Mammary tumors expressing the neu proto-oncogene possess elevated c-Src tyrosine kinase activity.
Amplification and overexpression of the neu (c-erbB2) proto-oncogene has been implicated in the pathogenesis of 20 to 30% of human breast cancers. Although the activation of Neu receptor tyrosine kinase appears to be a pivotal step during mammary tumorigenesis, the mechanism by which Neu signals cell proliferation is unclear. Molecules bearing a domain shared by the c-Src proto-oncogene (Src homology 2) are thought to be involved in signal transduction from activated receptor tyrosine kinases such as Neu. To test whether c-Src was implicated in Neu-mediated signal transduction, we measured the activity of the c-Src tyrosine kinase in tissue extracts from either mammary tumors or adjacent mammary epithelium derived from transgenic mice expressing a mouse mammary tumor virus promoter/enhancer/unactivated neu fusion gene. The Neu-induced mammary tumors possessed six- to eightfold-higher c-Src kinase activity than the adjacent epithelium. The increase in c-Src tyrosine kinase activity was not due to an increase in the levels of c-Src but rather was a result of the elevation of its specific activity. Moreover, activation of c-Src was correlated with its ability to complex tyrosine-phosphorylated Neu both in vitro and in vivo. Together, these observations suggest that activation of the c-Src tyrosine kinase during mammary tumorigenesis may occur through a direct interaction with activated Neu.
Muthuswamy
S K
SK
Institute for Molecular Biology and Biotechnology, McMaster University, Hamilton, Ontario, Canada.
Siegel
P M
PM
Dankort
D L
DL
Webster
M A
MA
Muller
W J
WJ
D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology / Q000209:etiology / Q000235:genetics; D000081247:CSK Tyrosine-Protein Kinase; D004789:Enzyme Activation / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D015870:Gene Expression; D016259:Genes, myc; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology* / Q000209:etiology / Q000235:genetics*; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D011519:Proto-Oncogenes; D018719:Erb-b2 Receptor Tyrosine Kinases; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D019061:src-Family Kinases
D000081247:CSK Tyrosine-Protein Kinase; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D018719:Erb-b2 Receptor Tyrosine Kinases; D019061:src-Family Kinases; C000715470:MAS1 protein, human; C000631346:CSK protein, human