SOCS2 negatively regulates growth hormone action in vitro and in vivo.

• 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.

Nyckelord

Amino Acid Motifs

genetics

Animals

Body Weight

drug effects

genetics

physiology

DNA-Binding Proteins

genetics

metabolism

Gene Expression Regulation

genetics

physiology

Growth Hormone

administration & dosage

genetics

physiology

Insulin-Like Growth Factor I

physiology

Liver

metabolism

pathology

Mice

Mice

Knockout

Phosphorylation

Protein Binding

genetics

physiology

Receptors

Somatotropin

genetics

metabolism

Repressor Proteins

genetics

metabolism

Signal Transduction

drug effects

genetics

physiology

Suppressor of Cytokine Signaling Proteins

Trans-Activators

genetics

metabolism

Tyrosine

metabolism

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