Biological evidence that SOCS-2 can act either as an enhancer or suppressor of growth hormone signaling.
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.
Walter and Eliza Hall Institute of Medical Research and the Cooperative Research for Cellular Growth Factors, PO Royal Melbourne Hospital, VIC 3050, Australia. greenhalgh@wehi.edu.au
Christopher J
CJ
Greenhalgh
Donald
D
Metcalf
Anne L
AL
Thaus
Jason E
JE
Corbin
Rachel
R
Uren
Phillip O
PO
Morgan
Louis J
LJ
Fabri
Jian-Guo
JG
Zhang
Helene M
HM
Martin
Tracy A
TA
Willson
Nils
N
Billestrup
Nicos A
NA
Nicola
Manuel
M
Baca
Warren S
WS
Alexander
Douglas J
DJ
Hilton
D000818:Animals; D004268:DNA-Binding Proteins; D013006:Growth Hormone / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D011485:Protein Binding; D011506:Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011986:Receptors, Somatotropin / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins; D015398:Signal Transduction / Q000502:physiology*; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators
D004268:DNA-Binding Proteins; D011506:Proteins; D011986:Receptors, Somatotropin; D011994:Recombinant Proteins; D012097:Repressor Proteins; C491409:Socs2 protein, mouse; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D013006:Growth Hormone