SOCS2 negatively regulates growth hormone action in vitro and in vivo

Greenhalgh, CJ; Rico-Bautista, E; Lorentzon, M; Thaus, AL; Morgan, PO; Willson, TA; Zervoudakis, P; Metcalf, D; Street, I; Nicola, NA; Nash, AD; Fabri, LJ; Norstedt, G; Ohlsson, C; Flores-Morales, A; Alexander, WS; Hilton, DJ

Author(s): Greenhalgh, CJ; Rico-Bautista, E; Lorentzon, M; Thaus, AL; Morgan, PO; Willson, TA; Zervoudakis, P; Metcalf, D; Street, I; Nicola, NA; Nash, AD; Fabri, LJ; Norstedt, G; Ohlsson, C; Flores-Morales, A; Alexander, WS; Hilton, DJ;
Details: Publication Year 2005-02,Volume 115,Issue #2,Page 397-406
Journal Title: JOURNAL OF CLINICAL INVESTIGATION
Publication Type: Journal Article
Abstract: Mice deficient in SOCS2 display an excessive growth phenotype characterized by a 30-50% increase in mature body size. Here we show that the SOCS2-/- phenotype is dependent upon the presence of endogenous growth hormone (GH) and that treatment with exogenous GH induced excessive growth in mice lacking both endogenous GH and SOCS2. This was reflected in terms of overall body weight, body and bone lengths, and the weight of internal organs and tissues. A heightened response to GH was also measured by examining GH-responsive genes expressed in the liver after exogenous GH administration. To further understand the link between SOCS2 and the GH-signaling cascade, we investigated the nature of these interactions using structure/function and biochemical interaction studies. Analysis of the 3 structural motifs of the SOCS2 molecule revealed that each plays a crucial role in SOCS2 function, with the conserved SOCS-box motif being essential for all inhibitory function. SOCS2 was found to bind 2 phosphorylated tyrosines on the GH receptor, and mutational analysis of these amino acids showed that both were essential for SOCS2 function. Together, the data provide clear evidence that SOCS2 is a negative regulator of GH signaling.
Publisher: AMER SOC CLINICAL INVESTIGATION INC
Keywords: MICE LACKING SUPPRESSOR; SIGNAL-TRANSDUCTION; GENE-EXPRESSION; CYTOKINE SIGNALING-1; CELL DIFFERENTIATION; BOX MOTIF; RECEPTOR; PROTEINS; INHIBITION; INSULIN
Publisher's Version: https://doi.org/10.1172/JCI200522710
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2005-02-01 12:00:00