Pregnancy-associated plasma proteins and Stanniocalcin-2 - Novel players controlling IGF-I physiology

Growth Horm IGF Res. 2020 Aug-Oct:53-54:101330. doi: 10.1016/j.ghir.2020.101330. Epub 2020 Jul 4.


IGF-I was originally discovered as a GH-dependent growth factor stimulating longitudinal growth. Currently, however, it has become evident that the biological activities of IGF-I extend well beyond those of a simple growth factor and impact such processes as insulin sensitivity, aging, cancer and cardiovascular disease. The vast majority of IGF-I is tightly bound to IGF-binding proteins (IGFBPs), which renders IGF-I unable to stimulate the IGF-I receptor (IGF-IR) in vivo. This binding means that liberation of IGF-I from the IGFBPs is an important step controlling IGF-I action. In this context, IGFBP-cleaving enzymes appear to play a key role. Enzymatic cleavage of the IGFBPs markedly lowers their ligand affinity, and as a consequence, IGF-I becomes liberated and hence available for stimulation of the IGF-IR. Two of the best-characterized IGFBP-cleaving enzymes are pregnancy-associated plasma protein-A (PAPP-A) and its paralog PAPP-A2. The two enzymes (often referred to as pappalysins) regulate the liberation of IGF-I in a highly controlled manner. PAPP-A is believed to act predominantly in tissues, serving to liberate IGF-I at the cell surface in close proximity to the IGF-IR. In keeping with this notion, mice lacking PAPP-A exhibit reduced body size, despite having normal circulating IGF-I concentrations. In contrast, human findings indicate that altered PAPP-A2 activity changes circulating IGF-I concentrations, although PAPP-A2 is also present in high concentrations in tissues. Thus, PAPP-A2 appears to impact circulating, as well as tissue, IGF-I activity. The enzymatic activity of PAPP-A and PAPP-A2 was recently discovered to be regulated by the protein Stanniocalcin-2 (STC2). By binding to the enzymatic sites of PAPP-A and PAPP-A2, STC2 inhibits their activity. To date, the majority of findings demonstrating the ability of pappalysins and STC2 to regulate IGF-I action are from preclinical studies. However, clinical studies are now beginning to emerge. In this review, we will summarize our data on STC2, PAPP-A and PAPP-A2 in humans. These results indicate that pappalysins and STC2 constitute an important IGF-I activity-regulating system that warrants further investigation.

Keywords: Extravascular concentrations.; Insulin-like growth factor I; Insulin-like growth factor binding proteins.; Pregnancy associated plasma protein A and A2.; Stanniocalcin-2..

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Female
  • Glycoproteins / metabolism*
  • Humans
  • Insulin-Like Growth Factor I / physiology*
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Mice
  • Pregnancy
  • Pregnancy-Associated Plasma Protein-A / metabolism*


  • Glycoproteins
  • Intercellular Signaling Peptides and Proteins
  • STC2 protein, human
  • Stc2 protein, mouse
  • Insulin-Like Growth Factor I
  • Pregnancy-Associated Plasma Protein-A