Hybrid tyrosine kinase/cytokine receptors transmit mitogenic signals in response to ligand.
While much is known about the mechanisms by which members of the receptor tyrosine kinase family effect mitogenic signal transduction, much less is known about such mechanisms for members of the hematopoietic cytokine receptor family. In an effort to determine the extent to which the signal transduction mechanisms of these two receptor families may be related, we constructed and tested interfamily hybrid receptors. Two hybrid receptors consisting of the ligand-binding domain of the epidermal growth factor receptor (EGFR) fused to the transmembrane and cytoplasmic domains of the erythropoietin receptor (EPOR), as well as the parental EPOR or EGFR, were introduced into interleukin-3-dependent 32D cells. Part of the EPOR extracellular region containing a conserved WSXWS amino acid motif was present in one of the hybrid receptors but not in the other. Cells expressing EGFR grew only poorly in response to EGF, whereas cells expressing either of the EGFR/EPOR hybrid receptors or EPOR grew robustly in epidermal growth factor or erythropoietin, respectively. This is the first demonstration of a chimera between these two unrelated receptor families that responds to ligand stimulation. The results indicate that the mechanisms by which receptor tyrosine kinases and cytokine receptors propagate mitogenic signals are sufficiently similar to allow interchange of their ligand binding domains and that generation of an efficient mitogenic signal by a cytokine receptor depends primarily on its cytoplasmic and/or transmembrane regions.
Pacifici
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Department of Molecular Biology, Amgen Inc., Amgen Center, Thousand Oaks, California 91320.
Thomason
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AR
D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects; D002999:Clone Cells; D017124:Conserved Sequence; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000096:biosynthesis / Q000302:isolation & purification / Q000378:metabolism*; D004921:Erythropoietin / Q000494:pharmacology*; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology*; D007700:Kinetics; D008024:Ligands; D051379:Mice; D008969:Molecular Sequence Data; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000302:isolation & purification / Q000378:metabolism*; D017467:Receptors, Erythropoietin / Q000096:biosynthesis / Q000302:isolation & purification / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D014162:Transfection; D020798:Two-Hybrid System Techniques
D007377:Interleukin-3; D008024:Ligands; D017467:Receptors, Erythropoietin; D011994:Recombinant Proteins; D004921:Erythropoietin; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases