BEYOND CARRIER PROTEINS Specifying the cellular responses to IGF signals: roles of IGF-binding proteins C Duan Department of Molecular, Cellular and Developmental Biology, University of Michigan, Natural Science Building, Ann Arbor, Michigan 48109–1048, USA (Requests for offprints should be addressed to C Duan; Email: cduan@umich.edu) Abstract Regulation of peptide growth factor/hormone activities by secreted hormone-binding proteins has emerged as a common theme in cell–cell signaling. Among the best- studied examples are members of the IGF-binding protein (IGFBP) gene family. These secreted proteins bind the IGF ligands with equal or even greater affinities than do the IGF receptors, and therefore are placed in a critical regulatory position between IGFs and their cell surface receptors. The circulating IGF/IGFBP complexes prolong the half-lives of IGFs and buffer the potential hypo- glycemic effects of IGFs. Locally expressed IGFBPs provide a means of localizing IGFs in specific cells and can alter the IGF biological activity. While some members of the IGFBP gene family have been consistently shown to inhibit IGF actions by preventing them from gaining access to the IGF receptors, others potentiate IGF actions by facilitating the ligand–receptor interaction. Further- more, recent studies indicate that some IGFBPs can regulate several cellular processes through ligand- independent mechanisms. This review will focus on the roles of IGFBPs in vascular smooth muscle cells. A conceptual model of the molecular mechanisms by which IGFBPs act to determine the specific physiological outcomes of IGF stimulation is proposed and discussed. Journal of Endocrinology (2002) 175, 41–54 Introduction Insulin-like growth factors (IGFs), including IGF-I and IGF-II, are a family of polypeptide growth factors struc- turally related to proinsulin. IGF-I mediates many of the growth-promoting effects of growth hormone during post- natal life. Studies utilizing ‘knock-out’ mice have demon- strated that both IGF-I and IGF-II are essential for fetal growth (Baker et al. 1993, Liu et al. 1993). Recent genetic studies in Xenopus indicate that the IGF signaling pathway is also required for head formation during vertebrate embryogenesis (Pera et al. 2001, Richard-Parpaillon et al. 2002). The biological actions of IGFs are mediated by the IGF-I receptor (IGF-IR), a transmembrane tyrosine kinase. In mammals, a second transmembrane IGF receptor, the IGF-II/cation-independent mannose-6- phosphate receptor exists. It has higher binding affinity for IGF-II over IGF-I. This receptor has no known signal transduction function, and binding of IGF-II to this receptor has been shown to cause internalization and degradation of IGF-II (LeRoith et al. 2001). Comparative studies indicate that the mannose-6-phosphate receptors of non-mammalian species do not possess the capacity to bind IGF with high affinity. Therefore, the IGF-II- binding property of this receptor as well as any of its physiological functions with regards to IGFs might have been a later acquisition during evolution (Duan 1998). The IGFs in serum and other extracellular environments are bound to specific IGF-binding proteins (IGFBPs). IGFBPs are a family of secreted proteins that specifically bind IGF-I and IGF-II with affinities that are equal to or greater than those of the IGF receptors. Six distinct IGFBPs, designated IGFBP-1 to -6, have been isolated and characterized from a variety of vertebrate species ranging from mammals to fish (Duan et al. 1999a, Hwa et al. 1999, Baxter 2000, Clemmons 2001, Maures & Duan 2002). These IGFBPs share a common domain organization. They all have a highly cysteine-rich N-terminal domain (12 cysteine residues), a cysteine-rich C-terminal domain (six cysteine residues), and a central (L) domain with no cysteine residue except in IGFBP-4. The N- and C-domains are highly conserved among various members of this gene family in a given species. These two domains also exhibit strong homology across vertebrate species. The L-domain is highly variable. These proteins bind IGF with high affinity and act as carrier 41 Journal of Endocrinology (2002) 175, 41–54 0022–0795/02/0175–041  2002 Society for Endocrinology Printed in Great Britain Online version via http://www.endocrinology.org Downloaded from Bioscientifica.com at 11/28/2021 10:02:42AM via free access