SOCS2 negatively regulates growth hormone action in vitro and in vivo
Christopher J. Greenhalgh, … , Warren S. Alexander, Douglas J. Hilton
Christopher J. Greenhalgh, … , Warren S. Alexander, Douglas J. Hilton
Published February 1, 2005
Citation Information: J Clin Invest. 2005;115(2):397-406. https://doi.org/10.1172/JCI22710.
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Article Endocrinology

SOCS2 negatively regulates growth hormone action in vitro and in vivo

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.

Authors

Christopher J. Greenhalgh, Elizabeth Rico-Bautista, Mattias Lorentzon, Anne L. Thaus, Phillip O. Morgan, Tracy A. Willson, Panagiota Zervoudakis, Donald Metcalf, Ian Street, Nicos A. Nicola, Andrew D. Nash, Louis J. Fabri, Gunnar Norstedt, Claes Ohlsson, Amilcar Flores-Morales, Warren S. Alexander, Douglas J. Hilton

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Figure 2

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SOCS2 controls growth responses to GH. (A) Male and female SOCS2+/+Ghrhr...
SOCS2 controls growth responses to GH. (A) Male and female SOCS2+/+Ghrhrlit/lit and SOCS2–/–Ghrhrlit/lit mice were weighed daily before being injected twice daily with 10 μg rpGH or saline for 28 days from 4 weeks of age. Growth curves were constructed from 5–10 male mice or 5–7 female mice per treatment group. (B) Differences in organ weights of male and female SOCS2+/+Ghrhrlit/lit (white bars) and SOCS2–/–Ghrhrlit/lit (black bars) mice are represented as a percentage increase over the mean of saline-injected mouse organ weights. *P < 0.05 vs. saline-injected mice; #P < 0.05 vs. SOCS2+/+Ghrhrlit/lit mice. Sal gland, salivary gland. (C) Picture of 6-month-old SOCS2–/–Ghrhrlit/lit mice that have had 3 pregnancies (upper) or no pregnancies (lower).