Cancer Cell Signalling

Dr Amanda Harvey, Brunel Institute for Cancer Genetics and Pharmacogenomics, Brunel University, Kingston Lane, Middlesex, UK.

List of contributors ix

Acknowledgements xi

Introduction xiii

About the companion website xvi

1 Epidermal growth factor receptor family 1
Amanda Harvey

1.1 ErbB receptors and their structure 1

1.2 ErbB ligands 2

1.3 Downstream signalling molecules and events 5

1.4 Signalling regulation 8

1.5 Dysregulation of signalling in cancer 10

1.6 Therapeutic opportunities 13

References 17

2 Insulin and the insulin-like growth factor (IGF) family 25
Maria Thorpe, Erald Shehu and Amanda Harvey

2.1 Receptors 25

2.2 Ligands 28

2.3 Downstream signalling molecules and events 30

2.4 Dysregulation of signalling in cancer 32

2.5 Therapeutic opportunities 34

References 37

3 Transforming growth factor-β receptor signalling 45
Gudrun Stenbeck

3.1 TGFβ receptors 45

3.2 Ligands 48

3.3 Downstream signalling molecules and events 49

3.4 Signalling regulation 53

3.5 Dysregulation of signalling in cancer 56

3.6 Therapeutic opportunities 58

References 60

4 Wnt signalling 67
David Tree

4.1 Introduction and overview 67

4.2 The ligands: Wnt proteins, their modification and secretion 69

4.3 The receptors: Frizzleds and LRPs, multiple receptors and combinations 70

4.4 Regulation of signalling 71

4.5 When good signalling goes bad: Wnt signalling in diseases 79

4.6 Taming the beast: drugs and small molecule inhibitors targeting Wnt signalling 80

4.7 Conclusion and perspectives 81

References 82

5 Mammalian target of rapamycin (mTOR) signalling 93
Maria Thorpe and Emmanouil Karteris

5.1 Discovery of mTOR 93

5.2 mTOR complexes 94

5.3 mTOR dysregulation in disease 99

5.4 Therapeutic opportunities 104

References 107

6 c-Met receptor signalling 115
Stephen Hiscox

6.1 Historical context – identification of the MET gene 115

6.2 c-Met expression, activation and signal transduction 119

6.3 Physiological roles of c-Met 121

6.4 c-Met and cancer 123

6.5 c-Met as a potential therapeutic target in malignancy 128

6.6 Summary 130

References 130

7 Vascular endothelial growth factor and its receptor family 139
Katarzyna Leszczynska, Christopher Hillyar and Ester M. Hammond

7.1 VEGF receptors 139

7.2 Ligands 140

7.3 Downstream signalling molecules and events 143

7.4 Signalling regulation 150

7.5 Dysregulation of signalling in cancer 152

7.6 Therapeutic opportunities 153

References 158

8 Progesterone receptor signalling in breast cancer models 171
Andrea R. Daniel, Todd P. Knutson, Christy R. Hagan and Carol A. Lange

8.1 Progesterone receptor function 172

8.2 Model systems: context for studying PR biochemistry 174

8.3 Progesterone receptor signalling 175

8.4 Regulation of signalling 176

8.5 Tissue specific PR actions (breast versus reproductive tract) 181

8.6 Progesterone receptor and cancer 183

8.7 Summary 183

References 184

9 Signalling cross-talk 193
Amanda Harvey

9.1 Introduction 193

9.2 Examples of cross-talk 195

9.3 Convergence of signalling at downstream foci 197

9.4 Common signalling components 198

9.5 Compensatory signalling 202

9.6 Summary 203

References 203

Index 207