For IGFs to reach the tissues from the bloodstream, the circulating complexes are believed to partly dissociate, possibly enhanced by limited proteolysis of IGFBP-3.
The IGF-1/IGFBP-3 ratio has sometimes been used as an index of IGF bioavailability in the human circulation, but this ignores IGF-1 binding to other IGFBPs (so the ratio is affected by the concentrations of all six IGFBPs), and the fact that IGF-2, which is three times more abundant than IGF-1 in the bloodstream of adults, occupies the majority of binding sites on circulating IGFBP-3.
Within tissues, IGFBP-3 can bind IGF-1 and IGF-2 released by many cell types, and block their access to the IGF-1 receptor (IGF1R), which is activated by both IGFs.
IGFBP-3 shares with the other five high-affinity IGFBPs and a 3-domain structure:[10] The linker domain is the site of most post-translational modification, which include glycosylation, phosphorylation, and limited proteolysis.
Many proteases are known to cleave IGFBP-3 at single linker-domain sites, and in the circulation of pregnant women, IGFBP-3 is entirely proteolyzed, yet still capable of carrying normal amounts of IGF-1 and IGF-2.
Binding capacity appears to be retained after proteolysis because of a cooperative interaction between the two proteolyzed fragments, that together maintain an active IGF-binding site.
[12] Rat liver IGFBP-3 mRNA is found in nonparenchymal cells including sinusoidal endothelium, but not in hepatocytes.
The most widely studied IGFBP3 polymorphism, at nucleotide-202 in the promoter region, is significantly associated with circulating IGFBP-3 levels, although the mechanism is unclear.
For example, in esophageal epithelial cells, responsiveness to IGF-1 stimulation is suppressed by secreted IGFBP-3 and restored when IGFBP-3 is downregulated by epidermal growth factor.
[34] IGF1R-independent growth inhibition by IGFBP-3 may involve the induction of pro-apoptotic proteins such as Bax and Bad[35] and may be mediated by ceramides (pro-apoptotic lipids),[36] or potentiate ceramide action[37] IGFBP-3 interaction with nuclear hormone receptors may also lead to inhibition of cell proliferation.
[36][39] Based on cell growth experiments, animal cancer models, and epidemiological studies, it appears that IGFBP-3 functions as a low-penetrance tumor suppressor gene.
For example, high plasma IGFBP-3 levels were associated with a reduced prospective risk of colorectal cancer in women.
[48] A large systematic review concluded that circulating IGFBP-3 levels showed a modest association with increased risk for a number of cancers, but the results vary among sites.