Enabling Endocrine Action of Fibroblast Growth Factors

Science's STKE  17 Apr 2007:
Vol. 2007, Issue 382, pp. tw133
DOI: 10.1126/stke.3822007tw133

There are 18 members of the fibroblast growth factor family. Most of these growth factors act in a paracrine manner, mediating signals between epithelial and mesenchymal cell layers that are critical for development. Three members of the fibroblast growth factor family, FGFs 19, 21, and 23, are unusual in that they function in an endocrine manner and regulate physiological processes distinct from those controlled by other family members, including glucose and lipid metabolism, energy and bile acid homeostasis, and regulation of phosphate and vitamin D concentrations. Goetz et al. solved the crystal structures of FGF19 and FGF23 alone or in complex with sucrose octasulfate, a disaccharide used to approximate binding of the receptors to heparin sulfate. Binding of most FGF proteins to their receptors is enhanced through interaction with heparin sulfate. However, the authors found that heparin binding appeared to be disrupted in FGF19 and FGF23, and they went on to confirm this in surface plasmon spectroscopy experiments. The authors propose that this failure to bind strongly to heparin sulfate allows these growth factors to avoid being retained by the pericellular heparin sulfate in the location where they are produced and to instead serve their endocrine signaling function. FGF19- and FGF23-receptor complexes have recently been shown to interact with Klotho or βKlotho proteins. Thus, the authors propose that Klotho proteins, rather than heparin sulfate, may serve to enhance receptor binding by FGF19 and FGF23, thereby restricting the endocrine actions of these factors to tissues where Klotho proteins are available.

R. Goetz, A. Beenken, O. A. Ibrahimi, J. Kalinina, S. K. Olsen, A. V. Eliseenkova, C. Xu, T. A. Neubert, F. Zhang, R. J. Linhardt, X. Yu, K. E. White, T. Inagaki, S. A. Kliewer, M. Yamamoto, H. Kurosu, Y. Ogawa, M. Kuro-o, B. Lanske, M. S. Razzaque, M. Mohammadi, Molecular insights into the Klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members. Mol. Cell. Biol. 27, 3417-3428 (2007). [Abstract] [Full Text]