Requirement for intrinsic protein tyrosine kinase in the immediate and late actions of the EGF receptor.
The epidermal growth factor (EGF) receptor is a transmembrane glycoprotein of relative molecular mass 170,000 with intrinsic ligand-dependent protein tyrosine kinase activity. Binding of EGF to its receptor activates a number of immediate biochemical processes, such as alterations of intracellular free calcium, pH, and increased transcription of several responsive genes, which usually culminate many hours later in DNA replication and cell division. Abolishing the tyrosine kinase activity of three related oncogenes, v-src, v-mos, and v-fps, eliminates their capacity to transform cell. Several reports have suggested that specific aspects of EGF receptor function are independent of the intrinsic tyrosine kinase activity; however, these studies used an antibody against EGF receptor which failed to activate phosphorylation of exogenous substrates and an insertional mutation in the EGF receptor tyrosine kinase domain which had not been shown to abolish protein kinase activity in cells. Because many transmembrane receptors interact with intrinsic membrane proteins to activate second messenger systems, it is important to resolve experimentally whether mechanisms, in addition to activation of the intrinsic tyrosine kinase activity, mediate some EGF actions. From functional analyses of an EGF receptor containing a single amino-acid mutation at a site required for phosphate transfer from ATP, we conclude that the tyrosine kinase activity of the EGF receptor is essential for the diverse biochemical effects of EGF, including rapid alterations in intracellular calcium, activation of gene transcription, receptor down-regulation and the ultimate stimulatory effects on cell proliferation.
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002455:Cell Division; D002460:Cell Line; D006224:Cricetinae; D004274:DNA, Recombinant; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000494:pharmacology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D007739:L Cells; D051379:Mice; D009154:Mutation; D009857:Oncogenes; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection
D004274:DNA, Recombinant; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D002118:Calcium