Emerging early in chordate evolution, the IGF-regulatory axis diverged from an insulin-like predecessor into a vertebrate regulatory system specializing in cell growth activation and allied anabolic functions. Essential to the divergence of the IGF and insulin systems was an early presence of soluble IGF-binding proteins (IGFBPs), which bind IGF peptides at much higher affinity than that of the insulin receptor but at comparable affinities to that of the IGF receptor. IGFBPs have no homology with IGF receptors. Instead, IGFBPs are a derived group of proteins within a superfamily of cysteine-rich growth factors, whose members are found throughout the animal taxa. While blocking IGF actions through the insulin receptor is a fundamental role, IGFBPs evolved within the vertebrate line into centralized, 'integrators' of the endocrine growth-regulatory apparatus. IGFBPs have substantial influences on the distribution and bioavailability of IGF peptides in the cellular and physiological environments, but they have a variety of other properties. The six principal mammalian IGFBPs exhibit an array of specialized properties that appear to be derived from a complex evolutionary history (including cell membrane association, interaction with proteins that post-translationally modify them, direct IGF-independent effects on cells, and others) and they are regulated by a diversity of 'outside' factors (e.g. other hormones, metabolic status, stress). Thus, IGFBPs are multifunctional integrators having diverse physiological 'agendas'. Much less is known about IGFBPs and their properties in the other vertebrate taxa. Increasingly, however, it is being recognized that they play equally important endocrine roles, in both conserved and non-conserved ways, when compared with those currently defined in mammals. This review highlights selected 'comparative aspects' in current IGFBP research, in an attempt to view this essential group of endocrine regulators from a wider, biological perspective.

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