Abstract
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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References
Slack, J.M., Isaacs, H.V., Song, J., Durbin, L. & Pownall, M.E. The role of fibroblast growth factors in early Xenopus development. Biochem. Soc. Symp. 62, 1–12 (1996).
Martin, G.R. The roles of FGFs in the early development of vertebrate limbs. Genes Dev. 12, 1571–1586 (1998).
Friesel, R. & Maciag, T. Fibroblast growth factor prototype release and fibroblast growth factor receptor signaling. Thromb. Haemost. 82, 748–754 (1999).
Groth, C. & Lardelli, M. The structure and function of vertebrate fibroblast growth factor receptor 1. Int. J. Dev. Biol. 46, 393–400 (2002).
Lacy, S.E., Bonnemann, C.G., Buzney, E.A. & Kunkel, L.M. Identification of FLRT1, FLRT2, and FLRT3: a novel family of transmembrane leucine-rich repeat proteins. Genomics 62, 417–426 (1999).
Christen, B. & Slack, J.M. FGF-8 is associated with anteroposterior patterning and limb regeneration in Xenopus. Dev. Biol. 192, 455–466 (1997).
Fürthauer, M., Reifers, F., Brand, M., Thisse, B. & Thisse, C. sprouty4 acts in vivo as a feedback-induced antagonist of FGF signaling in zebrafish. Development 128, 2175–2186 (2001).
Fürthauer, M., Lin, W., Ang, S.L., Thisse, B. & Thisse, C. Sef is a feedback-induced antagonist of Ras/MAPK-mediated FGF signalling. Nature Cell Biol. 4, 170–174 (2002).
Tsang, M., Friesel, R., Kudoh, T. & Dawid, I.B. Identification of Sef, a novel modulator of FGF signalling. Nature Cell Biol. 4, 165–169 (2002).
Niehrs, C. & Meinhardt, H. Modular feedback. Nature 417, 35–36 (2002).
Amaya, E., Musci, T.J. & Kirschner, M.W. Expression of a dominant negative mutant of the FGF receptor disrupts mesoderm formation in Xenopus embryos. Cell 66, 257–570 (1991).
Isaacs, H.V., Tannahill, D. & Slack, J.M. Expression of a novel FGF in the Xenopus embryo. A new candidate inducing factor for mesoderm formation and anteroposterior specification. Development 114, 711–720 (1992).
Smith, J.C., Price, B.M., Green, J.B., Weigel, D. & Herrmann, B.G. Expression of a Xenopus homolog of Brachyury (T) is an immediate-early response to mesoderm induction. Cell 67, 79–87 (1991).
Neilson, K.M. & Friesel, R. Ligand-independent activation of fibroblast growth factor receptors by point mutations in the extracellular, transmembrane, and kinase domains. J. Biol. Chem. 271, 25049–25057 (1996).
Whitman, M. & Melton, D.A. Involvement of p21ras in Xenopus mesoderm induction. Nature 357, 252–254 (1992).
Carballada, R., Yasuo, H. & Lemaire, P. Phosphatidylinositol-3 kinase acts in parallel to the ERK MAP kinase in the FGF pathway during Xenopus mesoderm induction. Development 128, 35–44 (2001).
Gotoh, Y., Masuyama, N., Suzuki, A., Ueno, N. & Nishida, E. Involvement of the MAP kinase cascade in Xenopus mesoderm induction. EMBO J. 14, 2491–2498 (1995).
Bhushan, A., Chen, Y. & Vale, W. Smad7 inhibits mesoderm formation and promotes neural cell fate in Xenopus embryos. Dev. Biol. 200, 260–268 (1998).
Heasman, J., Kofron, M. & Wylie, C. β-catenin signaling activity dissected in the early Xenopus embryo: a novel antisense approach. Dev. Biol. 222, 124–134 (2000).
Xu, Y., Piston, D.W. & Johnson, C.H. A bioluminescence resonance energy transfer (BRET) system: application to interacting circadian clock proteins. Proc. Natl Acad. Sci. USA 96, 151–156 (1999).
Angers, S. et al. Detection of β2-adrenergic receptor dimerization in living cells using bioluminescence resonance energy transfer (BRET). Proc. Natl Acad. Sci. USA 97, 3684–3689 (2000).
Pellegrini, L., Burke, D.F., von Delft, F., Mulloy, B. & Blundell, T.L. Crystal structure of fibroblast growth factor receptor ectodomain bound to ligand and heparin. Nature 407, 1029–1034 (2000).
Schlessinger, J. et al. Crystal structure of a ternary FGF–FGFR–heparin complex reveals a dual role for heparin in FGFR binding and dimerization. Mol. Cell 6, 743–750 (2000).
Gawantka, V., Delius, H., Hirschfeld, K., Blumenstock, C. & Niehrs, C. Antagonizing the Spemann organizer: role of the homeobox gene Xvent-1. EMBO J. 14, 6268–6279 (1995).
Glinka, A., Wu, W., Onichtchouk, D., Blumenstock, C. & Niehrs, C. Head induction by simultaneous repression of Bmp and Wnt signalling in Xenopus. Nature 389, 517–519 (1997).
Glinka, A. et al. Dickkopf-1 is a member of a new family of secreted proteins and functions in head induction. Nature 391, 357–362 (1998).
Sheldahl, L.C., Park, M., Malbon, C.C. & Moon, R.T. Protein kinase C is differentially stimulated by Wnt and Frizzled homologs in a G-protein-dependent manner. Curr. Biol. 9, 695–698 (1999).
Rupp, R.A., Snider, L. & Weintraub, H. Xenopus embryos regulate the nuclear localization of XMyoD. Genes Dev. 8, 1311–1223 (1994).
Mao, B. et al. Kremen proteins are Dickkopf receptors that regulate Wnt/β-catenin signalling. Nature 417, 664–667 (2002).
Acknowledgements
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.
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Böttcher, R., Pollet, N., Delius, H. et al. The transmembrane protein XFLRT3 forms a complex with FGF receptors and promotes FGF signalling. Nat Cell Biol 6, 38–44 (2004). https://doi.org/10.1038/ncb1082
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DOI: https://doi.org/10.1038/ncb1082
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