Fibroblast growth factors (FGFs) signal through high-affinity tyrosine kinase receptors to regulate a diverse range of cellular processes, including cell growth, differentiation and migration, as well as cell death1,2,3,4. Here we identify XFLRT3, a member of a leucine-rich-repeat transmembrane protein family, as a novel modulator of FGF signalling. XFLRT3 is co-expressed with FGFs, and its expression is both induced after activation and downregulated after inhibition of FGF signalling. In gain- and loss-of function experiments, FLRT3 and FLRT2 phenocopy FGF signalling in Xenopus laevis. XFLRT3 signalling results in phosphorylation of ERK and is blocked by MAPK phosphatase 1, but not by expression of a dominant-negative phosphatidyl inositol 3-OH kinase (PI(3)K) mutant. XFLRT3 interacts with FGF receptors (FGFRs) in co-immunoprecipitation experiments in vitro and in bioluminescence resonance energy transfer assays in vivo. The results indicate that XFLRT3 is a transmembrane modulator of FGF–MAP kinase signalling in vertebrates.
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Materials were kindly provided by E. Amaya, A. Bhushan, M. Eilers, W. Franke, R. Friesel, P. Lemaire, T. Knoch, L. Kunkel, J. Nathans, H. Okamoto, T. Pieler, J. Slack, N. Ueno and M. Whitman. R.B. received a PhD fellowship of the Deutsche Forschungsgemeinschaft. We thank U. Fenger and K. Kappes for in situ hybridizations, and G. Davidson and B. Mao for critical reading of the manuscript.
The authors declare no competing financial interests.
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