Insulin-like growth factor binding protein (IGFBP) signalling.

Abstract

Insulin-like growth factor-I and -II (IGF-I and -II) are peptides that regulate cell metabolism, growth, differentiation and survival according to physiological requirements and the tissue type involved. They bind to two transmembrane receptors, the type I and type II IGF receptors (IGF-IR and IGF-IIR), although their cellular action is mediated via IGF-IR which possesses tyrosine kinase activity. In serum and the extracellular fluids, IGFs associate with IGF binding proteins (IGFBPs) which comprise a family of six related secreted proteins and which specifically bind IGFs with high affinity. The characteristics of binding between IGFs and IGFBPs determine the relatively complex mechanisms regulating the bioavailability of the IGFs in circulating fluids and cellular surroundings. Apart from their roles as IGF carriers, IGFBPs also possess intrinsic activities that are divorced from their association with IGFs. These so-called IGF-independent activities modulate numerous cellular processes, including cell growth, differentiation and apoptosis. The very nature of IGFindependent activities would presuppose the ability to activate signalling pathways of their own that lead to specific cellular actions or modulate the effects of other factors. Although extensive research in this field has yielded an ever-growing number of publications, the variety of IGFBP preparations, cell models, and experimental conditions and techniques employed makes it difficult to formulate a coherent synthesis. This review therefore aims to provide an overview of the various intracellular signalling pathways via which IGFBPs are purported to mediate their IGF-independent action.