The fibroblast growth factor family

Abstract

Hepatocytes rarely divide in normal adult liver. However, liver regeneration is induced immediately after a large loss of liver parenchyma due to damage such as partial hepatectomy or chemical treatment. In the process, most of the hepatocytes as well as non-parenchymal liver cells divide, accompanied by alterations in patterns of gene expression. Cultured hepatocytes, isolated from liver by collagenase perfusion, undergo DNA synthesis and proliferate after addition of growth factors. This suggests that growth factors, particularly those within the local liver environment, may be activated and drive the regeneration process. Unlike circulating hormones and most other growth factor/cytokine families, expression and activity of the fibroblast growth factor (FGF) family is confined to the local tissue environment, and one or more members of the family and their receptors are ubiquitously present in tissues. Liver is no exception and the family has been implicated in the compensatory response of liver as well as liver development. Since FGF-1 was first found to be a mitogen for cultured hepatocytes, it has become clear that the FGF family is extremely diverse with respect to the molecular characteristics of both ligands and receptors, and multifunctional with respect to its biological effects which include growth, morphogenesis, inhibition of growth and differentiation. Moreover, the glycosaminoglycan moiety of endogenous heparan sulfate proteoglycans is intimately associated with the activity and assembly of the active FGF receptor. The FGF ligands include nine members that share homologies in amino acid sequence, structure and affinity for heparan sulfates. There are four distinct genes that code for FGF receptors, which are in the tyrosine kinase class. However, the bulk of the complexity of the receptor family arises by alternative splicing. In this chapter, we review the complexity of the FGF family in general and its role in liver in particular. For earlier general reviews on the FGF family, see Burgess and Maciag (1989), Klagsbrun (1989), Basilico and Moscatelli (1992), Jaye, Schlessinger and Dionne (1992) and Johnson and Williams (1993).