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

Abstract

Abstract: In eutherians, insulin-like growth factor-1 (IGF-1) and IGF-2 exert insulin-like activity by interacting with type 1 receptor. IGF bioavailability is finely regulated by six IGF-binding proteins (IGFBPs), IGFBP-1 to IGFBP-6, which bind IGF-1 and IGF-2 with high affinity but not insulin. Moreover, the pregnancy-associated plasma protein-A (PAPP-A) protease is able to specifically degrade IGFBP-2, IGFBP-4, and IGFBP-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, IGFBP-2, and IGFBP-3 appeared in lamprey, IGFBP-4 appeared in jawed fishes, and IGFBP-6 appeared in teleost, with the latter being lost in birds. We also showed that the 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 IGFBP-5, they were present in mammals, birds, and reptiles, but not in amphibians and fishes, and for IGFBP-4, they were present 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.

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