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

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Stanniocalcin-2 Inhibits Mammalian Growth by Proteolytic Inhibition of the Insulin-like Growth Factor Axis. / Jepsen, Malene R; Kloverpris, Soren; Mikkelsen, Jakob Hauge; Pedersen, Josefine Hvidkjær; Fuchtbauer, Ernst-Martin; Laursen, Lisbeth Schmidt; Oxvig, Claus.

I: Journal of Biological Chemistry, Bind 290, 06.02.2015, s. 3430-3439.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

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@article{f96a64c2e7154b1b802e6e512b4a4f12,
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 has remained 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 Cys120 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.",
author = "Jepsen, {Malene R} and Soren Kloverpris and Mikkelsen, {Jakob Hauge} and Pedersen, {Josefine Hvidkj{\ae}r} and Ernst-Martin Fuchtbauer and Laursen, {Lisbeth Schmidt} and Claus Oxvig",
note = "Copyright {\textcopyright} 2014, The American Society for Biochemistry and Molecular Biology.",
year = "2015",
month = feb,
day = "6",
doi = "10.1074/jbc.M114.611665",
language = "English",
volume = "290",
pages = "3430--3439",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology, Inc.",

}

RIS

TY - JOUR

T1 - Stanniocalcin-2 Inhibits Mammalian Growth by Proteolytic Inhibition of the Insulin-like Growth Factor Axis

AU - Jepsen, Malene R

AU - Kloverpris, Soren

AU - Mikkelsen, Jakob Hauge

AU - Pedersen, Josefine Hvidkjær

AU - Fuchtbauer, Ernst-Martin

AU - Laursen, Lisbeth Schmidt

AU - Oxvig, Claus

N1 - Copyright © 2014, The American Society for Biochemistry and Molecular Biology.

PY - 2015/2/6

Y1 - 2015/2/6

N2 - 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 has remained 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 Cys120 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.

AB - 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 has remained 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 Cys120 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.

U2 - 10.1074/jbc.M114.611665

DO - 10.1074/jbc.M114.611665

M3 - Journal article

C2 - 25533459

VL - 290

SP - 3430

EP - 3439

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

ER -