Decoding FGF/FGFR Signaling: Insights into Biological Functions and Disease Relevance

Abstract

Fibroblast Growth Factors (FGFs) and their cognate receptors, FGFRs, play pivotal roles in a plethora of biological processes, including cell proliferation, differentiation, tissue repair, and metabolic homeostasis. This review provides a comprehensive overview of FGF-FGFR signaling pathways while highlighting their complex regulatory mechanisms and interconnections with other signaling networks. Further, we briefly discuss the FGFs involvement in developmental, metabolic, and housekeeping functions. By complementing current knowledge and emerging research, this review aims to enhance the understanding of FGF-FGFR-mediated signaling and its implications for health and disease, which will be crucial for therapeutic development against FGF-related pathological conditions.

Keywords: FGF; FGF pathology; FGF receptor; FGF signaling; Fibroblast Growth Factors; mitogens.

Figure 3

Canonical and non-canonical functions of FGF23. (a) Canonical FGF23 signaling where FGF23-FGFR1c-alpha klotho interaction leads to internalization of NPT2a and NPT2c into proximal tubules and subsequent degradation, reducing their surface abundance. This reduces the phosphate reabsorption from proximal tubules and increases phosphate wasting. (b) Non-canonical FGF23 signaling is mediated through FGFR3 and FGFR4 isoforms independent of alpha klotho. During left ventricular hypertrophy and myocardial fibrosis, FGF23 interaction with FGFR4 gives rise to the PLCγ-calcineurin-NFAT3 and PI3K-AKT signaling pathways, aggravating the disease condition. This image was created with Biorender (https://biorender.com).

Figure 4

FGF-related pathological conditions. Due to dysregulated FGF signaling, many diseases can arise, such as skeletal defects, mitochondrial disorders, cancer, kidney diseases, obesity, dermatological issues, cardiovascular complications, and brain defects.

Figure 1

FGF signaling pathways. (a) Paracrine FGF signaling—The formation of the FGF-FGFR-HS complex induces 4 major FGFR-mediated intracellular signaling pathways: RAS-MAPK, PI3K-AKT, PLCγ, and STAT pathways. The RAS-MAPK pathway begins when FRS2α interacts with CRKL and stimulates phosphorylation of FRS2α by activated FGFR kinase. The adapter protein GRB2 is subsequently recruited by activated FRS2α, which then leads to recruitment of SOS. SOS activates RAS GTPases associated with the MAPK pathway. MAPK pathway-induced Ets family transcription factors, which is a family of transcription factors associated with inducing cell proliferation, angiogenesis, and cell differentiation; classic responses of paracrine FGFs (the intracellular mediators associated with MAPK pathway are shown in red). Alternatively, the FRS2α-GRB2 activated complex can recruit another adapter protein, GAB1, leading to the activation of the PI3K enzyme. PI3K then phosphorylated another enzyme called AKT. The physiological roles of AKT include activation of mTOR complex 1 (TSC2 and FOXO1 will be inhibited during AKT activation) and the ensuing PI3-AKT pathway (shown in green). The PLCγ pathway (in blue) is initiated when activated FGFR recruits the PLCγ enzyme, which induces hydrolysis of PIP₂ into IP₃ and DAG. IP₃-mediated signaling leads to calcium ion release from intracellular storages and activation of subsequent signaling pathways, whereas DAG stimulates PKC-mediated downstream signaling. Further, FGF-FGFR-mediated activation of the STAT pathway (in orange) is initiated by phosphorylation of STAT1, 3, and 5 in the cytoplasm, which then translocate to the nucleus. STATs act as transcription factors that are involved in the regulation of FGF-mediated signaling. (b) Endocrine FGF signaling complexes are comprised of klotho coreceptors in addition to the canonical FGF-FGFR-HS complex. FGF19 and FGF21 form stable complexes with β-klotho to initiate intracellular signaling pathways, whereas FGF23 signaling is mediated by α-klotho. This image was created with Biorender (https://biorender.com/).

Figure 2

After meals, bile acids travel to the intestine, where they activate the farnesoid X receptors, which in turn signal the transcription of FGF19 in the ileum. The mature FGF19 then travels through the hepatic portal to the liver, where it inhibits bile acid synthesis through a feedback mechanism.