A conditional feedback loop regulates Ras activity through EphA2

Cancer Cell, 8：111-118 (2005)

Speaker: 賴曉菁                               Date: 13:10~14:00, Dec. 7, 2005

Commentator: 周楠華 醫師                      Place: Room 601

Abstract:

There are two groups of Eph receptors: EphA and EphB, belonging to the receptor tyrosine kinase family. They are involved in axon guidance, cell migration, morphogenesis, and vasculature. One of the Eph receptor, EphA2, is overexpressed in many cancers, including prostate, melanoma and breast cancers. EphA2 overexpression also causes tumorigenesis of mammary epithelium cells. The role of EphA2 activation in regulation of the mitogen-activated protein kinase (MAPK) signal pathway is still contradictory. In this article, the authors proved that the expression levels of EphA2 mRNA and protein is up-regulated by Ras-Raf-MAPK pathway. The MEK inhibitor also inhibits EphA2 protein level indicating that EphA2 is a target of the MAPK pathway. The authors found that the expression levels of EphA2 receptor and its ligand, ephrin-A1, is inversely proportional, and ligand-stimulated EphA2 attenuates the RAS/MAPK pathway activity induced by growth factor EGF in some cancer cell lines. Coculturing EphA2 receptor-presenting cells with ephrin-A1 ligand-expression cells, EphA2 was dimmerized and tyrosine phosphorylated. It indicates that ligand induced activation of EphA2 is non-cell- autonomous and via ligand presented on neighboring cells. At last, ephrin-A1 expression can inhibit transformation of NIH-3T3 cell transformed by v-ErbB significantly. Taken together, Ras is frequently hyperactivated in human tumors. EphA2 signaling contributes to a feedback loop that regulates Ras activity and tumor development through ligand-dependent manner.

References:

1.          Dodelet, V. C., and Pasquale, E. B. (2000). Eph receptors and ephrin ligands: embryogenesis to tumorigenesis. Oncogene. 19, 5614-5619.

2.          Miao, H., Wei, B. R., Peehl, D. M., Li Q., Alexandrou, T., schelling, J.R., Rhim, J.S., Sedor, j.R., burnett, E., and Wang, B. (2001). Activation of EphA receptor tyrosine kinase inhibits the Ras/MAPK pathway. Nat .Cell Biol .3, 527-530.

3.          Macrae, M., Neve, R.M., Rodriguez-Viciznz, P., Haqq, C., Yeh, J., Chen, C., Gray, J.W., and McCormick F. (2005). A conditional feedback loop regulates Ras activity through EphA2.Cancer Cell. 8, 111-118.