3 - Structure and function of the heparin-binding (fibroblast) growth factor family

Abstract

Research over the past decade on polypeptide modulators capable of affecting proliferation and differentiation of cells in vitro and in vivo has led to a partial understanding of the global mechanisms of their synthesis, secretion and action. Many of these polypeptides and proteins, now universally called polypeptide growth factors-in view of their modulating influences on the competence or progression aspects of the different phases of the cell cycle (James and Bradshaw, 1984; Hearn et al, 1990)-manifest their function via interaction with specific cell surface-associated receptors with relatively high affinity constants. The synergistic influences of growth factors and their oncogenic relatives on intracellular properties of the cell typically involve a myriad of biochemical processes, including changes in cyclic nucleotide metabolism, attenuation of tyrosine kinase, and other kinase, activities and modification of other regulatory properties such as intracellular calcium levels and diacylglycerol-inositol 3-phosphate levels. Modulation of these processes are thus recognized as the initial hallmarks of growth factor function in vitro or in vivo . In addition, in many in vivo situations, the major physiological properties of polypeptide growth factors are now believed to be manifested via either autocrine or paracrine mechanisms, stimulating cells of the same phenotype, and proliferating morphologically associated normal or transformed cells which are in close proximity in a particular tissue or cellular structure. To achieve these properties, the biosynthesis and secretion of the majority of polypeptide growth factors, such as the insulinlike growth factors (IGFs) or epidermal growth factor (EGF), follow wellcharacterized molecular and cellular pathways, in terms of gene transcription, mRNA translation, processing of precursors to physiological mature forms and subsequent membrane transport and secretion . Why then have the fibroblast growth factor (FGF) family of proteins attracted so much intense recent interest related to their structure, functional properties in vitro, and their physiology and pharmacology in vivo? Simply stated, the FGF family of polypeptide growth factors essentially represent a new class of polypeptide growth factors with biological and structural properties which significantly diverge from other known growth factor families in many key features.