Tissue-specific transformation by epidermal growth factor receptor: a single point mutation within the ATP-binding pocket of the erbB product increases its intrinsic kinase activity and activates its sarcomagenic potential.
Avian c-erbB is activated to a leukemia oncogene following truncation of its amino-terminal, ligand-binding domain by retroviral insertion. The insertionally activated transcripts encode protein products that have constitutive tyrosine kinase activity and that can induce erythro-leukemia but not sarcomas. We have found that a single point mutation within the ATP-binding pocket of the tyrosine kinase domain in this truncated molecule can increase the ability of this oncogene to induce anchorage-independent growth of fibroblasts in vitro and fibrosarcoma formation in vivo. Associated with this increased transforming potential is a corresponding increase in the kinase activity of the mutant erbB protein product. The mutation, which converts a valine to isoleucine at position 157 of the insertionally activated c-erbB product, is at a residue that is highly conserved within the protein kinase family. To our knowledge, this is the first demonstration of a point mutation in the ATP-binding pocket that activates a tyrosine kinase.
Shu
H K
HK
Department of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, OH 44106.
Pelley
R J
RJ
Kung
H J
HJ
D000255:Adenosine Triphosphate / Q000378:metabolism; D001355:Alpharetrovirus / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002471:Cell Transformation, Neoplastic; D002642:Chick Embryo; D003062:Codon / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics*; D005354:Fibrosarcoma / Q000235:genetics / Q000382:microbiology; D015870:Gene Expression; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D015345:Oligonucleotide Probes; D010766:Phosphorylation; D010957:Plasmids; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D011519:Proto-Oncogenes; D018719:Erb-b2 Receptor Tyrosine Kinases; D012689:Sequence Homology, Nucleic Acid
D000255:Adenosine Triphosphate; D003062:Codon; D066246:ErbB Receptors; D015345:Oligonucleotide Probes; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases