A single autophosphorylation site confers oncogenicity to the Neu/ErbB-2 receptor and enables coupling to the MAP kinase pathway.
The transforming potential of the Neu/ErbB-2 receptor tyrosine kinase undergoes inactivation by deletion of the non-catalytic C-terminal tail, which contains five autophosphorylation sites. To determine which site is essential for oncogenicity, we tailed the C-terminally-deleted mutant with individual autophosphorylation sites. Complete restoration of the transforming action in vitro and in vivo was conferred by a stretch of 12 amino acids that contained the most C-terminal tyrosine autophosphorylation site (Y1253). Reconstitution of transformation was specific to this amino acid sequence because none of the other autophosphorylation sites, when grafted individually, caused transformation, and replacement of the tyrosine with a phenylalanine residue significantly reduced the oncogenic potential of both the full-length and the tailed proteins. When present alone the most C-terminal sequence enabled coupling to a biochemical pathway that includes Ras, MAP kinase and transactivation of Jun. These results indicate that the multiplicity of autophosphorylation sites on a receptor tyrosine kinase is not essential for transformability, and implicate the MAP kinase pathway in transduction of the oncogenic signal of Neu/ErbB-2.
Ben-Levy
R
R
Department of Chemical Immunology, Weizmann Institute of Science, Rehovot, Israel.
Paterson
H F
HF
Marshall
C J
CJ
Yarden
Y
Y
D000818:Animals; D001483:Base Sequence; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000235:genetics* / Q000302:isolation & purification; D005455:Fluorescent Antibody Technique; D051379:Mice; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000302:isolation & purification; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases; D017384:Sequence Deletion; D015398:Signal Transduction; D013329:Structure-Activity Relationship
D017871:Calcium-Calmodulin-Dependent Protein Kinases; D066246:ErbB Receptors; D011518:Proto-Oncogene Proteins; D016755:Proto-Oncogene Proteins c-jun; D016283:Proto-Oncogene Proteins p21(ras); D018719:Erb-b2 Receptor Tyrosine Kinases