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

• List of contributors ixAcknowledgements xiIntroduction xiiiAbout the companion website xvi1 Epidermal growth factor receptor family 1Amanda Harvey1.1 ErbB receptors and their structure 11.2 ErbB ligands 21.3 Downstream signalling molecules and events 51.4 Signalling regulation 81.5 Dysregulation of signalling in cancer 101.6 Therapeutic opportunities 13References 172 Insulin and the insulin-like growth factor (IGF) family 25Maria Thorpe, Erald Shehu and Amanda Harvey2.1 Receptors 252.2 Ligands 282.3 Downstream signalling molecules and events 302.4 Dysregulation of signalling in cancer 322.5 Therapeutic opportunities 34References 373 Transforming growth factor-β receptor signalling 45Gudrun Stenbeck3.1 TGFβ receptors 453.2 Ligands 483.3 Downstream signalling molecules and events 493.4 Signalling regulation 533.5 Dysregulation of signalling in cancer 563.6 Therapeutic opportunities 58References 604 Wnt signalling 67David Tree4.1 Introduction and overview 674.2 The ligands: Wnt proteins, their modification and secretion 694.3 The receptors: Frizzleds and LRPs, multiple receptors and combinations 704.4 Regulation of signalling 714.5 When good signalling goes bad: Wnt signalling in diseases 794.6 Taming the beast: drugs and small molecule inhibitors targeting Wnt signalling 804.7 Conclusion and perspectives 81References 825 Mammalian target of rapamycin (mTOR) signalling 93Maria Thorpe and Emmanouil Karteris5.1 Discovery of mTOR 935.2 mTOR complexes 945.3 mTOR dysregulation in disease 995.4 Therapeutic opportunities 104References 1076 c-Met receptor signalling 115Stephen Hiscox6.1 Historical context – identification of the MET gene 1156.2 c-Met expression, activation and signal transduction 1196.3 Physiological roles of c-Met 1216.4 c-Met and cancer 1236.5 c-Met as a potential therapeutic target in malignancy 1286.6 Summary 130References 1307 Vascular endothelial growth factor and its receptor family 139Katarzyna Leszczynska, Christopher Hillyar and Ester M. Hammond7.1 VEGF receptors 1397.2 Ligands 1407.3 Downstream signalling molecules and events 1437.4 Signalling regulation 1507.5 Dysregulation of signalling in cancer 1527.6 Therapeutic opportunities 153References 1588 Progesterone receptor signalling in breast cancer models 171Andrea R. Daniel, Todd P. Knutson, Christy R. Hagan and Carol A. Lange8.1 Progesterone receptor function 1728.2 Model systems: context for studying PR biochemistry 1748.3 Progesterone receptor signalling 1758.4 Regulation of signalling 1768.5 Tissue specific PR actions (breast versus reproductive tract) 1818.6 Progesterone receptor and cancer 1838.7 Summary 183References 1849 Signalling cross-talk 193Amanda Harvey9.1 Introduction 1939.2 Examples of cross-talk 1959.3 Convergence of signalling at downstream foci 1979.4 Common signalling components 1989.5 Compensatory signalling 2029.6 Summary 203References 203Index 207

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

• List of contributors ixAcknowledgements xiIntroduction xiiiAbout the companion website xvi1 Epidermal growth factor receptor family 1Amanda Harvey1.1 ErbB receptors and their structure 11.2 ErbB ligands 21.3 Downstream signalling molecules and events 51.4 Signalling regulation 81.5 Dysregulation of signalling in cancer 101.6 Therapeutic opportunities 13References 172 Insulin and the insulin-like growth factor (IGF) family 25Maria Thorpe, Erald Shehu and Amanda Harvey2.1 Receptors 252.2 Ligands 282.3 Downstream signalling molecules and events 302.4 Dysregulation of signalling in cancer 322.5 Therapeutic opportunities 34References 373 Transforming growth factor-β receptor signalling 45Gudrun Stenbeck3.1 TGFβ receptors 453.2 Ligands 483.3 Downstream signalling molecules and events 493.4 Signalling regulation 533.5 Dysregulation of signalling in cancer 563.6 Therapeutic opportunities 58References 604 Wnt signalling 67David Tree4.1 Introduction and overview 674.2 The ligands: Wnt proteins, their modification and secretion 694.3 The receptors: Frizzleds and LRPs, multiple receptors and combinations 704.4 Regulation of signalling 714.5 When good signalling goes bad: Wnt signalling in diseases 794.6 Taming the beast: drugs and small molecule inhibitors targeting Wnt signalling 804.7 Conclusion and perspectives 81References 825 Mammalian target of rapamycin (mTOR) signalling 93Maria Thorpe and Emmanouil Karteris5.1 Discovery of mTOR 935.2 mTOR complexes 945.3 mTOR dysregulation in disease 995.4 Therapeutic opportunities 104References 1076 c-Met receptor signalling 115Stephen Hiscox6.1 Historical context – identification of the MET gene 1156.2 c-Met expression, activation and signal transduction 1196.3 Physiological roles of c-Met 1216.4 c-Met and cancer 1236.5 c-Met as a potential therapeutic target in malignancy 1286.6 Summary 130References 1307 Vascular endothelial growth factor and its receptor family 139Katarzyna Leszczynska, Christopher Hillyar and Ester M. Hammond7.1 VEGF receptors 1397.2 Ligands 1407.3 Downstream signalling molecules and events 1437.4 Signalling regulation 1507.5 Dysregulation of signalling in cancer 1527.6 Therapeutic opportunities 153References 1588 Progesterone receptor signalling in breast cancer models 171Andrea R. Daniel, Todd P. Knutson, Christy R. Hagan and Carol A. Lange8.1 Progesterone receptor function 1728.2 Model systems: context for studying PR biochemistry 1748.3 Progesterone receptor signalling 1758.4 Regulation of signalling 1768.5 Tissue specific PR actions (breast versus reproductive tract) 1818.6 Progesterone receptor and cancer 1838.7 Summary 183References 1849 Signalling cross-talk 193Amanda Harvey9.1 Introduction 1939.2 Examples of cross-talk 1959.3 Convergence of signalling at downstream foci 1979.4 Common signalling components 1989.5 Compensatory signalling 2029.6 Summary 203References 203Index 207

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

• List of contributors ixAcknowledgements xiIntroduction xiiiAbout the companion website xvi1 Epidermal growth factor receptor family 1Amanda Harvey1.1 ErbB receptors and their structure 11.2 ErbB ligands 21.3 Downstream signalling molecules and events 51.4 Signalling regulation 81.5 Dysregulation of signalling in cancer 101.6 Therapeutic opportunities 13References 172 Insulin and the insulin-like growth factor (IGF) family 25Maria Thorpe, Erald Shehu and Amanda Harvey2.1 Receptors 252.2 Ligands 282.3 Downstream signalling molecules and events 302.4 Dysregulation of signalling in cancer 322.5 Therapeutic opportunities 34References 373 Transforming growth factor-β receptor signalling 45Gudrun Stenbeck3.1 TGFβ receptors 453.2 Ligands 483.3 Downstream signalling molecules and events 493.4 Signalling regulation 533.5 Dysregulation of signalling in cancer 563.6 Therapeutic opportunities 58References 604 Wnt signalling 67David Tree4.1 Introduction and overview 674.2 The ligands: Wnt proteins, their modification and secretion 694.3 The receptors: Frizzleds and LRPs, multiple receptors and combinations 704.4 Regulation of signalling 714.5 When good signalling goes bad: Wnt signalling in diseases 794.6 Taming the beast: drugs and small molecule inhibitors targeting Wnt signalling 804.7 Conclusion and perspectives 81References 825 Mammalian target of rapamycin (mTOR) signalling 93Maria Thorpe and Emmanouil Karteris5.1 Discovery of mTOR 935.2 mTOR complexes 945.3 mTOR dysregulation in disease 995.4 Therapeutic opportunities 104References 1076 c-Met receptor signalling 115Stephen Hiscox6.1 Historical context – identification of the MET gene 1156.2 c-Met expression, activation and signal transduction 1196.3 Physiological roles of c-Met 1216.4 c-Met and cancer 1236.5 c-Met as a potential therapeutic target in malignancy 1286.6 Summary 130References 1307 Vascular endothelial growth factor and its receptor family 139Katarzyna Leszczynska, Christopher Hillyar and Ester M. Hammond7.1 VEGF receptors 1397.2 Ligands 1407.3 Downstream signalling molecules and events 1437.4 Signalling regulation 1507.5 Dysregulation of signalling in cancer 1527.6 Therapeutic opportunities 153References 1588 Progesterone receptor signalling in breast cancer models 171Andrea R. Daniel, Todd P. Knutson, Christy R. Hagan and Carol A. Lange8.1 Progesterone receptor function 1728.2 Model systems: context for studying PR biochemistry 1748.3 Progesterone receptor signalling 1758.4 Regulation of signalling 1768.5 Tissue specific PR actions (breast versus reproductive tract) 1818.6 Progesterone receptor and cancer 1838.7 Summary 183References 1849 Signalling cross-talk 193Amanda Harvey9.1 Introduction 1939.2 Examples of cross-talk 1959.3 Convergence of signalling at downstream foci 1979.4 Common signalling components 1989.5 Compensatory signalling 2029.6 Summary 203References 203Index 207