title: A conditional feedback loop regulates Ras activity through EphA2.
abstract: 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.
authors.affiliation: Cancer Research Institute and Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California 94143, USA.
authors.forename: Madhu
authors.initials: M
authors.lastname: Macrae
authors.forename: Richard M
authors.initials: RM
authors.lastname: Neve
authors.forename: Pablo
authors.initials: P
authors.lastname: Rodriguez-Viciana
authors.forename: Christopher
authors.initials: C
authors.lastname: Haqq
authors.forename: Jennifer
authors.initials: J
authors.lastname: Yeh
authors.forename: Chira
authors.initials: C
authors.lastname: Chen
authors.forename: Joe W
authors.initials: JW
authors.lastname: Gray
authors.forename: Frank
authors.initials: F
authors.lastname: McCormick
mesh_terms: 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*
chemical_list: D036382:Ephrin-A1; D018739:Oncogene Proteins v-erbB; D036104:Receptor, EphA2; D048490:raf Kinases; D020930:MAP Kinase Kinase Kinases; D018631:ras Proteins