Growth Factor Signaling

Sef Antagonizes MAPK Signaling

Science's STKE  12 Feb 2002:
Vol. 2002, Issue 119, pp. tw65
DOI: 10.1126/stke.2002.119.tw65

The sef gene is one of a group of genes activated by fibroblast growth factor (FGF) 8. Sef is a transmembrane protein that can interact with Xenopus FGF receptors when expressed in transfected cells. Fürthauer et al. used zebrafish to investigate the role of Sef in Fgf8 and mitogen-activated protein kinase (MAPK) signaling. In zebrafish embryos treated to increase FGF signaling or to enhance activation of the MAPK pathway, enhanced sef expression suppressed the phenotypes, suggesting that Sef is an antagonist of MAPK signaling. Sef rescued phenotypes associated either with activation of the pathway mediated by hyperactivation of the receptor tyrosine kinase or with forced hyperactivation of the MAPK pathway, independent of the growth factor receptor. Sef inhibited phosphorylation of the extracellular signal-regulated kinase (ERK). Thus, Sef joins Sprouty as an inhibitor of the Ras-to-MAPK kinase cascade. The mechanism of inhibition may be quite different, because Sef can inhibit ERK phosphorylation in response to activated receptor tyrosine kinase, activated Ras, activated Raf, and activated MEK (the kinase immediately upstream of ERK); whereas Sprouty2 appears to act at the level of Raf.

M. Fürthauer, W. Lin, S.-L. Ang, B. Thisse, C. Thisse, Sef is a feedback-induced antagonist of Ras/MAPK-mediated FGF signalling. Nature Cell Biol. 4, 170-174 (2002). [Online Journal]

P. Yusoff, D.-H. Lao, S. H. Ong, E. S. M. Wong, J. Lim, T. L. Lo, H. F. Leong, C. W. Fong, G. R. Guy, Sprouty2 inhibits the Ras/MAP Kinase pathway by inhibiting the activation of Raf. J. Biol. Chem. 277, 3195-3201 (2002). [Abstract] [Full Text]