Biological evidence that SOCS-2 can act either as an enhancer or suppressor of growth hormone signaling

TY - JOUR

T1 - Biological evidence that SOCS-2 can act either as an enhancer or suppressor of growth hormone signaling

AU - Greenhalgh, Christopher J

AU - Metcalf, Donald

AU - Thaus, Anne L

AU - Corbin, Jason E

AU - Uren, Rachel

AU - Morgan, Phillip O

AU - Fabri, Louis J

AU - Zhang, Jian-Guo

AU - Martin, Helene M

AU - Willson, Tracy A

AU - Billestrup, Nils

AU - Nicola, Nicos A

AU - Baca, Manuel

AU - Alexander, Warren S

AU - Hilton, Douglas J

PY - 2002/10/25

Y1 - 2002/10/25

N2 - Suppressor of cytokine signaling (SOCS)-2 is a member of a family of intracellular proteins implicated in the negative regulation of cytokine signaling. The generation of SOCS-2-deficient mice, which grow to one and a half times the size of their wild-type littermates, suggests that SOCS-2 may attenuate growth hormone (GH) signaling. In vitro studies indicate that, while SOCS-2 can inhibit GH action at low concentrations, at higher concentrations it may potentiate signaling. To determine whether a similar enhancement of signaling is observed in vivo or alternatively whether increased SOCS-2 levels repress growth in vivo, we generated and analyzed transgenic mice that overexpress SOCS-2 from a human ubiquitin C promoter. These mice are not growth-deficient and are, in fact, significantly larger than wild-type mice. The overexpressed SOCS-2 was found to bind to endogenous GH receptors in a number of mouse organs, while phosphopeptide binding studies with recombinant SOCS-2 defined phosphorylated tyrosine 595 on the GH receptor as the site of interaction. Together, the data implicate SOCS-2 as having dual effects on GH signaling in vivo.

AB - Suppressor of cytokine signaling (SOCS)-2 is a member of a family of intracellular proteins implicated in the negative regulation of cytokine signaling. The generation of SOCS-2-deficient mice, which grow to one and a half times the size of their wild-type littermates, suggests that SOCS-2 may attenuate growth hormone (GH) signaling. In vitro studies indicate that, while SOCS-2 can inhibit GH action at low concentrations, at higher concentrations it may potentiate signaling. To determine whether a similar enhancement of signaling is observed in vivo or alternatively whether increased SOCS-2 levels repress growth in vivo, we generated and analyzed transgenic mice that overexpress SOCS-2 from a human ubiquitin C promoter. These mice are not growth-deficient and are, in fact, significantly larger than wild-type mice. The overexpressed SOCS-2 was found to bind to endogenous GH receptors in a number of mouse organs, while phosphopeptide binding studies with recombinant SOCS-2 defined phosphorylated tyrosine 595 on the GH receptor as the site of interaction. Together, the data implicate SOCS-2 as having dual effects on GH signaling in vivo.

KW - Animals

KW - DNA-Binding Proteins

KW - Growth Hormone

KW - Mice

KW - Mice, Transgenic

KW - Protein Binding

KW - Proteins

KW - Receptors, Somatotropin

KW - Recombinant Proteins

KW - Repressor Proteins

KW - Signal Transduction

KW - Suppressor of Cytokine Signaling Proteins

KW - Trans-Activators

U2 - 10.1074/jbc.C200450200

DO - 10.1074/jbc.C200450200

M3 - Journal article

C2 - 12208853

SN - 0021-9258

VL - 277

SP - 40181

EP - 40184

JO - The Journal of Biological Chemistry

JF - The Journal of Biological Chemistry

IS - 43

ER -