Signal Transduction by EGF Receptor Tyrosine Kinase
Members of the receptor tyrosine kinase family are frequently implicated in experimental models of neoplasia as well as in human cancer. One of the best studied receptor signaling systems from this family is the epidermal growth factor receptor (EGFR). The EGFR is widely expressed in mammals and has been implicated in various stages of embryonic development. Recently, EGFR knockout mice by targeted disruption of exon 1 (Sibilia and Wagner 1995) or exon 2 (Miettinen et al. 1995; Threadgill et al. 1995) of the mouse EGFR gene have been reported. The resulting phenotypes of EGFR-/- embryos or newborns were very similar. Growth retardation and epithelial immaturity were found, with the severity of defects being dependent on the mouse genetic background. These results indicate that the EGFR is of fundamental importance in the regulation of epithelial proliferation and differentiation. Experiments with transgenic mice suggest that an autocrine mechanism involving the EGFR could be expected to play a role in the initiation and/or progression of tumors. Transgenic mice expressing transforming growth factor-α (TGF-α) were reported to develop mammary and hepatocellular carcinoma as well as pancreatic hyperplasia (Jhappan et al. 1990; Sandgreen et al. 1990).
KeywordsEstrogen Tyrosine Serine Oncol Lysine
Unable to display preview. Download preview PDF.
- Defize LHK, Boonstra J, Meisenhelder J, Kruijer W, Tertoolen LGJ, Tilly BC, Hunter T, van Bergen en Henegouwen PMP, Moolenar WH, de Laat SW (1989) Signal transduction by epidermal growth factor occurs through the subclass of high affinity receptors. J Cell Biol 109: 2495–2507Google Scholar
- de Palazzo IEG, Adams GP, Sundaseshan P, Wong AJ, Testa JR, Bigner DD, Weiner LM. (1993) Expression of mutated epidermal growth factor receptor by non-small cell lung carcinoma. Cancer Res 53: 3217–3220Google Scholar
- McInnes C, Hoyt DW, Harkins RH, Debanne MT, O’Connor-McCourt M, Sykes BD (1996) NMR study of the transforming growth factor alpha/epidermal growth factor receptor complex: visualization of ligand binding determinants through NOE analysis of free and bound hTGFα. Biochemistry (in press)Google Scholar
- Montgomery RB, Moscatello DK, Wong AJ, Cooper JA, Stahl WL (1995) Differential modulation of mitogen-activated protein (MAP) kinase/extracellular signal-related kinase kinase and MAP kinase activities by a mutant epidermal growth factor receptor. J Biol Chem 270: 30562–30566PubMedCrossRefGoogle Scholar
- Riese DJ, Bermingham Y, van Raaij TM, Buckley S, Plowman GD, Stern DF (1996) Betacellulin activates the epidermal growth factor receptor and erbB-4, and induces cellular response patterns distinct from those stimulated by epidermal growth factor or neuregulin. Oncogene 12: 345–353PubMedGoogle Scholar
- Sainsbury JRC, Farnon JR, Needham GK, Malcolm AJ, Harris AL (1987) Epidermal-growth factor receptor states as predictor of early recurrence of and death from breast cancer. Lancet i: 1398–1402Google Scholar
- Threadgill DW, Dlugosz AA, Hansen LA, Tennenbaum T, Lichti U, Yee D, LaMantia C, Mourton T, Herrup K, Harris RC, Barnard JA, Yuspa SH, Coffey RJ, Magnuson T (1995) Targeted disruption of mouse EGF receptor: effect of genetic background on mutant phenotype. Science 269:230–234PubMedCrossRefGoogle Scholar