Decrease in fibrosis, and increase in number of hepatocytes, in Cl 4 C-cirrhotic rats after injection of the liver growth factor. LGF : [formula omitted]. Clínica Puerta de Hierro and Universidad Complutense, Madrid, Spain

Abstract

IGF actions are modulated by a family of six proteins, the IGFBPs. This review discussed structural aspects of the proteins and their genes, emphasizing in particular the posttranslational modifications—glycosylation, phosphorylation and proteolysis—which are believed to be important modifiers of IGFBP activity. The IGFBP genes all contain four coding exons, with only the IGFBP-3 gene having a fifth, non-coding exon. Consistent with a relatively conserved gene structure, the proteins themselves, all approximately 20–30 kDa in size, are highly conserved in primary structure, each consisting of three domains: cysteine-rich amino-terminal and carboxy-terminal domains with marked sequence similarity among all of the proteins, and central domains showing no conservation. Putative sites of N-linked glycosylation (three in IGFBP-3, and one in IGFBP-4 and -6) occur in this region, and appear occupied by carbohydrate in IGFBP-3 and -4, whereas IGFBP-1, -5, and -6 have varying amounts of O-linked carbohydrate. All of the IGFBPs bind both IGF-I and IGF-II, with IGFBP-6 having an outstanding preferential affinity for IGF-II. IGFBP-3, alone among the IGFBPs, binds to another ligand, the 85 kDa, leucine-rich acid-labile subunit, with which it forms a ternary complex, together with IGF-I or IGF-II, in the circulation.Certain of the IGFBPs can associate with cell surfaces or matrix, in the case of IGFBP-1 and -2, via an Arg-Gly-Asp motif which interacts with receptors of the integrin class, and in the case of IGFBP-3 and -5 via a highly basic motif in their carboxy-terminal domain. IGFBP-1, -3, and -5 can be serine-phosphorylated, resulting in changes in their cell-binding and/or IGF affinity. Finally, limited proteolysis by enzymes of a variety of classes can convert IGFBPs to stable forms of lower molecular weight with reduced IGF-binding affinity. These proteases are postulated to be of major importance in modulating the ways in which IGFBPs affect IGF activity in the cellular environment, and may also be important in determining the bioavailability of circulating IGFs.