Interaction of the neu/p185 and EGF receptor tyrosine kinases: implications for cellular transformation and tumor therapy.
Growth factor receptors such as the epidermal growth factor receptor (EGFR) and the p185c-neu protein serve vital roles in the transduction of differentiation, developmental, or mitogenic signaling within normal cells. Two methods of analysis suggest that the inappropriately high expression of either protein tyrosine kinase promotes malignant transformation. First, data from in vitro experiments indicate that overexpression of either EGFR or p185c-neu (or the human homolog c-erbB-2) transforms cell-lines. Second, analysis of primary tumors and tumor cell-lines derived from many epithelial tissues (breast, stomach, ovary, and pancreas) show growth factor receptor gene amplification and elevated protein levels. The physical and functional interaction of p185c-neu and EGFR leads to the formation of a highly active, heterodimeric tyrosine kinase complex which synergistically activates cellular transformation. Anti-receptor antibodies have shown potential utility for the down modulation of these cell-surface proteins and suppression of the malignant phenotype. Design of organic antibody "mimetics" based on the structure of antireceptor antibodies may provide useful therapies and biological reagents to affect growth factor receptor function.
Dougall
W C
WC
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104.
Qian
X
X
Greene
M I
MI
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000628:therapy*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases
D000911:Antibodies, Monoclonal; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases