Comparative endocrinology of the insulin-like growth factor-binding protein

Abstract

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.

Dual mode of cortisol action on GH/IGF-I/IGF binding proteins in the tilapia, Oreochromis mossambicus

“…The two larger IGFBPs (40 and 42 kDa) showed inverse correlations with plasma cortisol and glucose, suggesting their anabolic characteristics. Kelley et al (2002) also reported a marked reduction in .40-kDa IGFBP in the golden-mantled ground squirrel, Spermophilus lateralis, during hibernation, a catabolic situation. Consistent with these results, 40-to 50-kDa IGFBPs showed a positive correlation with growth activity in terms of cartilage 35 S-proteoglycan synthesis in several teleost species (Kelley et al 2002), further supporting the contention that the 40-kDa and 42-kDa IGFBPs in the tilapia are candidates for mammalian IGFBP-3.…”

“…The other two IGFBPs (24 and 28 kDa) are likely to be comparable to mammalian IGFBP-4 judging from the molecular sizes, which has non-glycosylated (24 kDa) and glycosylated (28 kDa) forms. As far as biological functions are concerned, IGFBP-1 has inhibitory effects on IGF action by sequestering IGFs in the extracellular environment (Collett-Solberg & Cohen 2000, Kelley et al 2002). Similarly, IGFBP-2 and -4 have inhibitory effects on IGF action locally.…”

“…Six distinct forms of IGFBPs, referred to as IGFBP-1 through IGFBP-6 with equal or greater affinities for IGFs than IGF receptors, have been identified in humans and other mammalian species. These IGF/IGFBP complexes prolong the residence time of IGFs in the circulation and control the action of IGFs by regulating availability of free IGFs to the target tissue receptors, a mechanism that is thought to prevent potential hypoglycemia (Collett-Solberg & Cohen 2000, Kelley et al 2002. In teleosts, at least three different forms of IGFBP, a 40-50 kDa and two smaller IGFBPs (24-31 kDa), have been constantly observed in the circulation (Park et al 2000, Shimizu et al 2000, Bauchat et al 2001, Kelley et al 2001.…”

Insulin-like growth factor binding protein-7 induces activation and transdifferentiation of hepatic stellate cells in vitro

“…In certain pathological conditions, IGFBP-1 through -6 all may inhibit the growth of cells. IGFBP-1 and -3 may destroy glucose equilibrium in humans; IGFBP-1, -5, and -6 may also disturb this capability [24] , whereas IGFBP-7 (rP1) could modulate proliferation, cohesion of cells, the regeneration of blood vessel and biosynthesis of prostacyclin [25] . IGFBP-8 (rP2) is considered to be a key cytokine in the fibrogenesis of tissues and organs [13] .…”

Salmon serum 22 kDa insulin-like growth factor-binding protein (IGFBP) is IGFBP-1

“…The 40-50 kDa form may be fish IGFBP-3, since it has a molecular mass similar to mammalian IGFBP-3 and is increased by growth hormone injection (Siharath et al 1995, Shimizu et al 2003. The two smaller fish IGFBPs at 20-25 and 28-30 kDa are candidates for IGFBP-1 because both forms are increased in catabolic states such as fasting, stress and diabetes (Kelley et al 2001(Kelley et al , 2002. Hormonal control of these lower-molecular-mass forms in fish are similar to those of human IGFBP-1.…”