Details

Autor(en) / Beteiligte

• Jepsen, Malene R.
• Kløverpris, Søren
• Mikkelsen, Jakob H.
• Pedersen, Josefine H.
• Füchtbauer, Ernst-Martin
• Laursen, Lisbeth S.
• Oxvig, Claus

Titel

Stanniocalcin-2 Inhibits Mammalian Growth by Proteolytic Inhibition of the Insulin-like Growth Factor Axis

Ist Teil von

• The Journal of biological chemistry, 2015-02, Vol.290 (6), p.3430-3439

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2015

Quelle

MEDLINE

Beschreibungen/Notizen

• Mammalian stanniocalcin-2 (STC2) is a secreted polypeptide widely expressed in developing and adult tissues. However, although transgenic expression in mice is known to cause severe dwarfism, and targeted deletion of STC2 causes increased postnatal growth, its precise biological role is still unknown. We found that STC2 potently inhibits the proteolytic activity of the growth-promoting metalloproteinase, pregnancy-associated plasma protein-A (PAPP-A). Proteolytic inhibition requires covalent binding of STC2 to PAPP-A and is mediated by a disulfide bond, which involves Cys-120 of STC2. Binding of STC2 prevents PAPP-A cleavage of insulin-like growth factor-binding protein (IGFBP)-4 and hence release within tissues of bioactive IGF, required for normal growth. Concordantly, we show that STC2 efficiently inhibits PAPP-A-mediated IGF receptor signaling in vitro and that transgenic mice expressing a mutated variant of STC2, STC2(C120A), which is unable to inhibit PAPP-A, grow like wild-type mice. Our work identifies STC2 as a novel proteinase inhibitor and a previously unrecognized extracellular component of the IGF system. Background: The biological function and biochemical activity of mammalian stanniocalcin-2 are unknown. Results: Stanniocalcin-2 inhibits proteolytic release of insulin-like growth factor (IGF), and its ability to cause growth retardation upon transgenic overexpression in mice depends on its proteinase inhibitory function. Conclusion: Stanniocalcin-2 is a novel component of the IGF axis. Significance: Altered stanniocalcin-2 expression may affect IGF signaling under pathological conditions.