1.A.108.  The Fibroblast Growth Factor 2 (FGF2) Family

Unconventional secretory proteins lack signal peptides and their export from cells is not affected by brefeldin A, an inhibitor of protein transport along the classical secretory pathway (Nickel 2010). Export can be mediated by direct translocation across plasma membranes of cytoplasmic proteins such as fibroblast growth factor 2 which can be modified by phosphorylation involving the Tec protein kinase (La Venuta et al. 2016) so that it inserts into membranes, creating oligomeric pores that are intermediates in the secretion process (see Nickel and Seedorf 2008 and TC# 9.A.48). Tyrosyl phosphorylation of FGF2 followed by association with phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) triggers formation of a lipidic membrane pore, essential for FGF2 secretion (Steringer et al. 2012). Formation of disulfide bridges is also essential for this process (Müller et al. 2015). The cytoplasmic domain of the Na+/K+ ATPase, ATP1A1 (α-subunit) may function as a direct interaction receptor for the process (Zacherl et al. 2015). Extracellular FGF2 is trapped by cell surface proteoglycans, and it then plays a role in tumor-indiced angiogenesis (La Venuta et al. 2015). Proteoglycans may also play a role in the secretion of the cytoskeletal Alzheimer's disease-associated tau protein (P10636; Pompa et al. 2017). Tau secretion correlated with tau phosphorylation and aggregation (Hannan et al. 2016).

Alpha-Klotho (α-Klotho) is a member of the Klotho family consisting of this protein and two other single-pass transmembrane proteins: betaKlotho (β-Klotho) and gammaKlotho (γ-Klotho); α-Klotho circulates in the blood. FGF23 is a member of the FGF superfamily of 22 genes/proteins. α-Klotho serves as a co-receptor with FGF receptors (FGFRs) to provide a receptacle for physiological FGF23 signaling, including regulation of phosphate metabolism (Hu et al. 2018). The extracellular domain of transmembrane α-Klotho is shed by secretases and released into blood circulation (soluble α-Klotho). Soluble alphaKlotho has both FGF23-independent and FGF23-dependent roles in phosphate homeostasis by modulating intestinal phosphate absorption, urinary phosphate excretion, and phosphate distribution into bone in concerted interactions with other calciophosphotropic hormones such as PTH and 1,25-(OH)2D. The direct role of alphaKlotho and FGF23 in the maintenance of phosphate homeostasis is partly mediated by modulation of type II Na+-dependent phosphate co-transporters in target organs. alphaKlotho and FGF23 are principal phosphotropic hormones, and manipulation of the alphaKlotho-FGF23 axis provides a therapeutic strategy for genetic and acquired phosphate disorders and for conditions with FGF23 excess or alphaKlotho deficiency such as chronic kidney disease (Hu et al. 2018).


 

References:

Hannan, S.B., N.M. Dräger, T.M. Rasse, A. Voigt, and T.R. Jahn. (2016). Cellular and molecular modifier pathways in tauopathies: the big picture from screening invertebrate models. J Neurochem 137: 12-25.
Hu, M.C., M. Shi, and O.W. Moe. (2018). Role of αKlotho and FGF23 in regulation of type II Na-dependent phosphate co-transporters. Pflugers Arch. [Epub: Ahead of Print]
La Venuta, G., M. Zeitler, J.P. Steringer, H.M. Müller, and W. Nickel. (2015). The Startling Properties of Fibroblast Growth Factor 2: How to Exit Mammalian Cells without a Signal Peptide at Hand. J. Biol. Chem. 290: 27015-27020.
La Venuta, G., S. Wegehingel, P. Sehr, H.M. Müller, E. Dimou, J.P. Steringer, M. Grotwinkel, N. Hentze, M.P. Mayer, D.W. Will, U. Uhrig, J.D. Lewis, and W. Nickel. (2016). Small Molecule Inhibitors Targeting Tec Kinase Block Unconventional Secretion of Fibroblast Growth Factor 2. J. Biol. Chem. 291: 17787-17803.
Müller, H.M., J.P. Steringer, S. Wegehingel, S. Bleicken, M. Münster, E. Dimou, S. Unger, G. Weidmann, H. Andreas, A.J. García-Sáez, K. Wild, I. Sinning, and W. Nickel. (2015). Formation of disulfide bridges drives oligomerization, membrane pore formation, and translocation of fibroblast growth factor 2 to cell surfaces. J. Biol. Chem. 290: 8925-8937.
Nickel, W. (2010). Pathways of unconventional protein secretion. Curr Opin Biotechnol 21: 621-626.
Nickel, W. and M. Seedorf. (2008). Unconventional mechanisms of protein transport to the cell surface of eukaryotic cells. Annu. Rev. Cell Dev. Biol. 24: 287-308.
Pompa, A., F. De Marchis, M.T. Pallotta, Y. Benitez-Alfonso, A. Jones, K. Schipper, K. Moreau, V. Žárský, G.P. Di Sansebastiano, and M. Bellucci. (2017). Unconventional Transport Routes of Soluble and Membrane Proteins and Their Role in Developmental Biology. Int J Mol Sci 18:.
Smith, E.R., S.G. Holt, and T.D. Hewitson. (2017). FGF23 activates injury-primed renal fibroblasts via FGFR4-dependent signalling and enhancement of TGF-β autoinduction. Int J Biochem. Cell Biol. 92: 63-78.
Steringer, J.P., S. Bleicken, H. Andreas, S. Zacherl, M. Laussmann, K. Temmerman, F.X. Contreras, T.A. Bharat, J. Lechner, H.M. Müller, J.A. Briggs, A.J. García-Sáez, and W. Nickel. (2012). Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2)-dependent oligomerization of fibroblast growth factor 2 (FGF2) triggers the formation of a lipidic membrane pore implicated in unconventional secretion. J. Biol. Chem. 287: 27659-27669.
Zacherl, S., G. La Venuta, H.M. Müller, S. Wegehingel, E. Dimou, P. Sehr, J.D. Lewis, H. Erfle, R. Pepperkok, and W. Nickel. (2015). A direct role for ATP1A1 in unconventional secretion of fibroblast growth factor 2. J. Biol. Chem. 290: 3654-3665.
Examples:

TC#NameOrganismal TypeExample
1.A.108.1.1

Fibroblast growth factor 2, FGF2, of 288 aas.  Forms oligomeric pores in the plasma membrane, and these are involved in its secretion to the external medium where it exerts its action (La Venuta et al. 2016; see family description). The ATP1A1 (TC# 3.A.3.1.1) serves as the receptor for membrane insertion (Zacherl et al. 2015).

FGF2 of Homo sapiens

 
1.A.108.1.2

Fibroblast growth factor 23, FGF23 of 251 aas.  Functions through FGF receptor 4 to regulate the level of the calcium/inorganic cation channel, TrpC6 or TRP6 (TC# 1.A.4.1.5) (Smith et al. 2017).

FGF23 of Homo sapiens