Instability restricts signaling of multiple fibroblast growth factors
- 877 Downloads
Fibroblast growth factors (FGFs) deliver extracellular signals that govern many developmental and regenerative processes, but the mechanisms regulating FGF signaling remain incompletely understood. Here, we explored the relationship between intrinsic stability of FGF proteins and their biological activity for all 18 members of the FGF family. We report that FGF1, FGF3, FGF4, FGF6, FGF8, FGF9, FGF10, FGF16, FGF17, FGF18, FGF20, and FGF22 exist as unstable proteins, which are rapidly degraded in cell cultivation media. Biological activity of FGF1, FGF3, FGF4, FGF6, FGF8, FGF10, FGF16, FGF17, and FGF20 is limited by their instability, manifesting as failure to activate FGF receptor signal transduction over long periods of time, and influence specific cell behavior in vitro and in vivo. Stabilization via exogenous heparin binding, introduction of stabilizing mutations or lowering the cell cultivation temperature rescues signaling of unstable FGFs. Thus, the intrinsic ligand instability is an important elementary level of regulation in the FGF signaling system.
KeywordsFibroblast growth factor FGF Unstable Proteoglycan Regulation
We thank M. Pokorna and K. Tvaruzkova for assistance with CD measurements, J. Medalova and T. Spoustova for assistance with manuscript preparation, and P. B. Mekikian for technical support. The study was supported by the Ministry of Education, Youth and Sports of the Czech Republic (KONTAKT LH12004, CZ.1.07/2.3.00/30.0053, LO1214), Grant Agency of Masaryk University (0071-2013), Czech Science Foundation (14-31540S, P207/12/0775, GBP302/12/G157), European Regional Development Fund (FNUSA-ICRC No.CZ.1.05/1.1.00/02.0123), European Union (ICRC-ERA-HumanBridge No.316345), Netherlands Organization for Scientific Research (700.59.426) and Polish National Science Centre (NCN, 2011/02/A/NZ1/00066).
- 13.Kato K, Jeanneau C, Tarp MA, Benet-Pagès A, Lorenz-Depiereux B, Bennett EP, Mandel U, Strom TM, Clausen H (2006) Polypeptide GalNAc-transferase T3 and familial tumoral calcinosis. Secretion of fibroblast growth factor 23 requires O-glycosylation. J Biol Chem 281(27):18370–18377CrossRefPubMedGoogle Scholar
- 28.Ornitz DM, Xu J, Colvin JS, McEwen DG, MacArthur CA, Coulier F, Gao G, Goldfarb M (1996) Receptor specificity of the fibroblast growth factor family. J Biol Chem 27:15292–15297Google Scholar
- 31.Goetz R, Beenken A, Ibrahimi OA, Kalinina J, Olsen SK, Eliseenkova AV, Xu C, Neubert TA, Zhang F, Linhardt RJ, Yu X, White KE, Inagaki T, Kliewer SA, Yamamoto M, Kurosu H, Ogawa Y, Kuro-o M, Lanske B, Razzaque MS, Mohammadi M (2007) Molecular insights into the klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members. Mol Cell Biol 27:3417–3428CrossRefPubMedCentralPubMedGoogle Scholar