A conditional feedback loop regulates Ras activity through EphA2.
The EphA2 receptor tyrosine kinase is frequently overexpressed in many cancers, including 40% of breast cancers. Here, we show that EphA2 is a direct transcriptional target of the Ras-Raf-MAPK pathway and that ligand-stimulated EphA2 attenuates the growth factor-induced activation of Ras. Thus, a negative feedback loop is created that regulates Ras activity. Interestingly, the expression of EphA2 and ephrin-A1 is mutually exclusive in a panel of 28 breast cancer cell lines. We show that the MAPK pathway inhibits ephrin-A1 expression, and the ligand expression inhibits EphA2 levels contributing to the receptor-ligand reciprocal expression pattern in these cell lines. Our results suggest that an escape from the negative effects of this interaction may be important in the development of cancer.
Macrae
Madhu
M
Cancer Research Institute and Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California 94143, USA.
Neve
Richard M
RM
Rodriguez-Viciana
Pablo
P
Haqq
Christopher
C
Yeh
Jennifer
J
Chen
Chira
C
Gray
Joe W
JW
McCormick
Frank
F
D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D036382:Ephrin-A1 / Q000378:metabolism; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D018739:Oncogene Proteins v-erbB / Q000378:metabolism; D036104:Receptor, EphA2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic; D048490:raf Kinases / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism*
D036382:Ephrin-A1; D018739:Oncogene Proteins v-erbB; D036104:Receptor, EphA2; D048490:raf Kinases; D020930:MAP Kinase Kinase Kinases; D018631:ras Proteins