The editors accept full responsibility for the table of contents, and apologize for any significant omissions. We have deliberately excluded classic peptide hormones whose actions are principally endocrine. We have not included many peptides whose biological activcities may have been described, but which have not yet been purified to homogeneity and sequenced. Essen­tially all of the molecules included in this treatise act at specific cell surface

x Preface

receptors, although we have included one peptide (glia-derived neurotrophic factor) which is a protease inhibitor. Because of the importance of growth­inhibitory actions of peptides, we have included chapters on two new sets of inhibitors (mammary-derived growth inhibitor and pentapeptide growth in­hibitors) for which there is only very preliminary knowledge of their structure, function, and mechanism of action.

The present era in research on peptide growth factors is indeed an exciting one. The biological activities resulting from the actions of these substances have been known for a very long time, as described in John Hunter's detailed descriptions of the healing Of severed tendons and gunshot wounds, made over 200 years ago. Modem cell and tissue culture owes its inception to the ac­tions of growth factors present in the embryo extracts used almost 100 years ago by the pioneers of this technique. However, it has been the recent intro­duction of new methods for purification of peptides, and the cloning and ex­pression of genes with recombinant DNA technology, which have truly revolutionized this field. These methods provide the scientific basis for the present treatise and the current excitement in this field. They also have provided the practical methodology for the creation of a whole new biotech­nology industry, which has made major commitments to develop peptide growth factors as clinical therapeutic agents. Applications being developed in­clude wound healing and other aspects of soft-tissue repair, repair of bone and cartilage, immunosuppression, enhancement of immune cell function, enhan­cement of bone marrow function in many disease states, and prevention and treatment of many proliferative diseases, including atherosclerosis and cancer. Since many of the peptides described in these pages function as growth factors in the embryo, they raise hope that they may be used some day to arrest or reverse the ravages of aging and degenerative disease.

There is no question that the peptides decribed here are of fundamental importance for understanding the behavior of all cells, and that they will be of major importance in the practice of clinical medicine in the years to come. These volumes, then, are a celebration not only of new basic knowledge, but also of the new therapeutic potential of this entire family of molecules, which have such intense potency to make cells move, grow, divide, and differentiate. We hope that this treatise will be of value to both scientists and clinicians in their pursuit and application of new knowledge in this promising area.

We wish to express our appreciation to many individuals who have par­ticipated in this venture from its inception. We are greatly indebted to Pedro Cuatrecasas, who initially suggested the writing of this treatise and has been a constant and enthusiastic supporter. We thank all of the authors for their devoted efforts to assimilate the huge literature in their respective fields and to condense this information into readable single chapters. Our secretary, Karen Moran, has been ofinvaluable help with numerous aspects of the organization and publication of these volumes. Finally, we would like to express our gratitude to Doris Walker and the staff at Springer-Verlag for all of their ef­forts in bringing this treatise to publication.

MICHAEL B. SPORN

ANITA B. ROBERTS

Contents

Section B: Individual Growth Factors and Their Receptors (Cont'd from Part I)

CHAPTER 19

Interferons J. VIL{::EK. With 3 Figures. 3

A. What Are Interferons? 3 B. Structure of Interferon Genes and Proteins . 4

I. Interferon-a/ p (Type I IFN) . . . . . 4 1. Human IFN-a/p Genes and Proteins 5 2. IFN-a/p Genes and Proteins of Other Animal Species. 7

II. Interferon-y (Type II IFN). . . 7 C. Interferon Induction and Production . . . . . . 9

I. Production ofIFN-a/p . . . . . . . . . . 9 II. Molecular Mechanisms ofIFN-a/p Induction 10

III. IFN-y Induction . 11 D. Interferon Receptors . 12

I. IFN-a/p Receptor 12 II. IFN-y Receptor . 13

E. Interferon Actions . . 15 I. Molecular Mechanisms 15

1. Proteins Induced by the Interferons. 15 2. Mechanisms of Gene Activation by Interferons. 18 3. Common Mechanisms of Gene Activation by Interferons,

Viruses, Double-Stranded RNA, Growth Factors, and Cytokines. . . . . . . . . 19

II. Spectrum of Biological Activities 21 1. Inhibition of Cell Growth . 21 2. Stimulation of Cell Growth . 23 3. Other Biological Activities. . 24 4. Possible Physiological Roles . 25 5. Roles in Pathophysiology and Therapeutic Applications . 26

References . . . . . . . . . . . . . . . . . . . . . . . .. 28

XII Contents

CHAPTER 20

Cachectin/Tumor Necrosis Factor and Lymphotoxin B. BEUTLER. With 2 Figures . . . . . . . . . . . . . . . . . . . 39

A Introduction. . . . . . . . . . . . . . . . . . . . . . . . 39 B. "Factor-Mediated" Diseases: The Hematopoietic Origin of Factors 40 C. Cachectin . . . . . . . . . . . . . . . . . . . . . . . . . 40 D. Tumor Necrosis Factor. . . . . . . . . . . . . . . . . . . 42 E. Physical Structure of Cachectin/TNF: Homology to Lymphotoxin. 43 F. Cachectin/TNF and Lymphotoxin: Production Sources, Kinetics,

and Stimuli . . . . . . . . . . . . . . . . . . . 45 G. Control of Cachectin Gene Expression . . . . . . . . . .. 46 H. Cachectin/TNF Receptor and Postreceptor Mechanisms. . .. 47 J. Biological Effects of Cachectin/TNF and Lymphotoxin: In Vivo

and In Vitro. . . . 48 I. Adipose Tissue 49

II. Muscle. . . . 49 III. Liver . . . . 49 IV. Gastrointestinal Tract 50 V. Central Nervous System 50

VI. Adrenal . . . . . 51 VII. Skin. . . . . . . . 51

VIII. Bone and Cartilage . 52 IX. Vascular Endothelium 52 X. Hematopoietic Elements 53

1. Neutrophils . . . . 53 2. Eosinophils . . . . 54 3. Monocyte/Macrophages 54 4. Lymphocytes. . . . . 55

K. Gross Physiologic and Pathologic Consequences of Cachectin/TNF Production or Administration . . . . . . . . . . . . . . . . 56

L. Disease States Associated with Elevated Levels of Cachectin/TNF. 57 M. Cachectin/TNF and Its Clinical Applications: To Be or Not To Be 58 References . . . . . . . . . . . . . . . . . . . . . . . . . . 59

CHAPTER 21

Bombesin and Gastrin-Releasing Peptide: Neuropeptides, Secretogogues, and Growth Factors A-M. LEBACQ-VERHEYDEN,J. TREPEL, E. A SAUSVILLE, andJ. F. BATTEY. With 3 Figures . . . . . . . . . . . . . . . . . 71

A Introduction. . . . . . . . . . . . . . . . . 71 B. Structure and Cellular Localization of the Peptides 71

I. Bombesin-Related Peptides. . . 71 II. Structure of Bombesin and GRP . . . . . 72

Contents XIII

III. Molecular Forms of GRP . . 72 IV. Cellular Localization of GRP . 74

1. Neuronal GRP. . . . . . 74 2. Neuroendocrine GRP . . . 75

C. Molecular Genetics of the Prepro-GRP Gene. 75 I. The Human Prepro-G RP Gene 75

1. Structure . 75 2. Expression. . . . . 76 3. Regulation. . . . . 77

II. Rat Prepro-GRP Gene. 77 1. Structure . . . . . 77 2. Expression. . . . . 78

III. Human Pro-GRP-Derived Peptides 78 1. Posttranslational Processing . . 78 2. Expression. . . . . . . . . . 79

D. Pharmacological Effects of Bombesin and GRP. 80 I. Effects Unrelated to Growth . . . . 80

1. In Vivo Effects. . . . . . . . . . . 80 2. In Vitro Effects on Isolated Organs . . 83 3. Direct Effects and Cellular Distribution of Receptors 85 4. Induced Release of Endogenous GRP 85

II. Effect on Growth . 86 1. In Vitro Studies . . . . . . . . 86 2. In Vivo Studies. . . . . . . . . 88

E. Cellular Responses to Bombesin and GRP . 89 I. Introduction to Bombesin-Mediated Signal Transduction 89

II. Bombesin Binding to Cells/Membranes: Definition of the Bombesin Receptor . . . . . . . . . . . . 89

III. Desensitization/Internalization of the Receptor . . . . 91 IV. Phospholipase Activation. . . . . . . . . . . . . . 91 V. Guanine Nucleotide-Binding Protein/Bombesin Receptor

Interaction . . . . . . 93 VI. Ion Fluxes . . . . . . . . . . 95

VII. Protein Phosphorylation . . . . 96 VIII. Bombesin Receptor Antagonists. 97

IX. Consequences of Bombesin-Evoked Second Messenger Production. . . . . . . . . 98 1. Secretion . . . . . . . . 98 2. Receptor Transmodulation . 99 3. Protooncogene Expression 99 4. DNA Synthesis. 100

F. Conclusions 101 Appendix . 101 References . . 104

XIV Contents

CHAPTER 22

Platelet-Derived Endothelial Cell Growth Factor K. MIYAZONO and C.-H. HELDIN. With 4 Figures. 125

A. Introduction. . . . . . . . . . . . . . . . . . . . . 125 B. Purification and Biochemical Characterization of PD-ECGF 126

I. Purification of PD-ECGF . . . . 126 II. Structural Properties of PD-ECGF 128

C. Primary Sequence of PD-ECGF . 129 D. Biological Activities of PD-ECGF 130

I. In Vitro Effects of PD-ECGF . 130 II. In Vivo Effects of PD-ECGF 131

E. Conclusion 132 References . . . . . . . . . . . 132

CHAPTER 23

Nerve Growth Factor M. V. CHAo. With 7 Figures.

A. Introduction. . . . . . . . . . . B. Nerve Growth Factor Gene Structure

I. Nerve Growth Factor Protein Complex II. Gene Structure. . . . . . . . . . .

III. Nerve Growth Factor Gene Promoter. IV. Amino Acid Sequence. . . V. Expression of Cloned NGF

VI. The 0(- and y-Subunits. . . C. In Vivo Expression of NGF . . D. Mechanism of Signal Transduction

I. Second Messengers . . . II. Role of Oncogenes . . .

III. Genes Induced by NGF . 1. Early Response Genes 2. Later Responses .

E. Receptor for NGF . . . . . I. Biochemical Analysis . .

II. Cloning of the NGF Receptor Gene III. Features of the NGF Receptor Gene IV. Kinetic Forms of the NGF Receptor V. Expression of Cloned NGF Receptors.

F. Conclusions References . . . . . . . . . . . . . . . .

135

135 135 135 136 137 138 140 140 142 143 143 145 146 146 148 148 149 150 152 154 155 156 157

Contents xv

CHAPTER 24

A Glia-Derived Nexin Acting as a Neurite-Promoting Factor D.MoNARD .................... . 167

A. Introduction. . . . . . . . . . . . . . . . . . . . . .. 167 B. A Glia-Derived Neurite-Promoting Factor Acting as a Protease

Inhibitor . . . . . . . . . 167 I. Biochemical Properties. . . . . . . . 167

II. Molecular Cloning . . . . . . . . . 168 III. Characteristics of the Primary Structures 168 IV. Biological Effects . . . . . . . . . . 170 V. Localization of Glia-Derived Nexin . . 171

VI. Glia-Derived Nexin, a Representative of a New Family of Neurite-Promoting Factors? . . . . . . . . . . .. 172

VII. Mode of Action of GDN? . . . . . . . . . . . .. 173 VIII. In Vivo Relevance of the Balance Between Proteases and

Protease Inhibitors for Neurite Outgrowth? . 174 C. Conclusion 174 References . . . . . . . . . . . . . . . . . . . 175

CHAPTER 25

Mullerian Inhibiting Substance R. L. CATE, P. K. DONAHOE, and D. T. MACLAUGHLIN. With 7 Figures. 179

A. Introduction. . . . . . . . . . . . 179 B. Structure of MIS. . . . . . . . . . 180

I. Bovine and Chicken MIS Proteins 180 II. Bovine and Human MIS Genes. . 182

III. Biosynthesis of Human MIS in CHO Cells. 185 C. MIS as a Member of the TGF-p Family. . 186

I. Structural Properties of the Family . . 186 II. Proteolytic Processing of Human MIS. 188

D. MIS Expression During Development. . . 190 I. Upstream Regions of the Bovine and Human MIS Genes 190

II. Expression of MIS in the Testis 194 III. Expression of MIS in the Ovary . . . . . . 196

E. Mechanism of Action. . . . . . . . . . . . . 198 I. MIS Receptor and Mullerian Duct Regression 198

II. Modulators of MIS Action and Mullerian Duct Regression . 200 F. Potential Activities of MIS. . . 201

I. Descent of the Testis . . . . . . 201 II. Fetal Lung Development . . . . 202

III. Antiproliferative Effects of MIS . 202 G. Summary . 203 References . . . . . . . . . . . . . . 204

XVI Contents

CHAPTER 26

The Inhibin/ Activin Family of Hormones and Growth Factors W. VALE, A. HSUEH, C. RIVIER, and J. Yu. With 4 Figures 211

A. Chemical Characterization of Inhibins and Activins 211 I. Inhibin . . . . . . . . . . . . . . . . . . 211

II. Activin . . . . . . . . . . . . . . . . . . 216 B. Actions of Inhibin and Activin on the Anterior Pituitary . 217 C. Development of Antisera Toward Inhibin Subunits 219 D. Gonadal Production of Inhibin . . 220

I. Granulosa Cells . . . . . . . . . . . 220 II. Sertoli Cells . . . . . . . . . . . . . 221

E. Intragonadal Actions of Inhibin and Activin 221 I. Paracrine Regulation . . . . . . . . 222

II. Autocrine Regulation. . . . . . . . 222 F. Role of Inhibin in Regulation of FSH Secretion In Vivo. 223

I. Female Rat . . . . . . . . . . 223 II. Male Rat . . . . . . . . . . . 226

G. Tissue Expression of Inhibin Subunits. 227 H. Inhibin and Activin in the Placenta . . 228 I. Activin and the Control of Oxytocin Secretion . 229 J. Roles of Activin and Inhibin in Erythropoiesis . 229

I. Complexity of Hematopoietic Control. . 230 II. Induction of Erythroid Differentiation. . . 231

III. Potentiation of Erythroid Colony Formation. . 232 IV. Expression of Activin/Inhibin Subunits in Hematopoietic Cells 234

K. Conclusions 235 References . . . . . . . . . . . . . . . . . . . . . . . . . . 236

CHAPTER 27

Mammary-Derived Growtb Inhibitor R. GROSSE and P. LANGEN. With 4 Figures .249

A. Introduction. . . 249 B. Results . . . . . 250

I. Purification . 250 II. Amino Acid Sequence Determination and Sequence Homologies 252

III. Cellular Activities . . . . . . . . 1. Ehrlich Ascites Carcinoma Cells . . . . . 2. Mammary Epithelial Cell Lines. . . . . .

IV. Biochemical and Cellular Mechanism of Action. 1. Interaction with Hydrophobic Ligands . . 2. Possible Role of Ribonucleotide Reductase

C. Conclusions References . . . . . . . . . . . . . . . . . . .

255 255 259 260 260 261 262 263

Contents XVII

CHAPTER 28

Pentapeptide Growth Inhibitors W. R. PAUKOVITS, K. ELGJO, and O. D. LAERUM. With 13 Figures . 267

A. Hemoregulatory Peptide. . . . . . . . . . . . 268 I. Preparation of the Hemoregulatory Peptide . 268

1. Sources . . . 268 2. Fractionation 269

II. Structural Studies 270 III. Synthesis. . . . 271 IV. Biological Activities on Normal Hematopoiesis 272

1. Growth-Promoting Activity of HP5b Dimer 272 2. Growth Inhibitory Activity of HP5b Monomer 274 3. Effects on Leukemic Cell Lines. . . . . . . 276 4. Specificity Tests and Activities not Related to Growth. 276

V. Effects on Perturbed Hematopoiesis . . 278 1. Inhibitory Effects of HP5b Monomer . . . . 278 2. Possible Clinical Implications. . . . . . . . 279

VI. Biochemical and Cellular Mechanisms of Action. 280 B. Epidermal Inhibitory Pentapeptide 281

I. Purification Procedures 281 II. Biological Properties. . . . 282

III. Long-Term Effects . . . . 285 IV. Repeated Treatments with the Epidermal Pentapeptide 286 V. Tissue Specificity . . . . . . . . . . . 287

VI. Epidermal Regeneration and Malignancy . 288 VII. Species Specificity . 288

VIII. Toxicity . . . . . . . . . . 289 IX. Precursors . . . . . . . . . 289 X. Possible Clinical Applications . 289

C. Conclusion 290 References . . . . . . . . . . . . . 291

Section C: Coordinate Actions of Growth Factors in Specific Tissues or Cells

CHAPTER 29

Coordinate Actions of Hematopoietic Growth Factors in Stimulation of Bone Marrow Function M. A. S. MOORE. With 11 Figures . . . . . . . . . . . . . 299

A. Introduction. . . . . . . . . . . . . . . . . . . . 299 B. Stem Cells, Growth Factors, and the Extracellular Matrix 299 C. Hematopoietic Growth Factor Interactions with Early Stem Cells . 301

XVIII Contents

I. Hematopoietic Growth Factor Interactions in the HPP-CFU Assay ......................... 301

II. Action ofIL-1 in Short-Term Marrow Suspension Culture (Delta Assay) . . . . . . . . . . . . . . . . . . .. 303

III. Hematopoietic Growth Factor Interactions in the Blast Cell Colony Assay . . . . . . . . . . . . . . . . . . 306

IV. Inhibitory Influences on Hematopoietic Stem Cells and Progenitor Cells . . . . . . . . . . . . . . . .. . 308

D. Synergistic Interactions Between IL-1, IL-3, and IL-5 in the Production and Activation of Eosinophils . . . . . . .. . 309

E. Hematopoietic Growth Factors and Basophil/Mast Cell Development 312 F. Preclinical In Vivo Experience with Hematopoietic Growth Factors 314

I. Murine Studies. . . . . . . . . . . . . . . . . .. . 314 1. In Vivo Interaction Between IL-1 and G-CSF in Mice

Treated with 5-FU. . . . . . . 317 II. Primate Studies . . . . . . . . . . . . . 320

G. Clinical Experience with G- and GM-CSF . . . . 321 I. CSFs in Chemotherapy-Induced Neutropenia. 321

II. CSFs in Autologous Bone Marrow Transplantation . 325 III. CSFs in Myelodysplastic Syndromes . . . . . . . 326 IV. In Vivo Studies of G-CSF in Congenital and Idiopathic

Neutropenia . 329 H. Conclusions 333 References . . . . . 335

CHAPTER 30

Peptide Growth Factors and the Ne"ous System M. E. GURNEY. . . . . . . . . . . .

A. Embryogenesis of Neural Tissues . . . . . B. Progenitor Cells in the Neural Crest. ...

I. Melanocytes Are a Terminally Differentiated Cell Type II. Heterogeneity of Cell Types Within the Neural Crest

III. SIF Cells Arise from HNK-1 + Progenitor Cells ... IV. SIF Cells Are Bipotential Progenitor Cells Within the

Sympathoadrenal Lineage ~ . . . . . . . . . . V. Does NGF Direct SIF Cells Toward Production of

Sympathetic Neurons In Vivo? ........ . VI. Neurotransmitter Choice is Determined by Environmental

Factors . . . . . . . . . . . . . . . . . ..... .

· 345

· 345 · 345

346 347 348

348

349

C. CNS Progenitor Cells Give Rise to Both Neurons and Glial Cells. 350 351 353 355 357

D. Identification of CNS Progenitor Cells In Vitro. . E. The 02A Glial Lineage . . . . . . . . . . . .

I. PDGF is Mitogenic for 02A Progenitor Cells

Contents XIX

II. IGF-1 and CNTF Direct the 02A Lineage Toward Production of Oligodendrocytes or Type-2 Astrocytes . 358

F. Neural Growth Factors . 360 References . . . . . . . . . . . . . . . . . . 363

CHAPTER 31

Role of Growth Factors in Cartilage and Bone Metabolism J. PFEILSCHIFTER, L. BONEWALD, and G. R. MUNDY . . . . 371

A. Origin of Growth Factors in Bone and Cartilage . . . 372 B. Receptors for Growth Factors in Bone and Cartilage . 374 C. Growth Factors in Bone Formation. . . . . . 375 D. Growth Factors in Cartilage. . . . . . . . . . . 380 E. Growth Factors in Bone and Cartilage Induction . . 383 F. Regulation of Growth Factor Activity in Bone and Cartilage. 383 G. Growth Factors and Cartilage Destruction. . . . . . . .. 386 H. Growth Factors and Disorders of Bone and Cartilage . . .. 387 I. Potential for Growth Factors as Therapeutic Agents in Diseases

of Bone Loss 388 References . . . . . . . . . . . . . . . . . . . . . . . .. 388

CHAPTER 32

Role of Lympbokioes in the Immune System E. S. VlTEITA and W. E. PAUL ..... .

A. Introduction. . . . . . . . . . . . . . . . I. Growth Regulation in the Immune System

II. Organization of the Immune System . III. T Lymphocytes . . .

1. THI and TH2 Cells .. . IV. B Cells. . . . ..... . V. Receptor-Mediated Signaling

VI. Cognate T -Cell-B-Cell Interactions VII. Secreted T-Cell Regulatory Proteins (Lymphokines)

1. Functions of Selected Lymphokines . . . . ... VIII. Lymphokines Produced by T HI and T H2 Cells; Implications

· 401

· 401 · 401 .402 .402 .402 · 403 · 403 .404 .404 · 405

for Immune Functions. . . . . . . . . . 407 B. Role of Lymphokines in the Immune Response. . . . . . 407

I. T-Cell Subsets . . . . . . . . . . . . . . . . . 407 II. Functional Differences Between T HI and T H2 Cells . . 409

III. Surface Markers of the Different T H-Cell Subtypes. . 409 IV. Proliferative Response of Clones of THl and TH2 Cells . 410 V. Regulation of the Activation of THI and TH2 Cells. . 410

VI. T HI and T H2 Cells In Vivo . . . . . . . . . . .. . 411

xx Contents

C. Action of Lymphokines on Macrophages . 412 D. Actions of Lymphokines in B-Cell Responses . 413

I. Activation . . . . . . . . . . . . . . 413 II. Growth Stimulation. . . . . . . . . . 414

III. Differentiation of B Cells into Antibody-Producing Cells . 414 IV. Lymphokine Regulation of Ig Class Switching. . . .. . 415 V. B-Cell Growth and Development Control by Action ofT-Cell-

Derived Lymphokines . 416 E. Conclusions . . . . . . . . . . . . . . . . . . . 416

I. Lymphoid Organs. . . . . . . . . . . . . . 417 II. Immune Responses Against Bacterial Antigens . 418

III. Immune Response to Viral Antigens. . 419 IV. Immune Response to Parasites . 420 V. Concluding Remarks . 420

References . . . . . . . . . . . . . . 421

CHAPTER 33

Coordinate Actions of Growth Factors in Monocytes/Macropbages C. F. NATHAN . . . 427

A. Introduction. . . . . . . . . 427 B. Migration . . . . . . . . . . 430 C. Extramedullary Proliferation. . 431 D. Changes in Shape . . . . . . 433 E. Endocytosis, Cell Surface Receptors, and Antigens . 434

I. Endocytic Receptors . . 434 II. Other Surface Antigens . 435

F. Secretion . . . . . . . . . 436 I. Cytokines . . . . . . . 437

II. Complement Components and Other Proteases . . 437 III. Sterols . . . . . . . . . . . . . . . . . . . 437 IV. Reactive Intermediates of Oxygen and of Nitrogen . 438

G. Activation. . . . . . . . . . . . . 438 I. Killing of Microbial Pathogens . . 438

II. Killing of Host-Type Cells. . . . 444 III. Promotion of Wound Healing . . 446 IV. Generation of Inflammatory and Immune Responses . 446 V. Scavenging of Senescent Cells . . . . . . . . . 447

H. Deactivation. . . . . . . . . . . . . . . . . . . 447 I. Mechanisms of Action of Cytokines on Macrophages . 450 J. Autocrine Effects. . . . . . . . 451

K. Polymorphonuclear Leukocytes. . 451 L. Conclusions . 452 References . . . . . . . . . . . . 453

Contents

CHAPTER 34

Extracellular Matrices, Cells, and Growth Factors G. R. MARTIN and A. C. SANK. With 3 Figures .

XXI

. 463

A. Introduction. . . . . . . . . . 463 B. Nature of Extracellular Matrices 464

I. Collagens . . 464 II. Glycoproteins . . . . . . 464

III. Proteoglycans . . . . . . 465 IV. Matrix Molecules in Supramolecular Complexes 466

C. Cell-Matrix Interactions. 466 I. Fibronectin 466

II. Laminin. . . . . 467 III. Collagen . . . . 468 IV. Matrix Receptors. 468

D. Role of Matrix Molecules in Cell Growth 469 I. Storage Sites for Growth Factors. . 469

II. Mitogenic Activities of Fibronectin and Laminin 469 III. Termination of Proliferation by Collagen . . . 470

E. Induction of Collagenase by Growth Factors - Role in Proliferation 472 References . . . . . . . . . . . . . . . . . . . . . . . . . . 474

Section D: Processes Regulated by Growth Factors

CHAPTER 35

Induction of Proteases and Protease Inhibitors by Growth Factors D. E. MULLINS and D. B. RIFKIN 481

A. Introduction. . . . . . . . . 481 B. Fibroblast Growth Factor. . . 481 C. Transforming Growth Factor-fJ . 484 D. Platelet-Derived Growth Factor 488 E. Epidermal Growth Factor 489 F. Interleukin-l. . 494

I. Hemostasis . . . 494 II. Cancer . . . . . 495

III. Glomerulonephritis 496 IV. Arthritis. . . . . 496

G. Tumor Necrosis Factor 499 H. Colony-Stimulating Factor 1 500 I. Discussion. 501

References . . . . . . . . . 502

XXII Contents

CHAPTER 36

Inflammation and Repair H. L. WONG and S. M. W ARL. With 1 Figure. . . . . . . . . . . . 509

A. Introduction. . . . . . . . . . . . . . . . . . . . . . . . 509 B. Inflammatory Phase: Inflammatory Cell Recruitment and Function 511

I. Platelets. . . . . . . . 511 II. Neutrophils . . . . . . . . . . . . 513

III. Monocytes/Macrophages . . . . . . 514 IV. Lymphocyte Function and Regulation. 521

C. Proliferative Phase . . . . . . . . . . . 524 I. Regulation of Fibroblast Proliferation. 524

II. Extracellular Matrix Synthesis 527 1. Collagen . . 527 2. Proteoglycans . . . . . . 529 3. Fibronectin . . . . . . . 529

III. Endothelial Cell Function and Angiogenesis 530 D. Remodeling Phase: Matrix Turnover and Fibrotic Disorders 532 E. Concluding Remarks 534 References . . . . . . . . . . . . . . . . . . . . . . . 537

CHAPTER 37

Angiogenesis M. KLAGSBRUN and J. FOLKMAN. With 1 Figure . 549

A. Introduction. . . . . . . 549 B. Bioassays for Angiogenesis. 550

I. In Vivo Methods 550 II. In Vitro Methods . . 552

C. Angiogenic Factors. . . . 553 I. Fibroblast Growth Factors . 553

II. Angiogenin. . . . . . . . 556 III. Transforming Growth Factor-ex 557 IV. Transforming Growth Factor-p 558 V. Tumor Necrosis Factor . . . 559

VI. Platelet-Derived Endothelial Cell Growth Factor 560 VII. Angiotropin . . . . . . . . . . . . . . . . 560

VIII. Low Molecular Weight Nonpeptide Angiogenesis Factors. 561 IX. Mechanisms of Angiogenesis Factor Action. . . . .. 562

D. Physiological Regulation of Angiogenic Molecules . . . .. 563 I. Role of Extracellular Matrix in Modulating Angiogenic

Factors . . . . . . . . . . . . . . . . . . . .. 564 II. Mast Cells and Heparin as Potentiators of Angiogenesis 565

III. Storage of Basic FGF in Basement Membrane - Role of Heparan Sulfate. . . . . . . . . . . . . . . . .. 565

Contents XXIII

IV. Regulation of Angiogenic Factors by Pericytes 566 V. Endocrine Regulation of Angiogenesis 567

1. Ovary. . . . 567 2. Endometrium . . . . . . . . . 567 3. Placenta. . . . . . . . . . . . 568

VI. Role of Hypoxia in Regulating Angiogenic Factors 568 E. Pathological Angiogenesis 569 F. Angiogenesis Inhibitors 570 G. Future Directions. . 573 References . . . . . . . . 574

CHAPTER 38

Metastasis E. SClllFFMANN, M. L. STRACKE, and L. A. LIOTTA. With 10 Figures . 587

A. Introduction. . . . . . . . . . . . . . . . . . . . 587 B. Invasion as an Active Process . . . . . . . . . . . . 587 C. Interaction of Tumor Cells with the Extracellular Matrix. 588 D. Three Stages in Invasion. . . . . . . . . . . . . . 589 E. Agents Inducing Migration: Autocrine Motility Factors 590 F. Melanoma Autocrine Motility Factor . . . . 591

I. Isolation and Characterization . . . . 593 II. Some Chemical Properties of the Protein 593

III. Signal Transduction in Tumor Cells . 593 G. Unique Features of Tumor Cell Motility. . 598 H. Growth Factors as Motility Stimulants 599

I. Thrombospondin . . . . . . 599 II. Bombesin . . . . . . . . . . . 599

III. Insulin-Like Growth Factors . . . 600 I. Autocrine Motility Responses in Nontransformed Cells . 603 J. Autocrine Motility Factors as Markers of Malignancy. . 605

References . . . . . . . . . . . . . . . . . . . . . . 606

CHAPTER 39

Expression of Growth Factors and Their Receptors in Development D. C. LEE and V. K. M. HAN. . . . . . . . . . 611

A. Introduction. . . . . . . . . . . . . . 611 B. The EGF/TGF-cx Family of Growth Factors . 613

I. Epidermal Growth Factor. . . . . . . 613 1. Introduction. . . . . . . . . . . . 613 2. Developmental Expression of the EGF Receptor. 613 3. Biological Actions of Exogenous EGF . . . 614 4. Developmental Expression of EGF. . . . . 616 5. Transplacental Transport of Maternal EGF . 617

XXIV Contents

II. Transforming Growth Factor-IX. . . . 618 1. Introduction. . . . . . . . . . . 618 2. Developmental Expression of TGF-IX 618

III. Link Between EGF-Related Growth Factors and Homeotic Loci . . . . . . . . . . . . . . . . . . . 621

IV. Developmental Expression of the Neu Oncogene 622 C. 13-Type TGFs . . . . . . . . . . . . 623

I. Introduction. . . . . . . . . . . . . . 623 II. Developmental Expression of TGF-f3 . . . 624

III. Role for TGF-f3 in Amphibian Development 627 D. Insulin-Like Growth Factors/Somatomedins . . 627

I. Introduction. . . . . . . . . . . . . . 627 II. Expression of IGF Receptors and Binding Proteins 628

III. IGFs in Fetal Tissues and Fluids . . . . 629 IV. Developmental Expression of IGF Genes 630

E. Platelet-Derived Growth Factor . . . . 633 I. Introduction. . . . . . . . . . . . . 633

II. Developmental Expression of PDGF . . 633 F. Fibroblast Growth Factor and Related Molecules. 634

I. Introduction. . . . . . . . . . . . . . . 634 II. Developmental Expression of FGF . . . . . 635

III. Developmental Expression of Related Molecules 636 G. Hematopoietic Growth Factors. . . . . . . . . . 637

I. Colony-Stimulating Factor 1 and Its Receptor (c-fms) 637 1. Introduction. . . . . . . . . . . 637 2. Developmental Expression of c-fms . 638

II. Related Growth Factors. 639 III. Interleukins-2 and -4 639

H. Nerve Growth Factor. . . . 640 I. Introduction. . . . . . 640

II. Localization of NGF and Its Receptor 641 I. Conclusions 643

References . . . . . . . . . . . . . . . . 643

CHAPTER 40

Relationships Between Oncogenes and Growth Control A. LEUTZ and T. GRAF. With 2 Figures

A. Introduction. . . . . . . . . . B. Growth Factor Genes. . . . . .

I. Growth Factor-Type Oncogenes 1. The v-sis Oncogene. . . . . 2. The int-1 and int-2 Oncogenes 3. The hst Oncogene . . . . .

. 655

655 657 658 658 659 660

Contents XXV

II. Growth Factor Genes Experimentally Shown to be Capable of Acting as Oncogenes . . . . . . . . . 660

C. Signal Transducer Genes . . . . . . . . . . 662 I. Receptor Tyrosine Kinase-Type Oncogenes 662

1. The v-erbB Oncogene. . . . . . . . . 662 2. The v-fms Oncogene . . . . . . . . . 664 3. Other Receptor-Type Tyrosine Kinase Oncogenes 665

II. Tyrosine Kinase-Type Oncogenes Lacking a Transmembrane Domain. . . . . . . . . . . . . . . 667

III. The ras Family Oncogenes. . . . . . . 668 IV. Serine Threonine Kinase-Type Oncogenes 669

D. Genes Encoding Nuclear Proteins. 671 I. Immediate Early Genes . 672

1. The fos Gene Family . 672 2. The jun Gene Family . 673

II. Early Genes . . . . . . 675 1. The myc Gene Family 675

III. Hormone Receptor Genes 676 1. The erbA Gene Family 676

IV. Other Nuclear Oncogenes 676 1. The myb Gene Family 676 2. The ets Gene Family . 677 3. The p53 Oncogene. . 678

E. Cooperation Between Oncogenes 678 References . . . . . . . . . . . 683

Appendix A. Alternate Names for Growth Factors. . . . . . . . . . 705

Appendix B. Chromosomal Locations of Growth Factors/Growth Factor Receptors. . . . . . . . . . . . . . . . . . . . . . . . . . . 709

Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . 711

Contents of Companion Volume 95, Part I

Section A: Introduction

CHAPTER 1 The Multifunctional Nature of Peptide Growth Factors. M. B. SPORN and A. B. ROBERTS

CHAPTER 2 Isolation and Characterization of Growth Factors. R. A. BRADSHAW and K. P. CAVANAUGH

CHAPTER 3 Properties and Regulation of Receptors for Growth Factors M. P. CZECH, K. B. CLAIRMONT, K. A. Y AGALOFF, and S. CORVERA

Section B: Individual Growth Factors and Their Receptors

CHAPTER 4 The Epidermal Growth Factor Family. G. CARPENTER and M. 1. WAHL

CHAPTER 5 Platelet-Derived Growth Factor. E. W. RAINES, D. F. BOWEN-POPE, and R.Ross

CHAPTER 6 Insulin-Like Growth Factors. M. M. RECHLER and S. P. NISSLEY

CHAPTER 7 Fibroblast Growth Factors. A. BAIRD and P. BOHLEN

CHAPTER 8 The Transforming Growth Factor-JJs. A. B. ROBERTS and M. B. SPORN

CHAPTER 9 Interleukin-l. J. A. SCHMIDT and M. J. TOCCI

XXVIII Contents of Companion Volume 95, Part I

CHAPTER 10 Interleukin-2. M. HATAKEYAMA and T. TANIGUCHI

CHAPTER 11 Interleukin-3. J. N. IHLE

CHAPTER 12 Interleukin-4. T. YOKOTA, N. ARAI, K.-1. ARAI, and A. ZLOTNIK

CHAPTER 13 Interleukin-S. T. HONJO and K. TAKATSU

CHAPTER 14 Interleukin-6. T. HIRANO and T. KISHIMOTO

CHAPTER 15 Colony-Stimulating Factor 1 (Macrophage Colony-Stimulating-Factor) C. J. SHERR and E. R. STANLEY

CHAPTER 16 Granulocyte Colony-Stimulating Factor. S. NAGATA

CHAPTER 17 Granulocyte-Macrophage Colony-Stimulating Factor. A. W. BURGESS

CHAPTER 18 Erythropoietin: The Primary Regulator of Red Cell Formation E. GOLDWASSER, N. BERU, and D. SMITH

Appendix A. Alternate Names for Growth Factors

Appendix B. Chromosomal Locations of Growth Factors/Growth Factor Receptors

Subject Index