- AlC

Peptide Growth Factorsand Their Receptors IIContributors j \ N^6 -

J.EBattey, B.Beutler, L.Bonewald, R.L.Cate, M.VChao,P.K.Donahoe, K.Elgjo, J.Folkman, T.Graf, R.Grosse,M.E.Gurney, VK.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.E Nathan, WR. Paukovits, WE. Paul, J.Pfeilschifter,D.B.Rifkin, C.Rivier, A.C.Sank, E.A.Sausville, E.Schiffmann,M.L.Stracke, J.Trepel, W.Vale, J.Vilcek, E.S.Vitetta,S.M.Wahl, H.L.Wong, J.Yu

Editors

Michael B. Sporn and Anita B. Roberts

Springer-VerlagBerlin Heidelberg New YorkLondon Paris TokyoHong Kong

Contents

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

CHAPTER 19

InterferonsJ. VILCEK. With 3 Figures 3

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

I. Interferon-oc/j? (Type I IFN) 41. Human IFN-a/yS Genes and Proteins 52. IFN-a//? Genes and Proteins of Other Animal Species . . . 7

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

I. Production of IFN-a/0 9II. Molecular Mechanisms of IFN-a/y? Induction 10

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

I. IFN-a/0 Receptor • • • • 12II. IFN-y Receptor : . . . 13

E. Interferon Actions 15I. Molecular Mechanisms 15

1. Proteins Induced by the Interferons 152. Mechanisms of Gene Activation by Interferons 183. Common Mechanisms of Gene Activation by Interferons,

Viruses, Double-Stranded RNA, Growth Factors, andCytokines 19

II. Spectrum of Biological Activities 211. Inhibition of Cell Growth 212. Stimulation of Cell Growth 233. Other Biological Activities 244. Possible Physiological Roles 255. Roles in Pathophysiology and Therapeutic Applications . . 26

References 28

XII Contents

CHAPTER 20

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

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

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

and In Vitro 48I. Adipose Tissue 49

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

VI. Adrenal 51VII. Skin 51

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

1. Neutrophils 532. Eosinophils 543. Monocyte/Macrophages 544. Lymphocytes 55

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

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

CHAPTER 21

Bombesin and Gastrin-Releasing Peptide: Neuropeptides, Secretogogues,and Growth FactorsA.-M. LEBACQ-VERHEYDEN, J. TREPEL, E. A. SAUSVILLE, and J. F. BATTEY.

With 3 Figures 71

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

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

Contents XIII

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

1. Neuronal GRP 742. Neuroendocrine GRP 75

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

1. Structure 752. Expression 763. Regulation 77

II. Rat Prepro-GRP Gene 771. Structure 772. Expression 78

III. Human Pro-GRP-Derived Peptides 781. Posttranslational Processing 782. Expression 79

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

1. In Vivo Effects 802. In Vitro Effects on Isolated Organs 833. Direct Effects and Cellular Distribution of Receptors . . 854. Induced Release of Endogenous GRP 85

II. Effect on Growth 861. In Vitro Studies 862. In Vivo Studies 88

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

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

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

Interaction ); . . . 93VI. Ion Fluxes . . 95

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

IX. Consequences of Bombesin-Evoked Second MessengerProduction 981. Secretion . 982. Receptor Transmodulation 993. Protooncogene Expression 994. DNA Synthesis . 100

F. Conclusions 101Appendix 101References 104

XIV Contents

CHAPTER 22

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

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

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

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

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

E. Conclusion 132References 132

CHAPTER 23

Nerve Growth FactorM. V. CHAO. With 7 Figures . 135

A. Introduction 135B. Nerve Growth Factor Gene Structure 135

I. Nerve Growth Factor Protein Complex 135II. Gene Structure 136

III. Nerve Growth Factor Gene Promoter 137IV. Amino Acid Sequence 138V. Expression of Cloned NGF 140

VI. The a- and y-Subunits 140C. In Vivo Expression of NGF 142D. Mechanism of Signal Transduction 143

I. Second Messengers 143II. Role of Oncogenes :. . . . 145

III. Genes Induced by NGF \. A . 1461. Early Response Genes 1462. Later Responses 148

E. Receptor for NGF 148I. Biochemical Analysis 149

II. Cloning of the NGF Receptor Gene 150III. Features of the NGF Receptor Gene .152IV. Kinetic Forms of the NGF Receptor 154V. Expression of Cloned NGF Receptors 155

F. Conclusions 156References 157

Contents XV

CHAPTER 24

A Glia-Derived Nexin Acting as a Neurite-Promoting FactorD. MONARD 167

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

Inhibitor 167I. Biochemical Properties 167

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

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

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

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

CHAPTER 25Mullerian Inhibiting SubstanceR. L. CATE, P. K. DONAHOE, and D. T. MACLAUGHLIN. With 7 Figures . 179

A. Introduction 179B. Structure of MIS 180

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

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

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

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

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

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

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

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

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

XVI Contents

CHAPTER 26

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

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

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

I. Granulosa Cells 220II. Sertoli Cells 221

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

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

I. Female Rat 223II. Male Rat 226

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

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

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

K. Conclusions 235References 236

CHAPTER 27Mammary-Derived Growth InhibitorR. GROSSE and P. LANGEN. With 4 Figures . 249

A. Introduction 249B. Results 250

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

HI. Cellular Activities 2551. Ehrlich Ascites Carcinoma Cells 2552. Mammary Epithelial Cell Lines 259

IV. Biochemical and Cellular Mechanism of Action 2601. Interaction with Hydrophobic Ligands 2602. Possible Role of Ribonucleotide Reductase 261

C. Conclusions 262References 263

Contents XVII

CHAPTER 28

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

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

1. Sources 2682. Fractionation 269

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

1. Growth-Promoting Activity of HP5b Dimer 2722. Growth Inhibitory Activity of HP5b Monomer 2743. Effects on Leukemic Cell Lines 2764. Specificity Tests and Activities not Related to Growth . . 276

V. Effects on Perturbed Hematopoiesis 2781. Inhibitory Effects of HP5b Monomer 2782. Possible Clinical Implications 279

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

I. Purification Procedures 281II. Biological Properties 282

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

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

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

C. Conclusion 290References ; 291

Section C: Coordinate Actions of Growth Factorsin Specific Tissues or Cells

CHAPTER 29

Coordinate Actions of Hematopoietic Growth Factors in Stimulationof Bone Marrow FunctionM.A. S.MOORE. With 11 Figures 299

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

XVIII Contents

I. Hematopoietic Growth Factor Interactions in the HPP-CFUAssay 301

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

III. Hematopoietic Growth Factor Interactions in the Blast CellColony Assay 306

IV. Inhibitory Influences on Hematopoietic Stem Cells andProgenitor Cells 308

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

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

I. Murine Studies 3141. In Vivo Interaction Between IL-1 and G-CSF in Mice

Treated with 5-FU 317II. Primate Studies 320

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

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

Neutropenia 329H. Conclusions 333References 335

CHAPTER 30Peptide Growth Factors and the Nervous SystemM. E. GURNEY 345

A. Embryogenesis of Neural Tissues \ . . 345B. Progenitor Cells in the Neural Crest . 345

I. Melanocytes Are a Terminally Differentiated Cell Type . . '. 346II. Heterogeneity of Cell Types Within the Neural Crest . . . . 347

III. SIF Cells Arise from HNK-1 + Progenitor Cells 348IV. SIF Cells Are Bipotential Progenitor Cells Within the

Sympathoadrenal Lineage : 348V. Does NGF Direct SIF Cells Toward Production of

Sympathetic Neurons In Vivo? 349VI. Neurotransmitter Choice is Determined by Environmental

Factors 350C. CNS Progenitor Cells Give Rise to Both Neurons and Glial Cells . 351D. Identification of CNS Progenitor Cells In Vitro 353E. The O2A Glial Lineage 355

I. PDGF is Mitogenic for O2A Progenitor Cells 357

Contents XIX

II. IGF-1 and CNTF Direct the O2A Lineage Toward Productionof Oligodendrocytes or Type-2 Astrocytes 358

F. Neural Growth Factors 360References 363

CHAPTER 31

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

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

of Bone Loss 388References 388

CHAPTER 32

Role of Lymphokines in the Immune SystemE. S. VITETTA and W. E. PAUL 401

A. Introduction 401I. Growth Regulation in the Immune System 401

II. Organization of the Immune System 402III. T Lymphocytes 402

1. TH1 and TH2 Cells \ . . . . 402IV. B Cells. . . 403V. Receptor-Mediated Signaling 403

VI. Cognate T-Cell-B-Cell Interactions 404VII. Secreted T-Cell Regulatory Proteins (Lymphokines) . . . . 404

1. Functions of Selected Lymphokines 405VIII. Lymphokines Produced by TH1 and TH2 Cells; Implications

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

I. T-Cell Subsets . 407II. Functional Differences Between TH1 and TH2 Cells 409

III. Surface Markers of the Different TH-Cell Subtypes 409IV. Proliferative Response of Clones of TH1 and TH2 Cells . . . 410V. Regulation of the Activation of TH1 and TH2 Cells 410

VI. TH1 and TH2 Cells In Vivo 411

XX Contents

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

I. Activation 413II. Growth Stimulation 414

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

Derived Lymphokines 416E. Conclusions 416

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

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

References 421

CHAPTER 33

Coordinate Actions of Growth Factors in Monocytes/MacrophagesC . F . N A T H A N 427

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

I. Endocytic Receptors 434II. Other Surface Antigens 435

F. Secretion 436I. Cytokines 437

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

G. Activation 438I. Killing of Microbial Pathogens 438

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

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

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

Contents XXI

CHAPTER 34

Extracellular Matrices, Cells, and Growth FactorsG. R. MARTIN and A. C. SANK. With 3 Figures 463

A. Introduction 463B. Nature of Extracellular Matrices 464

I. Collagens 464II. Glycoproteins 464

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

C. Cell-Matrix Interactions 466I. Fibronectin 466

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

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

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

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

Section D: Processes Regulated by Growth Factors

CHAPTER 35

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

A. Introduction 481B. Fibroblast Growth Factor 481C. Transforming Growth Factor-jS 484D. Platelet-Derived Growth Factor 488E. Epidermal Growth Factor 489F. Interleukin-1 494

I. Hemostasis 494II. Cancer 495

III. Glomerulonephritis 496IV. Arthritis 496

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

References 502

XXII Contents

CHAPTER 36

Inflammation and RepairH. L. WONG and S. M. WAHL. With 1 Figure 509

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

I. Platelets 511II. Neutrophils 513

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

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

II. Extracellular Matrix Synthesis 5271. Collagen 5272. Proteoglycans 5293. Fibronectin 529

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

CHAPTER 37AngiogenesisM. KLAGSBRUN and J. FOLKMAN. With 1 Figure 549

A. Introduction 549B. Bioassays for Angiogenesis 550

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

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

II. Angiogenin . 556III. Transforming Growth Factor-a 557IV. Transforming Growth Factor-)? 558V. Tumor Necrosis Factor 559

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

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

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

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

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

Contents XXIII

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

1. Ovary 5672. Endometrium 5673. Placenta 568

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

CHAPTER 38

MetastasisE. SCHIFFMANN, M. L. STRACKE, and L. A. LIOTTA. With 10 Figures . . 587

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

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

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

I. Thrombospondin 599II. Bombesin 599

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

References 606

CHAPTER 39Expression of Growth Factors and Their Receptors in DevelopmentD. C. LEE and V. K. M. HAN . , . . 611

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

I. Epidermal Growth Factor 6131. Introduction 6132. Developmental Expression of the EGF Receptor 6133. Biological Actions of Exogenous EGF 6144. Developmental Expression of EGF 6165. Transplacental Transport of Maternal EGF 617

XXIV Contents

II. Transforming Growth Factor-ot 6181. Introduction 6182. Developmental Expression of TGF-a 618

III. Link Between EGF-Related Growth Factors and HomeoticLoci 621

IV. Developmental Expression of the Neu Oncogene 622C. j8-Type TGFs 623

I. Introduction 623II. Developmental Expression of TGF-/? 624

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

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

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

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

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

I. Introduction 634II. Developmental Expression of FGF 635

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

I. Colony-Stimulating Factor 1 and Its Receptor {c-fms) . . . . 6371. Introduction 6372. Developmental Expression of c-fms 638

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

H. Nerve Growth Factor 640I. Introduction 640

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

References . 643

CHAPTER 40

Relationships Between Oncogenes and Growth ControlA. LEUTZ and T. GRAF. With 2 Figures 655

A. Introduction 655B. Growth Factor Genes 657

I. Growth Factor-Type Oncogenes 6581. The v-sis Oncogene 6582. The int-l and int-2 Oncogenes 6593. The hst Oncogene 660

Contents XXV

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

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

1. The v-erbB Oncogene 6622. The v-fms Oncogene 6643. Other Receptor-Type Tyrosine Kinase Oncogenes . . . . 665

II. Tyrosine Kinase-Type Oncogenes Lacking a TransmembraneDomain 667

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

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

1. The fos Gene Family 6722. They'wn Gene Family 673

II. Early Genes 6751. The myc Gene Family 675

III. Hormone Receptor Genes 6761. The erbA Gene Family 676

IV. Other Nuclear Oncogenes 6761. The myb Gene Family 6762. The ets Gene Family 6773. The p53 Oncogene 678

E. Cooperation Between Oncogenes 678References 683

Appendix A. Alternate Names for Growth Factors 705

Appendix B. Chromosomal Locations of Growth Factors/Growth FactorReceptors \ . . . 709

Subject Index 711