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.
Greenhalgh
Christopher J
CJ
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
Metcalf
Donald
D
Thaus
Anne L
AL
Corbin
Jason E
JE
Uren
Rachel
R
Morgan
Phillip O
PO
Fabri
Louis J
LJ
Zhang
Jian-Guo
JG
Martin
Helene M
HM
Willson
Tracy A
TA
Billestrup
Nils
N
Nicola
Nicos A
NA
Baca
Manuel
M
Alexander
Warren S
WS
Hilton
Douglas J
DJ
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