The Elegant Simplicity of Nature: The Fibroblast Growth Factor (FGF) Family.

Picture above depicts spiral forms found in developing systems throughout the universe. Left, the Pinwheel Galaxy 25 million light years from earth. Photo, the Hubble Consortium, NASA, ESA. Right, a conch shell on my table here on earth. Photo, Ranjan Mukherjee

Nature is elegant in its simplicity. There are a set of laws that explain her workings. They are simple, elegant and sometimes, used repeatedly. Consider the gravitational force between two bodies, first propounded by Newton. It is a force that varies inversely as the square of the distance (the inverse square law). Gravitation is a universal law, not because we have tested it everywhere in the universe (an impossibility) but because we have not seen any deviation anywhere yet. In fact, the trajectories of our spaceships and space probes are calculated largely based on these equations and they have held up so far with the space probe Voyager exploring right up to the cold wastes at the edge of our solar system. The inverse square law also explains another attractive force, the electrostatic force of attraction between two opposite, stationary charges (Coulomb’s law). These laws have withstood the test of time.

The same is true with life and its evolution. A useful paradigm like the genetic code is used throughout the animal kingdom. The four nucleotides that form a DNA molecule, the twenty amino acids that give rise to proteins are found in all bacteria, plants and animals. Evolution has selected for these and eliminated countless others. The eliminated ones are lost to history unless something turns up in the fossil record. When something so uniquely perfect is found, it makes sense to keep reusing the basic framework with subtle modifications to satisfy the specific needs. One example is the spiral forms seen in certain developing systems, inanimate or living, as gigantic and far flung as a faraway galaxy or as simple and down-to-earth as a growing sea shell (figure above). A second example, the main subject of this article, is The Fibroblast Growth Factor (FGF) family.

Consider how a multicellular organism grows from a single, fertilized egg. The single egg divides into two, then four, eight and so on. Soon the cells in the developing embryo begin to get organized into a particular pattern that heralds the shape of the adult to come. Regions like the limb bud begin to grow and then, after a fixed interval, stop growing. There must be signaling cues that instruct these cells where to grow, when to grow and when to stop. These cues are the growth factors. Fibroblast Growth Factors (FGFs) belong to this family of signaling proteins. They are extracellular signaling molecules that mediate a whole host of cellular processes; growth, proliferation, differentiation, angiogenesis, organogenesis, cell survival, epithelial repair and wound healing.

The first members, FGF1 and FGF2 were identified in the early 1970s. They induced proliferation of fibroblasts, hence the name: Fibroblast Growth Factors. At that time, they were called acidic FGF (aFGF) and basic FGF (bFGF) respectively, based on their isoelectric point. Unfortunately, the FGF name has stuck even though later members do not cause cell proliferation. Since then, 22 members of the mammalian FGF family have been identified based on sequence homology. They can be further sub-grouped according to their mode of action. Most of them act locally, either in a paracrine or autocrine manner. Notable examples of this subfamily are FGF1, FGF2, FGF7 and FGF10, to mention a few. These FGFs utilize heparin sulfate proteoglycans found on the cell surface and extracellular matrix as essential cofactors.

In contrast, three of the family members, FGF19, FGF21 and FGF23 are secreted directly into the bloodstream and act at distal sites in an endocrine manner. These do not utilize heparin sulfate but do require alpha or beta-klotho as essential cofactors. Recent studies including crystal structure analysis indicate these cofactors are essential to their mechanism of action.

The last group of FGFs (FGF11-FGF13), are not secreted and act intracellularly by modulating voltage gated ion channels.

The autocrine and endocrine FGFs mediate their activity by binding to and activating four FGF receptors (FGFR1 – FGFR4). These belong to another large family of transmembrane receptors, the receptor tyrosine kinases. Upon binding of the FGF ligand to the extracellular domain, there is a structural reorganization of the receptor dimer which induces phosphorylation at specific tyrosine residues in the intracellular domains. These, in turn, activate a number of signaling pathways depending on the ligand and cell type that lead to the dizzying list of activities mediated by the FGFs.

Perhaps, way back in time, such a signaling molecule and its cognate receptor evolved in a prehistoric life form. It proved versatile and useful. Nature is efficient. It reused the paradigm for other related purposes. The relevant genes were duplicated, random mutations were selected for by the inexorable forces of natural selection and soon several growth factors and kinase receptors appeared controlling the many different processes needed to grow and sustain a multi-cellular organism. Some examples are the Epidermal Growth Factors, Insulin and Insulin like Growth Factors, Vascular Endothelial Growth Factors and the Fibroblast Growth factors. The FGFs are the largest of this family with 22 members.

Recombinant FGF2 is used for the topical treatment of burns, skin grafts, recalcitrant skin ulcers, diabetic- gangrene and diabetes related ulcers in China. This is just one of the twenty two FGFs. Preclinical and clinical research are underway to find if the other members can be turned into useful drugs. In particular, the endocrine FGFs hold great promise. In preclinical studies, FGF21 has been shown to ameliorate diabetes, dyslipidemia, reduce body weight, liver fat and non-alcoholic steatohepatitis. If translated into the clinic, this could be a game changer in the treatment of many diseases associated with our modern lifestyle and abundance of high calorie, tasty foods and sugar-rich drinks. We look forward to more medicines from the FGF family.




Leave a Reply

Fill in your details below or click an icon to log in: Logo

You are commenting using your account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s