title: Stanniocalcin-2 inhibits mammalian growth by proteolytic inhibition of the insulin-like growth factor axis.
abstract: 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.
authors.affiliation: From the Department of Molecular Biology and Genetics, Aarhus University, DK-8000 Aarhus, Denmark.
authors.forename: Malene R
authors.initials: MR
authors.lastname: Jepsen
authors.affiliation: From the Department of Molecular Biology and Genetics, Aarhus University, DK-8000 Aarhus, Denmark.
authors.forename: Søren
authors.initials: S
authors.lastname: Kløverpris
authors.affiliation: From the Department of Molecular Biology and Genetics, Aarhus University, DK-8000 Aarhus, Denmark.
authors.forename: Jakob H
authors.initials: JH
authors.lastname: Mikkelsen
authors.affiliation: From the Department of Molecular Biology and Genetics, Aarhus University, DK-8000 Aarhus, Denmark.
authors.forename: Josefine H
authors.initials: JH
authors.lastname: Pedersen
authors.affiliation: From the Department of Molecular Biology and Genetics, Aarhus University, DK-8000 Aarhus, Denmark.
authors.forename: Ernst-Martin
authors.initials: EM
authors.lastname: Füchtbauer
authors.affiliation: From the Department of Molecular Biology and Genetics, Aarhus University, DK-8000 Aarhus, Denmark.
authors.forename: Lisbeth S
authors.initials: LS
authors.lastname: Laursen
authors.affiliation: From the Department of Molecular Biology and Genetics, Aarhus University, DK-8000 Aarhus, Denmark co@mbg.au.dk.
authors.forename: Claus
authors.initials: C
authors.lastname: Oxvig
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D003545:Cysteine / Q000737:chemistry / Q000235:genetics; D005260:Female; D006023:Glycoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006128:Growth / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D018974:Insulin-Like Growth Factor Binding Protein 4 / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D011266:Pregnancy-Associated Plasma Protein-A / Q000378:metabolism*; D011485:Protein Binding; D059748:Proteolysis; D017526:Receptor, IGF Type 1 / Q000378:metabolism
chemical_list: D006023:Glycoproteins; D018974:Insulin-Like Growth Factor Binding Protein 4; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; C485438:Stc2 protein, mouse; D017526:Receptor, IGF Type 1; D011266:Pregnancy-Associated Plasma Protein-A; D003545:Cysteine
keywords: Insulin-like Growth Factor (IGF); Metalloprotease; Protease Inhibitor; Protein Complex; Transgenic Mice