Biological Evidence That SOCS-2 Can Act Either as an Enhancer or Suppressor of Growth Hormone Signaling

• DOI: 10.1074/jbc.c200450200
• Publication Date: 2002-10-18T22:02:01Z
• Authors: Christopher J. Gr...; Donald Metcalf; Anne L. Thaus; Jason E. Corbin; Rachel Uren; Phillip O. Morgan; Louis J. Fabri; Jian-Guo Zhang; Helene M. Martin; Tracy A. Willson; Nils Billestrup; Nicos A. Nicola; Manuel Baca; Warren S. Alexander; Douglas J. Hilton
• Keywords: 0301 basic medicine; Somatotropin; Proteins; Mice, Transgenic; Suppressor of Cytokine Signaling Proteins; Receptors, Somatotropin; Transgenic; Recombinant Proteins; DNA-Binding Proteins; Repressor Proteins; Mice; 03 medical and health sciences; Growth Hormone; Receptors; Trans-Activators; Animals; Protein Binding; Signal Transduction

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.