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Ligand (FGF) binding typically triggers receptor dimerization with associated transphosphorylation of critical tyrosine residues. Once phosphorylated, various cytoplasmic proteins dock at/are activated by the FGF receptor. Docking is most likely mediated by a characteristic interaction between Src-homology 2 (SH2) domains of the cytoplasmic proteins and the phosphotyrosine residues on the activated receptor. The next stages of signal transduction are characterized only in part. Studies with FGFR-1 implicate at least four signalling pathways (Figure 7.5).
Phospholipase C-g (PLC-g) activation promotes the cleavage of phosphatidyl inositol 4,5 bisphosphate, generating inositol triphosphate and diacylglycerol, which, in turn, trigger an increase in intracellular calcium ion concentration and activation of protein kinase C. Interaction with FGFR-1 also appears to activate Src, a non-receptor tyrosine kinase. This, in turn, influences cytoskeletal structure. CrK is an additional ‘adaptor’ protein which may link the FGFR to the intracellular signalling molecules Shc, C3G and Cas, all of which could propagate mitogenic signals. Finally, the activated FGF-1 is known to phosphorylate (activate) the protein SNT-1 (i.e. FRS2). This protein, in turn, is important in the Ras/MAPK signalling pathway, known to mediate growth factor-induced cell cycle progression.
Whatever the mode of signal transduction, FGFs display a wide range of biological activities. They function as growth factors for a range of cell types and are known to promote wound repair. Some FGFs are known to promote repair to damaged myocardial tissue in animal models. Although no FGF-based product has thus far been approved for general medical use, such biological activities render them attractive candidates for clinical appraisal. In addition, FGFs play a central role in embryonic development and inappropriate FGF-like signalling has been linked to various tumour types. Autocrine over-stimulation linked to overexpression of FGFs is a characteristic feature of most human gliomas. Overexpression of/the presence of constitutively activated FGF receptor mutants is observed in various cancers of the brain, breast, prostrate, thyroid and skin. As such, downregulation of FGF signal transduction activity could be of benefit in the future treatment of various cancer types.
TRANSFORMING GROWTH FACTORS (TGFs)
Transforming growth factors (TGFs) represent yet another family of polypeptide mitogens. The members of this family include TGF-a, as well as several species of TGF-8.
TGF-a is initially synthesized as an integral membrane protein. Proteolytic cleavage releases the soluble growth factor, which is a 50 amino acid polypeptide. This growth factor exhibits a high
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Figure 7.4. 3-D of acidic (a) and basic (b) fibroblast growth factor. Photos from Zhu et al. (1991), by
courtesy of the Protein Data Bank: http://www.rcsb.org/pdb/
Figure 7.5. Binding of FGF to an FGF receptor, and the possible intracellular events triggered upon binding. Refer to the text for specific details
amino acid homology with EGF, and it induces its biological effects by binding to the EGF receptor. It is synthesized by various body tissues, as well as by monocytes and keratinocytes. It is also manufactured by many tumour cell types, for which it can act as an autocrine growth factor.
TGF-b was first described as a growth factor capable of inducing transformation of several fibroblast cell lines (hence the name, transforming growth factors). It is now recognized that
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‘TGF-b’ actually consists of three separate growth factors: TGF-b1, -fi2 and -b3. Although the product of distinct genes, all exhibit close homology. In the mature form, they exist as homodimers, with each subunit containing 112 amino acid residues. Most body cells synthesize TGF-b, singly or in combination.
TGF-bs are pleiotrophic cytokines. They are capable of inhibiting the cell cycle and hence growth of several cell types, most notably epithelial and haemopoietic cells. These factors, however, stimulate the growth of other cell types, most notably cells that give rise to connective tissue, cartilage and bone. They induce the synthesis of extracellular matrix proteins, and modulate the expression of matrix proteases. They also serve as a powerful chemoattractant for monocytes and fibroblasts. Given such activities, it is not surprising that the major physiological impact of TGF-bs appear to relate to:
• tissue remodelling;
• wound repair;
Such activities render them potentially useful therapeutic agents and several are being assessed medically (Table 7.2). The effect of TGF-b on haemopoietic cells has recently received increasing attention. Along with TNF-a and IFN-g, TGF-b is a physiologically relevant negative regulator of haemopoiesis. TGF-b also inhibits the growth of various human leukaemia cell lines in vitro, rendering it of potential interest as a putative anti-cancer agent.