Abstract
The insulin-like growth factor binding protein (IGFBP) family is a critical component of the insulin-like growth factor (IGF) system which regulate the biological actions of the IGFs and may also be capable of IGF-independent actions. To date, seven distinct IGFBPs have been described. Among these IGFBPs, IGFBPs-1-6 bind IGFs with high affinity, while only IGFBP-7 binds with low affinity. Recently, we have demonstrated that connective tissue growth factor (CTGF) also binds IGFs with low affinity, suggesting that a family of low-affinity IGFBPs, distinct from the high-affinity members, may exist, and together these constitute an IGFBP superfamily. IGFBPs have various biological roles. IGFBPs act not only as a carrier proteins, but also as a modulators of IGF actions by involving in IGF ligand-receptor interactions through influences on both the bioavailability and distribution of IGFs in the extracellular environment. In addition, some IGFBPs (IGFBPs-1, -3, and -5) appears to have intrinsic activity independent of IGFs. This review will focus on recent studies on the biological roles of IGFBPs in IGF-dependent and IGF-independent modes.
Highlights
Insulin-like growth factors (IGFs) are important mitogenic and anabolic polypeptides thought to be involved in normal and malignant cellular proliferation (Daughaday and Rotwein, 1989; Rotwein 1991)
Over the course of evolution, ancestral “insulin-like” gene gave rise to insulin and insulin-like growth factor (IGF), having distinct anabolic roles (Nagamatsu et al, 1991). These facts are supported by the findings that 1) human IGF-I and proinsulin share an overall amino acid sequence homology of 48% (Rinderknecht and Humbel, 1978); and 2) a gene encoding a polypeptide with a deduced sequence that contains features of both insulin and IGFs was detected in the primitive cephalochordate Branchiostoma californiensis (Chan et al, 1990)
IGFs differ from insulin in at least two respects: 1) the insulin gene is expressed exclusively in the pancreatic β-cells (Falkmer, 1985), while the IGFs are expressed in virtually all cell types; and 2) IGFs are bound in biological fluids to the IGF binding proteins (IGFBPs), while insulin reportedly has no affinity for any of the insulin-like growth factor binding protein (IGFBP) (Rechler, 1993; Rosenfeld et al, 1994)
Summary
Insulin-like growth factors (IGFs) are important mitogenic and anabolic polypeptides thought to be involved in normal and malignant cellular proliferation (Daughaday and Rotwein, 1989; Rotwein 1991). Over the course of evolution, ancestral “insulin-like” gene gave rise to insulin and IGFs, having distinct anabolic roles (Nagamatsu et al, 1991) These facts are supported by the findings that 1) human IGF-I and proinsulin share an overall amino acid sequence homology of 48% (Rinderknecht and Humbel, 1978); and 2) a gene encoding a polypeptide with a deduced sequence that contains features of both insulin and IGFs was detected in the primitive cephalochordate Branchiostoma californiensis (Chan et al, 1990). We have recently demonstrated that the protein product of the human connective tissue growth factor (CTGF) cDNA is structurally related to the IGFBPs, and binds IGFs, with relatively low affinity, thereby constituting another new member of the IGFBP family, IGFBP-8 (Kim et al, 1997).
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