FGF-9 (fibroblast growth factor-9), also called HBGF-9 (heparin-binding growth factor-9) and GAF (glia-activating factor), is an approximately 26 kDa secreted glycoprotein of the FGF family [1-3]. FGFs exhibit heparin-dependent regulation of cell prolifer ation, differentiation, and function, and are characterized by a core heparin-binding FGF domain of approximately 120 amino acids (aa) that exhibits a beta -trefoil structure [1]. FGF-9, -16 and -20 form a subfamily that shares 65-71% aa sequence identity, binds FGF R3 (IIIb), and are efficiently secreted despite having an uncleavable, bipartite signal sequence [1-3]. Secreted human FGF-9 is a 205-207 aa protein that lacks the N-terminal 1-3 aa and shares 98% sequence identity with mouse, rat, equine, porcine and bovine FGF-9. In addition to FGF R3 (IIIb), FGF-9 binding to the IIIc splice forms of FGF R1, R2 and R3 are variably reported [3-5]. An unusual constitutive dimerization of FGF-9 buries receptor interaction sites which lowers its activity and increases heparin affinity which inhibits diffusion [4-6]. A spontaneous mouse mutant, Eks, interferes with dimerization, resulting monomeric, diffusible FGF-9 that causes elbow and knee synostoses (joint fusions) due to FGF-9 misexpression in developing joints [6]. In humans, FGF-9 mutations that lower receptor binding cause multiple synostoses syndrome (SYNS) [7]. Expression in brain and kidney are reported in the adult rat [2, 8]. In the mouse embryo the location and timing of FGF-9 expression affects development of the skeleton, cerebellum, lungs, heart, vasculature, digestive tract, and testes [1, 6-11]. Deletion of mouse FGF-9 is lethal at birth due to lung hypoplasia, and causes rhizomelia, or shortening of the proximal skeleton [1, 10, 11]. Altered FGF-9 expression or function is reported in human colon, endometrial, and ovarian cancers, correlating with progression, invasiveness, and survival [12-15].
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