Structure, Function, and Dysregulation of FGF3 in Human Biology

Fibroblast growth factor 3 (FGF3), also known as oncogene INT-2, is a member of the fibroblast growth factor signalling family. The binding of FGF family proteins to cell-surface fibroblast growth factor receptors (FGFRs) has been shown to tightly control a variety of biological processes including cell proliferation, differentiation, migration, and tissue repair. The FGF3 gene was first identified as an important gene involved in the murine mammary tumor virus-induced tumorigenesis. The FGF3 has also been shown to be essential for embryonic inner ear morphogenesis, nervous system development and extension of the axial skeleton. Alterations in the FGF3 signalling pathway have been shown to be associated with a number of human diseases including congenital developmental defects and a number of different cancers.

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FGF3 and Receptor Complexes

FGF7 subfamily (FGF3, FGF7, FGF10 and FGF22) is one of five paracrine FGF subfamilies. Paracrine FGFs have only recently been found to play crucial roles in organogenesis and tissue patterning during embryonic development as well as in wound healing and tissue homeostasis in adults. Signaling by this subfamily of paracrine FGFs has also been found to be dysregulated in a variety of hereditary and acquired disorders, including congenital deafness, LADD syndrome, inflammatory bowel disease, Apert syndrome and prostate cancer.

Figure 1. Structure-based sequence alignment of human FGF10, FGF3, FGF7, and FGF22
(Source: Zinkle A, et al. 2019)

FGF family members all possess a shared structural characteristic of a β-trefoil motif formed by 12 antiparallel β-strands that constitute the major ligand-receptor binding surface. FGFs bind to and activate FGFRs on the cell surface. The extracellular region of FGFRs has been shown to be composed of three immunoglobulin-like domains (D1, D2 and D3) with D2 and D3 domains responsible for FGF ligand binding. Much of the specificity of ligand-receptor binding is imparted by alternative splicing of the D3 domain. FGF3 is a secreted signaling molecule that contains a highly conserved core domain of ~120 amino acids shared with other FGF family members. The human FGF3 gene is located on chromosome 11q13.3 and is predicted to encode a precursor protein that is 240 amino acids in length. Signal peptide cleavage and possibly glycosylation changes yield a mature protein that is secreted into the extracellular matrix to carry out its function. Like the other paracrine FGF family members, FGF1 and FGF2, FGF3 extracellular biological activity is HS/HSPG dependent. Heparan sulfate (HS) acts as a low affinity co-receptor to protect FGF3 from proteolytic degradation, to stabilize FGF3 conformation and to facilitate the interaction with the high affinity receptors (FGFRs) to form a stable ternary complex (FGF3–FGFR–HS) for downstream signal transduction activation. This mechanism likely plays a role in fine-tuning the specificity and magnitude of FGF signaling.

FGF3 and Disease

Abnormal activation (gain-of-function) or loss-of-function of the FGF3 signaling pathway can contribute to a wide variety of human diseases, both inherited and acquired, such as cancer. The most common cause of LAMM syndrome (deafness, labyrinthine aplasia, microtia and microdontia) is the presence of loss-of-function mutations in FGF3. In these patients, the disease presentation is obvious, as they display symptoms of severe-to-profound sensorineural hearing loss, small ears (microtia) and microdontia. All of these malformations reflect the lack of organ primordia, which are crucially dependent on the normal function of FGF3. The link between FGF3 and these human developmental defects was first demonstrated in a study of nine patients from three nonconsanguineous Turkish families. All of the affected patients had congenital profound sensorineural hearing loss, type I microtia and microdontia. The CT imaging studies revealed bilateral absence of the inner ear structures, while the middle ear was present and completely normal. The disease locus was mapped to chromosome 11q13 and the gene mutated in all of the affected patients was FGF3. Three different homozygous disease-causing mutations, all of which were predicted to lead to FGF3 protein loss-of-function, were identified in the three different families. These mutations were not present in 300 control subjects without disease. The work was the first to directly link mutations in FGF3 to a human multiple malformation syndrome and firmly establish FGF3 as an essential player in human embryonic development. In contrast to the mouse Fgf3 knockout, where the inner ear malformations are mild (endolymphatic sac dysgenesis), the human FGF3 patients have a complete absence of the inner ear. This highlights a more significant and likely species-specific role for FGF3 in human inner ear development. In addition to loss of function mutations, dysregulation of the signaling network that involves FGF3 can also result in a variety of other disorders. Activating mutations in a downstream receptor, FGFR3, for example, are the direct cause of several human skeletal dysplasias, including achondroplasia and thanatophoric dysplasia.

Figure 3. FGF3 gene mutations associated with labyrinth agenesis, microtia, and microdontia syndrome
(Source: Jamshidi F, et al. 2023)

Oncogenic overexpression or gene amplification of FGF3 contributes to the tumorigenesis and progression of multiple malignant tumors. In cancer cells and their microenvironment, FGF3 overexpression may constantly activate FGFRs by paracrine or autocrine signaling and further stimulate tumor cell proliferation, survival, angiogenesis and metastasis. In breast cancer cells, FGF3 is frequently overexpressed, leading to hyperactivation of FGF3–FGFR1–STAT3 signal transduction, resulting in the promotion of tumor growth. Co-overexpression of FGF3 has also been reported to have a key role in the pathogenesis of lung cancer.

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