FGF Family (FGFs and Receptors)

FGF Family: Regulators of Cellular Processes

The FGF family, known as Fibroblast Growth Factors (FGFs), encompasses a group of polypeptide growth factors that are widely distributed in various tissues throughout the body. These factors play crucial roles in regulating cell proliferation, migration, differentiation, and apoptosis. The name "FGFs" originated from their remarkable ability to stimulate fibroblast growth, and they have significant implications in embryonic development and the maintenance of overall bodily stability. Owing to their potent regenerative properties, FGFs have found extensive applications in modern medical surgery and cosmetic procedures.

FGF Family: Structural Features and Secretion Mechanisms

The Fibroblast Growth Factor (FGF) family comprises 23 identified members, ranging from FGF1 to FGF23. These members exhibit amino acid sequence homology of approximately 25% to 50%, and each member shares a central axis consisting of 140 amino acids that are highly conserved. Structural analysis reveals that this central axis folds into 12 antiparallel β-strands, forming a cylindrical structure.

Within the FGF family, some members possess a typical signal peptide sequence at their N-terminus, composed of around 30 amino acid residues. This signal peptide enables their secretion outside the cell through the classic pathways of the endoplasmic reticulum-Golgi complex, facilitating autocrine and paracrine signaling. Conversely, certain FGFs lack a signal peptide structure and cannot be secreted under normal circumstances. However, these FGFs can be released when cells are damaged.

While most FGFs possess a typical signal peptide sequence, allowing for efficient secretion into the extracellular space, FGF16 and FGF20 lack a clear signal peptide sequence but can still be secreted effectively. FGF1 and FGF2, despite lacking signal peptide sequences and conventional secretion pathways, can also be found in the extracellular matrix. It is postulated that these two FGFs may originate from injured cells or be released extracellularly. Furthermore, FGF 11-14 lack a typical signal peptide sequence, suggesting their intracellular functional role. Although FGF family members share 25%-50% amino acid sequence homology and possess common molecular structures, each FGF molecule exhibits unique biological effects alongside shared characteristics.

FGF Receptors and Their Mechanism of Action with FGF

FGF exerts its biological functions by binding to receptors on the surface of target cell membranes. FGF receptors, which are present in nearly all tissues of the body, consist of single-chain polypeptide molecules. The molecular weight of the receptors varies (110-150 kDa) depending on the specific effector cells. There are five types of FGF receptors, FGFR1-5, which can be categorized into two groups: high-affinity receptors, belonging to the tyrosine protein kinase receptor family, with a molecular weight of 125-156 kDa, and low-affinity receptors, known as the heparin-like receptors, with a Kd value of 210-9 mol/L.

Members of the FGF family can compete with each other for receptor binding. For example, FGF1 and FGF2 can interact with receptors of 145 kDa and 125 kDa, but FGF1 exhibits higher affinity for 125 kDa receptors, while FGF2 has a higher affinity for 145 kDa receptors. The binding of FGF to receptors can be inhibited by lectins, suggesting that FGF receptors may contain N2 acyl glucosamine and galactose residues. Similar to other polypeptide receptors, FGFR is composed of three main parts: an intracellular tyrosine protein kinase active domain, a transmembrane domain consisting of hydrophobic amino acids, and an extracellular ligand-binding domain composed of three immunoglobulin-like repeat sequences.

The extracellular region of the FGF receptor contains three immunoglobulin-like domains known as Loop I, II, and III. Loop III primarily determines the binding specificity of the ligand. Among FGFR1-3, FGFRIIIb and FGFRIIIc isoforms are formed due to the differences in Loop III. An acidic box, consisting of conserved acidic amino acid residues, is present between the domains of Loop I and Loop II. Loop III has two alternatively spliced exons, IIIb and IIIc, which encode its C-terminus. IIIb is more highly transcribed in endothelial cells, while IIIc is more highly transcribed in epidermal cells. FGF1, FGF7, and FGF10 primarily bind to FGFRIIIb and play essential roles in tissue and organ formation. FGF2, FGF4, FGF6, FGF8, and FGF9 specifically activate FGFR2-IIIc, and the specificity of this binding is closely related to heparan sulfate and the cellular membrane environment. FGF10 has a higher affinity for FGFR2-IIIb and is the specific ligand for FGFR2-IIIb. In the case of a point mutation (S252W) in the extracellular segment of FGFR2, FGF2, FGF6, and FGF9 can activate FGFR2-IIIb, while FGF7 and FGF10 can also activate FGFR2-IIIc, resulting in the activation of cells expressing these FGFs through autocrine signaling.

FGFR is also expressed in skin tissues, primarily distributed in epidermal basal cells, dermis, subcutaneous tissue, fibroblasts, hair follicles, and epithelial cells of sweat glands.

Signal Transduction of the FGF Family

Members of the FGF (fibroblast growth factor) family initiate complex signal transduction networks by binding to high-affinity receptors on the cell surface. This process is essential for various biological processes including cell survival, proliferation, differentiation, and migration.

FGF receptors, including FGFR1, FGFR2, FGFR3, and FGFR4, belong to the tyrosine kinase receptor class. Upon FGF binding, the receptor's tyrosine kinase activity is activated, triggering downstream signal transmission.

The major downstream signal transduction pathways include the RAS-MAPK (mitogen-activated protein kinase) pathway and the PI3K-AKT (phosphatidylinositol 3-kinase-protein kinase B) pathway. The RAS-MAPK pathway regulates cell proliferation, differentiation, and migration, while the PI3K-AKT pathway governs cell survival, proliferation, and metabolism.

Additionally, FGFs can activate other signaling molecules such as the JAK-STAT (Janus kinase-signal transducer and activator of transcription) and PLCγ (phospholipase C gamma) pathways, which further regulate cellular physiological and pathological processes.

The signal transduction process of FGFs is influenced by various regulatory factors. Heparan sulfate glucosaminoglycans (HSPGs) act as co-receptors to enhance the binding of FGF to receptors. Transcription factors, enzymes, and proteases also play a role in modulating the strength and timing of FGF signaling.

Clinical Significance of the FGF Family

The FGF (fibroblast growth factor) family holds significant clinical implications as it influences various physiological and pathological processes, impacting human health and disease development.

1. Tissue Repair and Regeneration: FGF family members play a crucial role in wound healing, fracture repair, and tissue regeneration. They stimulate cell proliferation, migration, and differentiation, facilitating the restoration and regeneration of damaged tissues.
2. Angiogenesis: Specific FGF members (e.g., FGF-2 and FGF-9) participate in angiogenesis, promoting the formation of new blood vessels and the proliferation of vascular endothelial cells. This process is vital for vascular reconstruction and the restoration of blood supply.
3. Neuroprotection and Regeneration: Certain FGF members (e.g., FGF-2 and FGF-20) exhibit neuroprotective effects, supporting the survival of nerve cells, promoting axon growth, and facilitating synapse formation. These properties hold potential for the treatment of neurological diseases and nerve damage repair.
4. Cancer Treatment: The FGF family plays a significant role in cancer development and metastasis. Overexpression of FGF members and their receptors in certain cancer cells promotes tumor angiogenesis and cell proliferation. Consequently, inhibiting FGF signaling presents a potential strategy for cancer treatment.

Summary of the FGF Family

In summary, the FGF (fibroblast growth factor) family plays critical roles in various biological processes, including cell growth, development, angiogenesis, neuroprotection, and inflammation regulation. Research on the FGF family enhances our understanding of its involvement in physiological and pathological processes and offers prospects for the development of novel therapeutic strategies and drugs for related diseases.

References:
[1] Krejci, P. ,  Prochazkova, J. ,  Bryja, V. ,  Kozubik, A. , &  Wilcox, W. R. . (2010). Molecular pathology of the fibroblast growth factor family. Human Mutation, 30(9), 1245-1255.
[2] Zhang, X. ,  Ibrahimi, O. A. ,  Olsen, S. K. ,  Umemori, H. ,  Mohammadi, M. , &  Ornitz, D. M. . (2006). Receptor specificity of the fibroblast growth factor family the complete mammalian fgf family. J. Biol. Chem, 281(23), 15694-15700.
[3] Shukla, A. K. ,  Bora, U. , &  Dubey, V. K. . (2009). Functional adaptations in fibroblast growth factor (fgfs) family. Journal of Proteins & Proteomics, 1(1), 11-13.
[4] Turner N, Grose R. Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer. 2010 Feb;10(2):116-29. doi: 10.1038/nrc2780