TY - JOUR
T1 - A conditional feedback loop regulates Ras activity through EphA2
AU - Macrae, Madhu
AU - Neve, Richard M.
AU - Rodriguez-Viciana, Pablo
AU - Haqq, Christopher
AU - Yeh, Jennifer
AU - Chen, Chira
AU - Gray, Joe W.
AU - McCormick, Frank
N1 - Funding Information:
The authors are grateful to Dr. Martin McMahon for cell lines expressing RafER and RafAR fusion proteins and Dr. Bill Weiss for NIH3T3 cells expressing v-ErbB. We thank Drs. Nigel Carter and Tony Hunter for providing EphA2 and ephrin-A1 expression constructs. DNA sequencing and quantitative RT-PCR were performed by the Genome Analysis Core facility (UCSF Cancer Center), and confocal microscopy was performed by the Laboratory for Cell Analysis (UCSF Cancer Center). This work was supported, in part, by a grant from the Avon Foundation and from a gift to F.M. from the Bristol-Myers Squibb Foundation.
PY - 2005/8
Y1 - 2005/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=23644451946&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=23644451946&partnerID=8YFLogxK
U2 - 10.1016/j.ccr.2005.07.005
DO - 10.1016/j.ccr.2005.07.005
M3 - Article
C2 - 16098464
AN - SCOPUS:23644451946
VL - 8
SP - 111
EP - 118
JO - Cancer Cell
JF - Cancer Cell
SN - 1535-6108
IS - 2
ER -