Evolutionary dynamics and functional refinement of IGF bioavailability in the vertebrate phylum : focus on IGFBPs.

In eutherians, Insulin-like Growth Factor-I (IGF-I) and IGF-II exert insulin-like activity by interacting with type-I receptor. IGF bioavailability is finely regulated by six IGF-Binding Proteins (IGFBPs), IGFBP-1 to -6, which bind IGF-I and -II with high affinity but not insulin. Moreover, the Pregnancy-Asssociated Plasma Protein-A protease in able to specifically degrade IGFB-2, -4, -5. In the present work, we were interested in the evolution of this regulation of bioavailability in vertebrates, in particular in the question of the different nodes of appearance of IGFs, IGFBPs and PAPP-A in the tree of life. We confirmed that insulin-like/IGF peptides and their receptors appeared in non-vertebrate species, whereas IGFBPs first appeared in the vertebrate ancestor. More precisely, the first IGFBP that appeared was IGFBP-5 in amphioxus, whereas IGFBP-1, -2 and -3 apperaed in lamprey, IGFBP-4 in jawed fishes, and IGFBP-6 in teleost with a loss in birds. We also showed that the pregnancy-associated plasma protein A (PAPP-A) and PAPP-A2 metzincin proteases, which degrade several IGFBPs, might have appeared in non-vertebrates and that their two inhibitors, proMBP and STC, probably appeared before both proteases. Interestingly, the cleavage sites of IGFBP were restricted to some species : for IGFBP-2 and -5, it was present in mammals, birds and reptiles, but not in amphibians and fishes; for IGFBP-4 in Mammals only. Another important point is that another insulin-like peptide-binding protein found in the fruit fly, IMPL2, has probably disappeared in vertebrates.