FIGURE 2.

FGF secretion, dimerization, and receptor shedding regulate the availability and activity of FGFs. (a) Unconventional secretion of FGF2 (adapted from Zacherl et al., 2015). ATP1A1, the α1-chain of Na/K-ATPase, interacts with FGF2 and recruits it to the inner plasma membrane, and promotes oligomerization. FGF2 oligomerization requires phosphatidylinositol 4,5-bisphosphate and FGF2 surface cysteines. Phosphorylation of FGF2 by Tec Kinase further promotes membrane insertion of FGF2 oligomers to form a membrane pore. FGF2, which is released into the extracellular space is bound and sequestered by cell surface HSPGs. (b) Dimerization of the FGF9 subfamily increases affinity for HS and prevents receptor binding by blocking the receptor-binding interface (blue). Mutations in FGF9 prevent homodimerization, decrease affinity for HS, and increase ligand diffusion. Only FGF9 monomers are able to interact with FGFRs. (c) Proteolytic cleavage of FGFRs by ADAM proteases 10 and 17 can release a soluble extracellular domain of the receptor that has the ability to bind and sequester FGF ligands