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The discovery of receptor tyrosine kinases: targets for cancer therapy

Abstract

Receptor tyrosine kinases are a subclass of cell-surface growth-factor receptors with an intrinsic, ligand-controlled tyrosine-kinase activity. They regulate diverse functions in normal cells and have a crucial role in oncogenesis. Twenty years ago, the first primary structure of a receptor tyrosine kinase, the epidermal growth factor receptor, was elucidated. The characterization of both the molecular architecture of receptor tyrosine kinases and the main functions of these proteins and their ligands in tumorigenesis opened the door to a new era in molecular oncology and paved the way to the development of the first target-specific cancer therapeutics.

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Figure 1: The epidermal growth factor receptor signalling network.
Figure 2: Receptor tyrosine kinases: sites of therapeutic intervention.

References

  1. 1

    Levi-Montalcini, R. Effects of mouse tumor transplantation on the nervous system. Ann. NY Acad. Sci. 55, 330–344 (1952).

    CAS  PubMed  Google Scholar 

  2. 2

    Cohen, S. & Levi-Montalcini, R. Purification and properties of a nerve growth-promoting factor isolated from mouse sarcoma 180. Cancer Res. 17, 15–20 (1957).

    CAS  PubMed  Google Scholar 

  3. 3

    Levi-Montalcini, R. & Cohen, S. Effects of the extract of the mouse submaxillary salivary glands on the sympathetic system of mammals. Ann. NY Acad. Sci. 85, 324–341 (1960).

    CAS  PubMed  Google Scholar 

  4. 4

    Cohen, S. Isolation of a mouse submaxillary gland protein accelerating incisor eruption and eyelid opening in the new-born animal. J. Biol. Chem. 237, 1555–1562 (1962).

    CAS  PubMed  Google Scholar 

  5. 5

    Cohen, S. The stimulation of epidermal proliferation by a specific protein (EGF). Dev. Biol. 12, 394–407 (1965).

    CAS  PubMed  Google Scholar 

  6. 6

    Carpenter, G., Lembach, K. J., Morrison, M. M. & Cohen, S. Characterization of the binding of 125I-labeled epidermal growth factor to human fibroblasts. J. Biol. Chem. 250, 4297–4304 (1975).

    CAS  PubMed  Google Scholar 

  7. 7

    Carpenter, G., King, L. Jr & Cohen, S. Epidermal growth factor stimulates phosphorylation in membrane preparations in vitro. Nature 276, 409–410 (1978).

    CAS  PubMed  Google Scholar 

  8. 8

    Eckhart, W., Hutchinson, M. A. & Hunter, T. An activity phosphorylating tyrosine in polyoma T antigen immunoprecipitates. Cell 18, 925–933 (1979).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Hunter, T. & Sefton, B. M. Transforming gene product of Rous sarcoma virus phosphorylates tyrosine. Proc. Natl Acad. Sci. USA 77, 1311–1315 (1980).

    CAS  PubMed  Google Scholar 

  10. 10

    Ushiro, H. & Cohen, S. Identification of phosphotyrosine as a product of epidermal growth factor-activated protein kinase in A-431 cell membranes. J. Biol. Chem. 255, 8363–8365 (1980).

    CAS  PubMed  Google Scholar 

  11. 11

    Kasuga, M., Zick, Y., Blithe, D. L., Crettaz, M. & Kahn, C. R. Insulin stimulates tyrosine phosphorylation of the insulin receptor in a cell-free system. Nature 298, 667–669 (1982).

    CAS  PubMed  Google Scholar 

  12. 12

    Ek, B., Westermark, B., Wasteson, A. & Heldin, C. H. Stimulation of tyrosine-specific phosphorylation by platelet-derived growth factor. Nature 295, 419–420 (1982).

    CAS  PubMed  Google Scholar 

  13. 13

    Hunter, T. & Cooper, J. A. Epidermal growth factor induces rapid tyrosine phosphorylation of proteins in A431 human tumor cells. Cell 24, 741–752 (1981).

    CAS  PubMed  Google Scholar 

  14. 14

    Cooper, J. A., Bowen-Pope, D. F., Raines, E., Ross, R. & Hunter, T. Similar effects of platelet-derived growth factor and epidermal growth factor on the phosphorylation of tyrosine in cellular proteins. Cell 31, 263–273 (1982).

    CAS  PubMed  Google Scholar 

  15. 15

    Ullrich, A. et al. Rat insulin genes: construction of plasmids containing the coding sequences. Science 196, 1313–1319 (1977).

    CAS  PubMed  Google Scholar 

  16. 16

    Sures, I., Goeddel, D. V., Gray, A. & Ullrich, A. Nucleotide sequence of human preproinsulin complementary DNA. Science 208, 57–59 (1980).

    CAS  PubMed  Google Scholar 

  17. 17

    Gray, A., Dull, T. J. & Ullrich, A. Nucleotide sequence of epidermal growth factor cDNA predicts a 128,000-molecular weight protein precursor. Nature 303, 722–725 (1983).

    CAS  PubMed  Google Scholar 

  18. 18

    Scott, J. et al. Structure of a mouse submaxillary messenger RNA encoding epidermal growth factor and seven related proteins. Science 221, 236–240 (1983).

    CAS  PubMed  Google Scholar 

  19. 19

    Dull, T. J., Gray, A., Hayflick, J. S. & Ullrich, A. Insulin-like growth factor II precursor gene organization in relation to insulin gene family. Nature 310, 777–781 (1984).

    CAS  PubMed  Google Scholar 

  20. 20

    Ullrich, A., Gray, A., Berman, C. & Dull, T. J. Human β-nerve growth factor gene sequence highly homologous to that of mouse. Nature 303, 821–825 (1983).

    CAS  PubMed  Google Scholar 

  21. 21

    Johnsson, A. et al. The c-sis gene encodes a precursor of the B chain of platelet-derived growth factor. EMBO J. 3, 921–928 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Chiu, I. M. et al. Nucleotide sequence analysis identifies the human c-sis proto-oncogene as a structural gene for platelet-derived growth factor. Cell 37, 123–129 (1984).

    CAS  PubMed  Google Scholar 

  23. 23

    Derynck, R., Roberts, A. B., Winkler, M. E., Chen, E. Y. & Goeddel, D. V. Human transforming growth factor-α: precursor structure and expression in E. coli. Cell 38, 287–297 (1984).

    CAS  PubMed  Google Scholar 

  24. 24

    Itakura, K. et al. Expression in Escherichia coli of a chemically synthesized gene for the hormone somatostatin. Science 198, 1056–1063 (1977).

    CAS  PubMed  Google Scholar 

  25. 25

    Martial, J. A., Hallewell, R. A., Baxter, J. D. & Goodman, H. M. Human growth hormone: complementary DNA cloning and expression in bacteria. Science 205, 602–607 (1979).

    CAS  PubMed  Google Scholar 

  26. 26

    Ullrich, A. et al. Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells. Nature 309, 418–425 (1984).

    CAS  PubMed  Google Scholar 

  27. 27

    Downward, J. et al. Close similarity of epidermal growth factor receptor and v-erb-B oncogene protein sequences. Nature 307, 521–527 (1984).

    CAS  PubMed  Google Scholar 

  28. 28

    Yamamoto, T., Hihara, H., Nishida, T., Kawai, S. & Toyoshima, K. A new avian erythroblastosis virus, AEV-H, carries erbB gene responsible for the induction of both erythroblastosis and sarcomas. Cell 34, 225–232 (1983).

    CAS  PubMed  Google Scholar 

  29. 29

    Ullrich, A. et al. Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes. Nature 313, 756–761 (1985).

    CAS  PubMed  Google Scholar 

  30. 30

    Ebina, Y. et al. The human insulin receptor cDNA: the structural basis for hormone-activated transmembrane signalling. Cell 40, 747–758 (1985).

    CAS  PubMed  Google Scholar 

  31. 31

    Ullrich, A. et al. Insulin-like growth factor I receptor primary structure: comparison with insulin receptor suggests structural determinants that define functional specificity. EMBO J. 5, 2503–2512 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Yarden, Y. et al. Structure of the receptor for platelet-derived growth factor helps define a family of closely related growth factor receptors. Nature 323, 226–232 (1986).

    CAS  PubMed  Google Scholar 

  33. 33

    Yarden, Y. et al. Human proto-oncogene c-kit: a new cell surface receptor tyrosine kinase for an unidentified ligand. EMBO J. 6, 3341–3351 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Coussens, L. et al. Structural alteration of viral homologue of receptor proto-oncogene fms at carboxyl terminus. Nature 320, 277–280 (1986).

    CAS  PubMed  Google Scholar 

  35. 35

    Blume-Jensen, P. & Hunter, T. Oncogenic kinase signalling. Nature 411, 355–365 (2001).

    CAS  Google Scholar 

  36. 36

    Riedel, H., Dull, T. J., Schlessinger, J. & Ullrich, A. A chimaeric receptor allows insulin to stimulate tyrosine kinase activity of epidermal growth factor receptor. Nature 324, 68–70 (1986).

    CAS  PubMed  Google Scholar 

  37. 37

    Schlessinger, J. Signal transduction by allosteric receptor oligomerization. Trends Biochem. Sci. 13, 443–447 (1988).

    CAS  PubMed  Google Scholar 

  38. 38

    Wiesmann, C. et al. Crystal structure at 1.7 Å resolution of VEGF in complex with domain 2 of the Flt-1 receptor. Cell 91, 695–704 (1997).

    CAS  Google Scholar 

  39. 39

    Wiesmann, C., Ultsch, M. H., Bass, S. H. & de Vos, A. M. Crystal structure of nerve growth factor in complex with the ligand-binding domain of the TrkA receptor. Nature 401, 184–188 (1999).

    CAS  PubMed  Google Scholar 

  40. 40

    Lemmon, M. A. et al. Two EGF molecules contribute additively to stabilization of the EGFR dimer. EMBO J. 16, 281–294 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Ogiso, H. et al. Crystal structure of the complex of human epidermal growth factor and receptor extracellular domains. Cell 110, 775–787 (2002).

    CAS  PubMed  Google Scholar 

  42. 42

    Garrett, T. P. et al. Crystal structure of a truncated epidermal growth factor receptor extracellular domain bound to transforming growth factor α. Cell 110, 763–773 (2002).

    CAS  PubMed  Google Scholar 

  43. 43

    Kamata, T. & Feramisco, J. R. Epidermal growth factor stimulates guanine nucleotide binding activity and phosphorylation of ras oncogene proteins. Nature 310, 147–150 (1984).

    CAS  PubMed  Google Scholar 

  44. 44

    Smith, M. R., DeGudicibus, S. J. & Stacey, D. W. Requirement for c-ras proteins during viral oncogene transformation. Nature 320, 540–543 (1986).

    CAS  PubMed  Google Scholar 

  45. 45

    Margolis, B. et al. EGF induces tyrosine phosphorylation of phospholipase C-II: a potential mechanism for EGF receptor signaling. Cell 57, 1101–1107 (1989).

    CAS  PubMed  Google Scholar 

  46. 46

    Meisenhelder, J., Suh, P. G., Rhee, S. G. & Hunter, T. Phospholipase C-γ is a substrate for the PDGF and EGF receptor protein-tyrosine kinases in vivo and in vitro. Cell 57, 1109–1122 (1989).

    CAS  PubMed  Google Scholar 

  47. 47

    Moran, M. F. et al. Src homology region 2 domains direct protein–protein interactions in signal transduction. Proc. Natl Acad. Sci. USA 87, 8622–8626 (1990).

    CAS  PubMed  Google Scholar 

  48. 48

    Matsuda, M., Mayer, B. J., Fukui, Y. & Hanafusa, H. Binding of transforming protein, p47gag-crk, to a broad range of phosphotyrosine-containing proteins. Science 248, 1537–1539 (1990).

    CAS  PubMed  Google Scholar 

  49. 49

    Wolfman, A. & Macara, I. G. A cytosolic protein catalyzes the release of GDP from p21ras. Science 248, 67–69 (1990).

    CAS  PubMed  Google Scholar 

  50. 50

    Downward, J., Riehl, R., Wu, L. & Weinberg, R. A. Identification of a nucleotide exchange-promoting activity for p21ras. Proc. Natl Acad. Sci. USA 87, 5998–6002 (1990).

    CAS  PubMed  Google Scholar 

  51. 51

    Lowenstein, E. J. et al. The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling. Cell 70, 431–442 (1992).

    CAS  PubMed  Google Scholar 

  52. 52

    Matuoka, K., Shibata, M., Yamakawa, A. & Takenawa, T. Cloning of ASH, a ubiquitous protein composed of one Src homology region (SH) 2 and two SH3 domains, from human and rat cDNA libraries. Proc. Natl Acad. Sci. USA 89, 9015–9019 (1992).

    CAS  PubMed  Google Scholar 

  53. 53

    Matuoka, K., Shibasaki, F., Shibata, M. & Takenawa, T. Ash/Grb-2, a SH2/SH3-containing protein, couples to signaling for mitogenesis and cytoskeletal reorganization by EGF and PDGF. EMBO J. 12, 3467–3473 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    McCormick, F. Signal transduction. How receptors turn Ras on. Nature 363, 15–16 (1993).

    CAS  PubMed  Google Scholar 

  55. 55

    Marshall, C. J. Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell 80, 179–185 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Bjorge, J. D., Chan, T. O., Antczak, M., Kung, H. J. & Fujita, D. J. Activated type I phosphatidylinositol kinase is associated with the epidermal growth factor (EGF) receptor following EGF stimulation. Proc. Natl Acad. Sci. USA 87, 3816–3820 (1990).

    CAS  PubMed  Google Scholar 

  57. 57

    Franke, T. F. et al. The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase. Cell 81, 727–736 (1995).

    CAS  PubMed  Google Scholar 

  58. 58

    Zhong, Z., Wen, Z. & Darnell, J. E. Jr. Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science 264, 95–98 (1994).

    CAS  Google Scholar 

  59. 59

    Yamauchi, T. et al. Tyrosine phosphorylation of the EGF receptor by the kinase Jak2 is induced by growth hormone. Nature 390, 91–96 (1997).

    CAS  PubMed  Google Scholar 

  60. 60

    Moro, L. et al. Integrins induce activation of EGF receptor: role in MAP kinase induction and adhesion-dependent cell survival. EMBO J. 17, 6622–6632 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Zwick, E. et al. Critical role of calcium-dependent epidermal growth factor receptor transactivation in PC12 cell membrane depolarization and bradykinin signaling. J. Biol. Chem. 272, 24767–24770 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

    King, C. R., Borrello, I., Porter, L., Comoglio, P. & Schlessinger, J. Ligand-independent tyrosine phosphorylation of EGF receptor and the erbB-2/neu proto-oncogene product is induced by hyperosmotic shock. Oncogene 4, 13–18 (1989).

    CAS  PubMed  Google Scholar 

  63. 63

    Daub, H., Weiss, F. U., Wallasch, C. & Ullrich, A. Role of transactivation of the EGF receptor in signalling by G-protein-coupled receptors. Nature 379, 557–560 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    Prenzel, N. et al. EGF receptor transactivation by G-protein-coupled receptors requires metalloproteinase cleavage of proHB-EGF. Nature 402, 884–888 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    Gschwind, A., Hart, S., Fischer, O. M. & Ullrich, A. TACE cleavage of proamphiregulin regulates GPCR-induced proliferation and motility of cancer cells. EMBO J. 22, 2411–2421 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    Asakura, M. et al. Cardiac hypertrophy is inhibited by antagonism of ADAM12 processing of HB-EGF: metalloproteinase inhibitors as a new therapy. Nature Med. 8, 35–40 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    Lemjabbar, H. & Basbaum, C. Platelet-activating factor receptor and ADAM10 mediate responses to Staphylococcus aureus in epithelial cells. Nature Med. 8, 41–46 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Keates, S. et al. cag+Helicobacter pylori induce transactivation of the epidermal growth factor receptor in AGS gastric epithelial cells. J. Biol. Chem. 276, 48127–48134 (2001).

    CAS  PubMed  Google Scholar 

  69. 69

    Threadgill, D. W. et al. Targeted disruption of mouse EGF receptor: effect of genetic background on mutant phenotype. Science 269, 230–234 (1995).

    CAS  Google Scholar 

  70. 70

    Miettinen, P. J. et al. Epithelial immaturity and multiorgan failure in mice lacking epidermal growth factor receptor. Nature 376, 337–341 (1995).

    CAS  Google Scholar 

  71. 71

    Sibilia, M. & Wagner, E. F. Strain-dependent epithelial defects in mice lacking the EGF receptor. Science 269, 234–238 (1995).

    CAS  Google Scholar 

  72. 72

    Lee, K. F. et al. Requirement for neuregulin receptor erbB2 in neural and cardiac development. Nature 378, 394–398 (1995).

    CAS  PubMed  Google Scholar 

  73. 73

    Erickson, S. L. et al. ErbB3 is required for normal cerebellar and cardiac development: a comparison with ErbB2-and heregulin-deficient mice. Development 124, 4999–5011 (1997).

    CAS  PubMed  Google Scholar 

  74. 74

    Gassmann, M. et al. Aberrant neural and cardiac development in mice lacking the ErbB4 neuregulin receptor. Nature 378, 390–394 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Luetteke, N. C. et al. Targeted inactivation of the EGF and amphiregulin genes reveals distinct roles for EGF receptor ligands in mouse mammary gland development. Development 126, 2739–2750 (1999).

    CAS  PubMed  Google Scholar 

  76. 76

    Luetteke, N. C. et al. TGFα deficiency results in hair follicle and eye abnormalities in targeted and waved-1 mice. Cell 73, 263–278 (1993).

    CAS  PubMed  Google Scholar 

  77. 77

    Mann, G. B. et al. Mice with a null mutation of the TGFα gene have abnormal skin architecture, wavy hair, and curly whiskers and often develop corneal inflammation. Cell 73, 249–261 (1993).

    CAS  PubMed  Google Scholar 

  78. 78

    Iwamoto, R. et al. Heparin-binding EGF-like growth factor and ErbB signaling is essential for heart function. Proc. Natl Acad. Sci. USA 100, 3221–3226 (2003).

    CAS  PubMed  Google Scholar 

  79. 79

    Jackson, L. F. et al. Defective valvulogenesis in HB-EGF and TACE-null mice is associated with aberrant BMP signaling. EMBO J. 22, 2704–2716 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80

    Black, R. A. et al. A metalloproteinase disintegrin that releases tumour-necrosis factor-α from cells. Nature 385, 729–733 (1997).

    CAS  PubMed  Google Scholar 

  81. 81

    Peschon, J. J. et al. An essential role for ectodomain shedding in mammalian development. Science 282, 1281–1284 (1998).

    CAS  Google Scholar 

  82. 82

    Sunnarborg, S. W. et al. Tumor necrosis factor-α converting enzyme (TACE) regulates epidermal growth factor receptor ligand availability. J. Biol. Chem. 277, 12838–12845 (2002).

    CAS  Google Scholar 

  83. 83

    Sizeland, A. M. & Burgess, A. W. Anti-sense transforming growth factor α oligonucleotides inhibit autocrine stimulated proliferation of a colon carcinoma cell line. Mol. Biol. Cell 3, 1235–1243 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Humphrey, P. A. et al. Anti-synthetic peptide antibody reacting at the fusion junction of deletion-mutant epidermal growth factor receptors in human glioblastoma. Proc. Natl Acad. Sci. USA 87, 4207–4211 (1990).

    CAS  PubMed  Google Scholar 

  85. 85

    Malden, L. T., Novak, U., Kaye, A. H. & Burgess, A. W. Selective amplification of the cytoplasmic domain of the epidermal growth factor receptor gene in glioblastoma multiforme. Cancer Res. 48, 2711–2714 (1988).

    CAS  PubMed  Google Scholar 

  86. 86

    Peschard, P. & Park, M. Escape from Cbl-mediated downregulation: a recurrent theme for oncogenic deregulation of receptor tyrosine kinases. Cancer Cell 3, 519–523 (2003).

    CAS  PubMed  Google Scholar 

  87. 87

    Levkowitz, G. et al. c-Cbl/Sli-1 regulates endocytic sorting and ubiquitination of the epidermal growth factor receptor. Genes Dev. 12, 3663–3674 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88

    Thien, C. B. & Langdon, W. Y. Tyrosine kinase activity of the EGF receptor is enhanced by the expression of oncogenic 70Z-Cbl. Oncogene 15, 2909–2919 (1997).

    CAS  PubMed  Google Scholar 

  89. 89

    Coussens, L. et al. Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. Science 230, 1132–1139 (1985).

    CAS  PubMed  Google Scholar 

  90. 90

    King, C. R., Kraus, M. H. & Aaronson, S. A. Amplification of a novel v-erbB-related gene in a human mammary carcinoma. Science 229, 974–976 (1985).

    CAS  PubMed  Google Scholar 

  91. 91

    Schechter, A. L. et al. The neu oncogene: an erb-B-related gene encoding a 185,000-Mr tumour antigen. Nature 312, 513–516 (1984).

    CAS  PubMed  Google Scholar 

  92. 92

    Drebin, J. A., Stern, D. F., Link, V. C., Weinberg, R. A. & Greene, M. I. Monoclonal antibodies identify a cell-surface antigen associated with an activated cellular oncogene. Nature 312, 545–548 (1984).

    CAS  PubMed  Google Scholar 

  93. 93

    Slamon, D. J. et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235, 177–182 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94

    Slamon, D. J. et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244, 707–712 (1989).

    CAS  PubMed  Google Scholar 

  95. 95

    Stern, D. F. & Kamps, M. P. EGF-stimulated tyrosine phosphorylation of p185neu: a potential model for receptor interactions. EMBO J. 7, 995–1001 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96

    King, C. R., Borrello, I., Bellot, F., Comoglio, P. & Schlessinger, J. Egf binding to its receptor triggers a rapid tyrosine phosphorylation of the erbB-2 protein in the mammary tumor cell line SK-BR-3. EMBO J. 7, 1647–1651 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97

    Graus-Porta, D., Beerli, R. R., Daly, J. M. & Hynes, N. E. ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling. EMBO J. 16, 1647–1655 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98

    Hudziak, R. M. et al. p185HER2 monoclonal antibody has antiproliferative effects in vitro and sensitizes human breast tumor cells to tumor necrosis factor. Mol. Cell. Biol. 9, 1165–1172 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99

    Fendly, B. M. et al. Characterization of murine monoclonal antibodies reactive to either the human epidermal growth factor receptor or HER2/neu gene product. Cancer Res. 50, 1550–1558 (1990).

    CAS  PubMed  Google Scholar 

  100. 100

    Agus, D. B. et al. Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth. Cancer Cell 2, 127–137 (2002).

    CAS  PubMed  Google Scholar 

  101. 101

    Kawamoto, T. et al. Growth stimulation of A431 cells by epidermal growth factor: identification of high-affinity receptors for epidermal growth factor by an anti-receptor monoclonal antibody. Proc. Natl Acad. Sci. USA 80, 1337–1341 (1983).

    CAS  PubMed  Google Scholar 

  102. 102

    Sato, J. D. et al. Biological effects in vitro of monoclonal antibodies to human epidermal growth factor receptors. Mol. Biol. Med. 1, 511–529 (1983).

    CAS  PubMed  Google Scholar 

  103. 103

    Yaish, P., Gazit, A., Gilon, C. & Levitzki, A. Blocking of EGF-dependent cell proliferation by EGF receptor kinase inhibitors. Science 242, 933–935 (1988).

    CAS  PubMed  Google Scholar 

  104. 104

    Honegger, A. M. et al. Point mutation at the ATP binding site of EGF receptor abolishes protein-tyrosine kinase activity and alters cellular routing. Cell 51, 199–209 (1987).

    CAS  PubMed  Google Scholar 

  105. 105

    Honegger, A. M. et al. A mutant epidermal growth factor receptor with defective protein tyrosine kinase is unable to stimulate proto-oncogene expression and DNA synthesis. Mol. Cell. Biol. 7, 4568–4571 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106

    Redemann, N. et al. Anti-oncogenic activity of signalling-defective epidermal growth factor receptor mutants. Mol. Cell. Biol. 12, 491–498 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107

    Fry, D. W. et al. A specific inhibitor of the epidermal growth factor receptor tyrosine kinase. Science 265, 1093–1095 (1994).

    CAS  PubMed  Google Scholar 

  108. 108

    Osherov, N. & Levitzki, A. Epidermal-growth-factor-dependent activation of the src-family kinases. Eur. J. Biochem. 225, 1047–1053 (1994).

    CAS  PubMed  Google Scholar 

  109. 109

    Wakeling, A. E. et al. Specific inhibition of epidermal growth factor receptor tyrosine kinase by 4-anilinoquinazolines. Breast Cancer Res. Treat. 38, 67–73 (1996).

    CAS  PubMed  Google Scholar 

  110. 110

    Druker, B. J. et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr–Abl positive cells. Nature Med. 2, 561–566 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111

    Buchdunger, E. et al. Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptors. J. Pharmacol. Exp. Ther. 295, 139–145 (2000).

    CAS  Google Scholar 

  112. 112

    Joensuu, H. et al. Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N. Engl. J. Med. 344, 1052–1056 (2001).

    CAS  PubMed  Google Scholar 

  113. 113

    Ferrara, N. VEGF and the quest for tumour angiogenesis factors. Nature Rev. Cancer 2, 795–803 (2002).

    CAS  Google Scholar 

  114. 114

    Folkman, J. Tumor angiogenesis: therapeutic implications. N. Engl. J. Med. 285, 1182–1186 (1971).

    CAS  Google Scholar 

  115. 115

    de Vries, C. et al. The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science 255, 989–991 (1992).

    CAS  PubMed  Google Scholar 

  116. 116

    Terman, B. I. et al. Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor. Biochem. Biophys. Res. Commun. 187, 1579–1586 (1992).

    CAS  Google Scholar 

  117. 117

    Millauer, B. et al. High affinity VEGF binding and developmental expression suggest Flk-1 as a major regulator of vasculogenesis and angiogenesis. Cell 72, 835–846 (1993).

    CAS  PubMed  Google Scholar 

  118. 118

    Quinn, T. P., Peters, K. G., De Vries, C., Ferrara, N. & Williams, L. T. Fetal liver kinase 1 is a receptor for vascular endothelial growth factor and is selectively expressed in vascular endothelium. Proc. Natl Acad. Sci. USA 90, 7533–7537 (1993).

    CAS  PubMed  Google Scholar 

  119. 119

    Fong, G. H., Rossant, J., Gertsenstein, M. & Breitman, M. L. Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature 376, 66–70 (1995).

    CAS  Google Scholar 

  120. 120

    Shalaby, F. et al. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 376, 62–66 (1995).

    CAS  Google Scholar 

  121. 121

    Kim, K. J. et al. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 362, 841–844 (1993).

    CAS  Google Scholar 

  122. 122

    Millauer, B., Shawver, L. K., Plate, K. H., Risau, W. & Ullrich, A. Glioblastoma growth inhibited in vivo by a dominant-negative Flk-1 mutant. Nature 367, 576–579 (1994).

    CAS  Google Scholar 

  123. 123

    Millauer, B. et al. Dominant-negative inhibition of Flk-1 suppresses the growth of many tumor types in vivo. Cancer Res. 56, 1615–1620 (1996).

    CAS  PubMed  Google Scholar 

  124. 124

    Presta, L. G. et al. Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res. 57, 4593–4599 (1997).

    CAS  PubMed  Google Scholar 

  125. 125

    Fong, T. A. et al. SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types. Cancer Res. 59, 99–106 (1999).

    CAS  PubMed  Google Scholar 

  126. 126

    Shaheen, R. M. et al. Antiangiogenic therapy targeting the tyrosine kinase receptor for vascular endothelial growth factor receptor inhibits the growth of colon cancer liver metastasis and induces tumor and endothelial cell apoptosis. Cancer Res. 59, 5412–5416 (1999).

    CAS  PubMed  Google Scholar 

  127. 127

    O'Farrell, A. M. et al. SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood 101, 3597–3605 (2003).

    CAS  PubMed  Google Scholar 

  128. 128

    Wedge, S. R. et al. ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administration. Cancer Res. 62, 4645–4655 (2002).

    CAS  Google Scholar 

  129. 129

    Wood, J. M. et al. PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration. Cancer Res. 60, 2178–2189 (2000).

    CAS  Google Scholar 

  130. 130

    Gorre, M. E. et al. Clinical resistance to STI-571 cancer therapy caused by BCR–ABL gene mutation or amplification. Science 293, 876–880 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131

    Heinrich, M. C. et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J. Clin. Oncol. 21, 4342–4349 (2003).

    CAS  PubMed  Google Scholar 

  132. 132

    Bardelli, A. et al. Mutational analysis of the tyrosine kinome in colorectal cancers. Science 300, 949 (2003).

    CAS  Google Scholar 

  133. 133

    Soriano, P. The PDGF α receptor is required for neural crest cell development and for normal patterning of the somites. Development 124, 2691–2700 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. 134

    Soriano, P. Abnormal kidney development and hematological disorders in PDGF β-receptor mutant mice. Genes Dev. 8, 1888–1896 (1994).

    CAS  PubMed  Google Scholar 

  135. 135

    Ferrara, N. et al. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380, 439–442 (1996).

    CAS  PubMed  Google Scholar 

  136. 136

    Carmeliet, P. et al. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380, 435–439 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Correction: The DOI number given for this article in the May 2004 print issue of Nature Reviews Cancer was wrong. The correct DOI number is: doi:10.1038/nrc1360.

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Correspondence to Axel Ullrich.

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DATABASES

Cancer.gov

breast cancer

colorectal cancer

gastrointestinal cancer

non-small-cell lung cancer

ovarian cancer

LocusLink

EGF

EGFR

FLT1

FMS

GRB2

IGF1

IGF1R

IGF2

INSR

KIT

NGF

PDGF

PDGFR

PLCγ1

RAS

TGF-α

TRKA

VEGF

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Gschwind, A., Fischer, O. & Ullrich, A. The discovery of receptor tyrosine kinases: targets for cancer therapy. Nat Rev Cancer 4, 361–370 (2004). https://doi.org/10.1038/nrc1360

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