FGF family
Fibroblast growth factors (FGFs) constitute a family of 20 small peptide growth factors that share a highly homologous core of 140 amino acids and strong affinity for heparin and heparin-like glycosaminoglycans (HLGAGs) of the extracellular matrix (ECM).
FGF signaling and interactions with the ECM has attracted the attention of numerous cancer researchers because of the potential role of the FGFs in promoting the progression of some tumors from a hormone-dependent to a hormone-independent pattern of growth. Others are attracted to FGF studies from observations that development of many cancers positively correlate with local tissue secretion of proteases and changes in pH, which might act to change concentrations of biologically available FGFs in the local tissue environment. Both FGF-I (also known as acidic FGF or aFGF) and FGF-2 (also known as basic FGF or bFGF) were first identified from extracts of bovine pituitary glands based on the capacity of the proteins to stimulate DNA synthesis in cultured fibroblasts. Members of this family of growth factors are linked by structural similarities and capacity to bind heparin or HLGAGs, and not specifically by their growth-stimulating activity. By convention they continued to be designated as FGFs, despite the fact that not all of the proteins actually stimulate proliferation of fibroblasts. Consequently, several members of the FGF family have emerged as stroma-derived mitogens, which may act in a paracrine manner, for example in the mammary gland, to locally influence epithelial cell proliferation and glandular morphogenesis (Hovey et al., 1999; Powers et al., 2000).Although the FGFs function after they appear in the extracellular environment via binding to high-affinity cell surface receptors, neither FGF-I nor FGF-2 are synthesized with a leader peptide sequence. You may recall from our discussion of cell physiology that the leader sequence is a strand of hydrophobic amino acids at the amino terminal of the newly synthesized peptides that serve to control the secretion destination of the protein; that is, whether the protein will be retained within the cell or secreted.
The leader peptide is recognized by a signal recognition particle (SRP), which temporarily halts translation and serves to transport the translation complex to the endoplasmic reticulum (ER). At this point, protein synthesis resumes and the nascent peptide chain is vectored into the cisternal space of the ER where it subsequently passes to the Golgi for packaging into secretory vesicles for secretion from the cell. This feature has attracted cell biologists to the study of these FGF variants to decipher this secretion mechanism. Because FGFs are also involved in wound healing, it has been suggested that mechanical damage provides a mechanism for release of FGF from endothelial cells, but such a mechanism would seemingly lack the regulation necessary for secretion of FGFs in many other situations, for example, if they play a role in normal glandular development.FGF-I likely functions as a paracrine mitogen for epithelial cells. For example, transgenic mouse experiments that targeted overexpression of a defective FGF receptor to the mammary gland showed that Iobulo- alveolar development was distinctly impaired. Of the various rat mammary cell types, fibroblasts express the greatest level of FGF-I mRNA in vitro. Appearance of mRNA and protein within both the intact mouse mammary gland and epithelial cleared mammary fat pad strongly supports the idea that FGF is stromal in origin. At least three of the known FGF variants (FGF-1, FGF-2, and FGF-7, also known as keratinocyte growth factor KGF), are proposed to be involved in ruminant mammary development. These FGFs and their receptors are expressed during mammogenesis, lactation, and mammary involution. The highest levels of expression were in glands of virgin heifers and in primiparous heifers during involution.
Although FGF-2 mRNA expression is greatest in the stromal tissue, immunocytochemical studies show that the FGF-2 protein associates with myoepithelial cells. This distribution may simply reflect the high affinity of FGF-2 for specific components of the ECM, further supporting its proposed role as a paracrine/ autocrine mitogen for myoepithelial cells. Synthesis of FGF-2 in the mouse mammary fat pad is hormonally regulated, based on observations that expression is greatest during late pregnancy in correspondence with the appearance of higher tissue concentrations of the protein at this time. Expression is also increased in the bovine mammary gland in late gestation. Interaction between epithelium and the surrounding stroma likely influence paracrine FGF-2 expression; in rodents and ruminants, expression is greater in the stroma adjacent to the developing parenchymal tissue.