KELLEY, Kevin M.: Comparative Biology of the Insulin-like Growth Factor-binding Protein (IGFBP)

Early in the chordate line, the IGF axis diverged from the insulin system and specialized in cell growth activation and allied anabolic functions. Supporting this divergence was an early presence of soluble IGFBPs which bind IGF peptides with higher affinities than that of the insulin receptor. While blocking IGF actions through the insulin receptor is arguably their fundamental role, IGFBPs developed through the vertebrate line into centrally positioned integrators of the entire growth endocrine axis, in large part by virtue of the fact that they bind IGF peptide at affinities comparable to that of the cellular type-1 IGF receptor and thereby compete in IGF ligand-receptor interactions. In addition, IGFBPs evolved a number of other specific properties, making these proteins multifunctional growth regulators. In mammals, six different IGFBPs exhibit an array of properties, including specific cell membrane association (e.g., to particular extracellular matrix components), direct IGF-independent actions mediated by IGFBP ‘receptors’, and even intracellular actions on the transcriptional apparatus. In addition, the IGFBPs are themselves regulated by a host of “outside” factors, including other hormones, metabolic factors, and proteases that clip them into lower-affinity IGFBP forms. Among non-mammalian vertebrates, there is increasing information indicating that many aspects of the system are well-conserved, while there are interesting alternative adaptations in certain groups. This discussion will take a comparative approach, including consideration of mammalian, reptilian, amphibian, and piscine representatives, in an attempt to bring a more biological perspective to understanding the “multifunctional IGFBP”. (Support in part by NSF grants IBN-9600783 & -0115975).