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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Levi-Montalcini, R. Effects of mouse tumor transplantation on the nervous system. Ann. NY Acad. Sci. 55, 330–344 (1952).
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).
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).
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).
Cohen, S. The stimulation of epidermal proliferation by a specific protein (EGF). Dev. Biol. 12, 394–407 (1965).
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).
Carpenter, G., King, L. Jr & Cohen, S. Epidermal growth factor stimulates phosphorylation in membrane preparations in vitro. Nature 276, 409–410 (1978).
Eckhart, W., Hutchinson, M. A. & Hunter, T. An activity phosphorylating tyrosine in polyoma T antigen immunoprecipitates. Cell 18, 925–933 (1979).
Hunter, T. & Sefton, B. M. Transforming gene product of Rous sarcoma virus phosphorylates tyrosine. Proc. Natl Acad. Sci. USA 77, 1311–1315 (1980).
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).
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).
Ek, B., Westermark, B., Wasteson, A. & Heldin, C. H. Stimulation of tyrosine-specific phosphorylation by platelet-derived growth factor. Nature 295, 419–420 (1982).
Hunter, T. & Cooper, J. A. Epidermal growth factor induces rapid tyrosine phosphorylation of proteins in A431 human tumor cells. Cell 24, 741–752 (1981).
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).
Ullrich, A. et al. Rat insulin genes: construction of plasmids containing the coding sequences. Science 196, 1313–1319 (1977).
Sures, I., Goeddel, D. V., Gray, A. & Ullrich, A. Nucleotide sequence of human preproinsulin complementary DNA. Science 208, 57–59 (1980).
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).
Scott, J. et al. Structure of a mouse submaxillary messenger RNA encoding epidermal growth factor and seven related proteins. Science 221, 236–240 (1983).
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).
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).
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).
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).
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).
Itakura, K. et al. Expression in Escherichia coli of a chemically synthesized gene for the hormone somatostatin. Science 198, 1056–1063 (1977).
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).
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).
Downward, J. et al. Close similarity of epidermal growth factor receptor and v-erb-B oncogene protein sequences. Nature 307, 521–527 (1984).
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).
Ullrich, A. et al. Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes. Nature 313, 756–761 (1985).
Ebina, Y. et al. The human insulin receptor cDNA: the structural basis for hormone-activated transmembrane signalling. Cell 40, 747–758 (1985).
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).
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).
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).
Coussens, L. et al. Structural alteration of viral homologue of receptor proto-oncogene fms at carboxyl terminus. Nature 320, 277–280 (1986).
Blume-Jensen, P. & Hunter, T. Oncogenic kinase signalling. Nature 411, 355–365 (2001).
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).
Schlessinger, J. Signal transduction by allosteric receptor oligomerization. Trends Biochem. Sci. 13, 443–447 (1988).
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).
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).
Lemmon, M. A. et al. Two EGF molecules contribute additively to stabilization of the EGFR dimer. EMBO J. 16, 281–294 (1997).
Ogiso, H. et al. Crystal structure of the complex of human epidermal growth factor and receptor extracellular domains. Cell 110, 775–787 (2002).
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).
Kamata, T. & Feramisco, J. R. Epidermal growth factor stimulates guanine nucleotide binding activity and phosphorylation of ras oncogene proteins. Nature 310, 147–150 (1984).
Smith, M. R., DeGudicibus, S. J. & Stacey, D. W. Requirement for c-ras proteins during viral oncogene transformation. Nature 320, 540–543 (1986).
Margolis, B. et al. EGF induces tyrosine phosphorylation of phospholipase C-II: a potential mechanism for EGF receptor signaling. Cell 57, 1101–1107 (1989).
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).
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).
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).
Wolfman, A. & Macara, I. G. A cytosolic protein catalyzes the release of GDP from p21ras. Science 248, 67–69 (1990).
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).
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).
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).
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).
McCormick, F. Signal transduction. How receptors turn Ras on. Nature 363, 15–16 (1993).
Marshall, C. J. Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell 80, 179–185 (1995).
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).
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).
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).
Yamauchi, T. et al. Tyrosine phosphorylation of the EGF receptor by the kinase Jak2 is induced by growth hormone. Nature 390, 91–96 (1997).
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).
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).
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).
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).
Prenzel, N. et al. EGF receptor transactivation by G-protein-coupled receptors requires metalloproteinase cleavage of proHB-EGF. Nature 402, 884–888 (1999).
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).
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).
Lemjabbar, H. & Basbaum, C. Platelet-activating factor receptor and ADAM10 mediate responses to Staphylococcus aureus in epithelial cells. Nature Med. 8, 41–46 (2002).
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).
Threadgill, D. W. et al. Targeted disruption of mouse EGF receptor: effect of genetic background on mutant phenotype. Science 269, 230–234 (1995).
Miettinen, P. J. et al. Epithelial immaturity and multiorgan failure in mice lacking epidermal growth factor receptor. Nature 376, 337–341 (1995).
Sibilia, M. & Wagner, E. F. Strain-dependent epithelial defects in mice lacking the EGF receptor. Science 269, 234–238 (1995).
Lee, K. F. et al. Requirement for neuregulin receptor erbB2 in neural and cardiac development. Nature 378, 394–398 (1995).
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).
Gassmann, M. et al. Aberrant neural and cardiac development in mice lacking the ErbB4 neuregulin receptor. Nature 378, 390–394 (1995).
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).
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).
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).
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).
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).
Black, R. A. et al. A metalloproteinase disintegrin that releases tumour-necrosis factor-α from cells. Nature 385, 729–733 (1997).
Peschon, J. J. et al. An essential role for ectodomain shedding in mammalian development. Science 282, 1281–1284 (1998).
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).
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).
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).
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).
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).
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).
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).
Coussens, L. et al. Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. Science 230, 1132–1139 (1985).
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).
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).
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).
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).
Slamon, D. J. et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244, 707–712 (1989).
Stern, D. F. & Kamps, M. P. EGF-stimulated tyrosine phosphorylation of p185neu: a potential model for receptor interactions. EMBO J. 7, 995–1001 (1988).
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).
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).
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).
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).
Agus, D. B. et al. Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth. Cancer Cell 2, 127–137 (2002).
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).
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).
Yaish, P., Gazit, A., Gilon, C. & Levitzki, A. Blocking of EGF-dependent cell proliferation by EGF receptor kinase inhibitors. Science 242, 933–935 (1988).
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).
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).
Redemann, N. et al. Anti-oncogenic activity of signalling-defective epidermal growth factor receptor mutants. Mol. Cell. Biol. 12, 491–498 (1992).
Fry, D. W. et al. A specific inhibitor of the epidermal growth factor receptor tyrosine kinase. Science 265, 1093–1095 (1994).
Osherov, N. & Levitzki, A. Epidermal-growth-factor-dependent activation of the src-family kinases. Eur. J. Biochem. 225, 1047–1053 (1994).
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).
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).
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).
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).
Ferrara, N. VEGF and the quest for tumour angiogenesis factors. Nature Rev. Cancer 2, 795–803 (2002).
Folkman, J. Tumor angiogenesis: therapeutic implications. N. Engl. J. Med. 285, 1182–1186 (1971).
de Vries, C. et al. The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science 255, 989–991 (1992).
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).
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).
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).
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).
Shalaby, F. et al. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 376, 62–66 (1995).
Kim, K. J. et al. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 362, 841–844 (1993).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Heinrich, M. C. et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J. Clin. Oncol. 21, 4342–4349 (2003).
Bardelli, A. et al. Mutational analysis of the tyrosine kinome in colorectal cancers. Science 300, 949 (2003).
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).
Soriano, P. Abnormal kidney development and hematological disorders in PDGF β-receptor mutant mice. Genes Dev. 8, 1888–1896 (1994).
Ferrara, N. et al. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380, 439–442 (1996).
Carmeliet, P. et al. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380, 435–439 (1996).
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.
The authors declare no competing financial interests.
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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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