The Fibroblast Growth Factor (FGF) family comprises a large group of related signaling proteins. These proteins are involved in various cellular processes, acting as messengers to facilitate communication between cells. FGFs are known to bind to heparin and heparan sulfate, a defining characteristic.
There are 22 identified members of the human FGF family, with molecular masses ranging from 17 to 34 kilodaltons. Although initially discovered for stimulating fibroblasts, the term “FGFs” now broadly refers to this family of structurally similar proteins. Their importance lies in regulating cell proliferation, migration, differentiation, and survival across a wide range of biological contexts.
Key Functions in the Human Body
Fibroblast Growth Factors play varied roles throughout the human body, influencing many biological processes. Their functions are broadly categorized based on the stages of life and the types of tissues involved.
During embryonic development, FGFs are involved in forming various organs, limbs, and the nervous system. For instance, FGF10 is important for the organogenesis of many branched organs, including the lungs, pancreas, and kidneys, as well as the development of teeth, mammary glands, and limbs. These growth factors guide tissue patterning and formation.
FGFs also contribute to tissue repair and wound healing in adults. They signal cells to multiply and migrate to injured areas, aiding in the recovery of damaged tissues like skin or bone. FGF1 and FGF2, for example, stimulate the formation of granulation tissue, which fills wound spaces early in the healing process. FGF7 and FGF10 also promote the repair of injured skin and mucosal tissues.
Beyond development and repair, FGFs help maintain normal function in adult tissues, including regulating metabolism and brain function. Some FGFs, such as FGF15/19, FGF21, and FGF23, can act as hormones, exerting systemic effects throughout the body.
The FGF Signaling Mechanism
Fibroblast Growth Factors exert their effects by interacting with specific receptors on cell surfaces. These receptors are known as Fibroblast Growth Factor Receptors (FGFRs), and in mammals, there are four main types: FGFR1, FGFR2, FGFR3, and FGFR4. This interaction is like a lock and key system, where a specific FGF protein binds to its matching FGFR.
When an FGF protein binds to an FGFR, it causes the receptor to change shape and often form a pair with another FGFR, a process called dimerization. This pairing activates the internal part of the receptor, which has tyrosine kinase activity. This activation triggers a chain reaction of signals inside the cell, known as a signaling cascade.
This cascade involves the activation of several intracellular signaling pathways, including the RAS-MAPK, PI3K-AKT, PLCĪ³, and STAT pathways. These pathways then transmit the signal, instructing the cell to perform specific actions such as growing, dividing, migrating, or differentiating into a specialized cell type. Heparan sulfate proteoglycans on the cell surface often act as cofactors, facilitating the binding of FGFs to their receptors and the activation of these signaling pathways.
Connection to Human Diseases
Problems with FGF signaling, known as dysregulation, can lead to various human diseases. These issues can arise from either an overactive or underactive signaling pathway.
In cancer, overactive FGF signaling contributes to uncontrolled cell growth and division. This can promote tumor formation and angiogenesis, the growth of new blood vessels that supply nutrients to the tumor. Dysregulation of FGFR signaling is associated with various cancers, including lung cancer, multiple myeloma, and bladder carcinoma.
Skeletal disorders are another group of conditions linked to dysregulated FGF signaling, often due to mutations in FGF receptors. Achondroplasia, the most common form of dwarfism, is caused by a specific mutation, typically a Gly380Arg mutation, in the FGFR3 gene. This mutation leads to increased FGFR3 signaling, which suppresses the proliferation and maturation of growth plate cartilage cells, resulting in reduced bone elongation and short stature. Other skeletal dysplasias, such as hypochondroplasia and thanatophoric dysplasia, also stem from mutations in the FGFR3 gene.
Therapeutic and Research Applications
Understanding the FGF family has opened avenues for developing new treatments and advancing scientific research. Scientists are exploring ways to modulate FGF signaling to address various health conditions.
One promising area involves targeted therapies for cancers. Drugs known as FGFR inhibitors are being developed to block overactive FGF signaling. These inhibitors interfere with activated FGFRs, helping to slow or stop uncontrolled cell growth in tumors. Clinical trials have shown that some FGFR inhibitors, such as erdafitinib, can shrink tumors and improve outcomes for patients with specific FGFR mutations.
FGFs also hold potential in regenerative medicine to promote healing and tissue repair. Recombinant FGF proteins have been applied in advanced wound care to accelerate the healing of skin wounds, diabetic ulcers, and bone fractures. FGF2, for example, has been shown to reduce healing time and improve scar quality in various types of wounds. Research is also exploring the use of FGFs to repair damaged tissues, such as restoring cardiac function after a heart attack.