IGFBP-3 (Insulin Growth Factor Binding Protein–3)

IGFBP-3 is the most abundant IGF-binding protein, accounting for as much as 75% or more of the circulating IGF-binding capacity in healthy subjects. IGFBP-3 shares functional properties with IGFBP-5 in that both peptides are able to form high molecular weight ternary complexes of ~150 kilo Dalton with ALS and either IGF-I or –II. However, IGFBP-5 circulates in much lower concentrations than IGFBP-3, and in healthy subjects the ternary complexes carry as much as 90% of IGFBP-3 but only about 50% of IGFBP-5. Originally, the IGFBPs were thought to serve as IGF-carrier proteins, stabilizing plasma IGF levels and controlling the egress of IGF from the circulation to the extra-vascular compartment. Furthermore, it was assumed that IGFBP-complexed IGF was biologically more or less inactive, being deprived its ability to interact with the IGF-I receptor. However, it soon became apparent that in some experimental settings the IGFBPs stimulated rather than inhibited IGF-I mediated actions, and accordingly, the IGFBPs are now often referred to as modulators of IGF-I bioactivity. In addition, the majority of the IGFBPs, and in particular IGFBP-3, exerts IGF-I and
IGF-I receptor independent effects, possible involving interactions with specific receptors located at the cell surface and intracellular. For example, IGFBP-3 is nowadays considered to serve as an anti-cancer molecule, apparently protecting against several common cancers, and effects of IGFBP-3 on insulin signaling in cultured adipocytes have also been suggested. The turnover of the ternary complexes is very slow, and the plasma concentration of IGFBP-3 remains stable throughout the day, being unaffected by short-term nutritional changes. Thus, the level of IGFBP-3 may be determined by one single measurement. GH is the primary regulator of IGFBP-3 as well as of IGF-I and ALS and therefore, all three peptides increase during the pubertal growth spurt, where after levels gradually decline with increasing age. In children, IGFBP-3 has been shown to correlate with the 24-h integrated GH secretion and in particular in children IGFBP-3 may be helpful in the diagnosis of GH deficiency.