FGF/FGFR signaling in health and disease

Abstract

Growing evidences suggest that the fibroblast growth factor/FGF receptor (FGF/FGFR) signaling has crucial roles in a multitude of processes during embryonic development and adult homeostasis by regulating cellular lineage commitment, differentiation, proliferation, and apoptosis of various types of cells. In this review, we provide a comprehensive overview of the current understanding of FGF signaling and its roles in organ development, injury repair, and the pathophysiology of spectrum of diseases, which is a consequence of FGF signaling dysregulation, including cancers and chronic kidney disease (CKD). In this context, the agonists and antagonists for FGF-FGFRs might have therapeutic benefits in multiple systems.

Fig. 1

Summary of the main roles of FGF/FGFR signaling in organ development, metabolism, and disease. FGF/FGFR signaling participates in the development of almost all organ such as lung, heart, urinary system, brain, skeleton, muscle, and skin/appendage, as well as angiogenesis and lymphangiogenesis. FGFs/FGFRs also have important effects on tissue repair, regeneration, and inflammation. Furthermore, endocrine FGFs play critical roles in metabolism by regulating kidney, liver, brain, intestine, and adipose tissue. The malfunctions of FGF/FGFR signaling lead to multiple kinds of diseases, such as genetic diseases, cancer, COPD, and CKD. The roles of FGF signaling in appendage development, such as epidermis, hair, and glands, and so on, is not mentioned in this review. ACH achondroplasia, CKD chronic kidney disease, COPD chronic obstructive pulmonary disease, PS Pfeiffer syndrome, RDS respiratory distress syndrome, EndMT endothelial-to-mesenchymal transition

Fig. 2

The classical FGF/FGFR pathways. Binding of appropriate growth factors to receptors triggers the conformational changes of FGFRs, resulting in dimerization and activation of FGFRs. Activated FGFRs phosphorylate FRS2a and FRS2a binds to SH2 domain-containing adaptor Grb2. Grb2 will subsequently bind to SOS, GAB1, and Cbl through its SH3 domain to activate Ras/Raf/MAPKs, including ERK MAPK, p38 MAPK, and JNK MAPK. The activated FGFRs also activate phosphatidylinositol (PI)-3 kinase and STAT. FGFRs recruit and phosphorylate PLCγ. Among the members of the FGF synexpression group, SEF and XFLRT3 are transmembrane proteins and can interact directly with FGFRs. SEF functions as a negative regulator by affecting the phosphorylation of the MAPK ERK cascade. XFLRT3 forms a complex with FGF receptors and enhances FGF/FGFR signaling. Spry acts at the level of Grb2 and/or the level of Raf to attenuate FGF/FGFR signaling. MKP3 negatively regulates FGF/FGFR signaling by dephosphorylating the activated ERK. FRS2α FGFR substrate 2α, GAB1 GRB2 associated binding protein 1, GRB2 growth factor receptor-bound 2, PKC protein kinase C, SOS son of sevenless

Fig. 3

The regulation of FGF15/19 on energy metabolism. FGF15/19 regulates energy metabolism both peripherally and centrally. In the liver, FGF15/19 inhibits BA production and promotes gallbladder filling. As for lipid and glucose metabolism, FGF15/19 improves glycogen synthesis, but suppresses lipogenesis and gluconeogenesis. In the adipose tissue, FGF15/19 promotes energy expenditure and fatty acid oxidation. In the brain, FGF15/19 promotes the expression of CRF in the hypothalamus and stimulates sympathetic nerve activity, and then increases energy expenditure in the adipose tissue. Furthermore, FGF15/19 promotes peripheral insulin sensitivity and glucose metabolism by repressing HPA axis and AGRP/NPY neuron activity. AGRP agouti-related protein, BA bile acid, HPA hypothalamic-pituitary-adrenal, NPY neuropeptide Y

Fig. 4

The regulation of FGF21 on energy metabolism. FGF21 regulates energy metabolism in peripheral and central manners. In the liver, FGF21 promotes gluconeogenesis and lipid oxidation, and thus improves ketogenesis and insulin sensitivity. In the adipose tissue, FGF21 simulates glucose uptake in both WAT and BAT and induces WAT browning, as well as promotes energy expenditure, while FGF21 inhibits lipolysis. In the brain, FGF21 stimulates the HPA axis, thus contributing to corticosterone release and ultimately promoting gluconeogenesis in the liver. Furthermore, FGF21 improves CRF expression in the hypothalamus and stimulates sympathetic nerve activity, and then promotes energy expenditure in BAT. BAT brown adipose tissue, CRF corticotropin-releasing factor, HPA hypothalamic-pituitary-adrenal, WAT white adipose tissue

Fig. 5

The regulation of FGF23 and its effect on phosphate homeostasis. The bone-derived FGF23 is regulated by several factors such as iron, phosphate, and 1,25(OH)₂D₃ and PTH in blood, as well as DMP1, PHEX, and FGFR1 in the bone. FGF23 downregulates serum phosphate. In the kidney, FGF23 reduces 1,25(OH)₂D₃ level and inhibits renal phosphate resorption by inhibiting the expression of NaPi-2a/2c. In the intestine, FGF23 inhibits phosphate absorption by reducing NaPi-2b expression or indirectly suppressing 1,25(OH)₂D₃. In the parathyroid, FGF23 inhibits PTH synthesis and secretion, and then contributes to its own negative feedback regulation. 1,25VD₃ 1,25(OH)₂D₃, NaPi-2 type IIa sodium-phosphate co-transporter, PTH parathyroid hormone