Mechanism of Inhibition of Growth Hormone Receptor Signaling by Suppressor of Cytokine Signaling Proteins

• DOI: 10.1210/mend.13.11.0368
• Publication Date: 2014-01-08T17:29:56Z
• Authors: Johnny A. Hansen; Karen Lindberg; Douglas J. Hilton; Jens H. Nielsen; Nils Billestrup
• Keywords: Transcription, Genetic; Molecular Sequence Data; Somatotropin; CHO Cells; src Homology Domains; 03 medical and health sciences; Genetic; Cricetinae; Proto-Oncogene Proteins; Receptors; STAT5 Transcription Factor; Animals; Amino Acid Sequence; Phosphorylation; 0303 health sciences; Proteins; Receptors, Somatotropin; Janus Kinase 2; Protein-Tyrosine Kinases; Milk Proteins; DNA-Binding Proteins; Growth Hormone; Trans-Activators; Carrier Proteins; Transcription; Signal Transduction

In this study we have investigated the role of suppressor of cytokine signaling (SOCS) proteins in GH receptor-mediated signaling. GH-induced transcription was inhibited by SOCS-1 and SOCS-3, while SOCS-2 and cytokine inducible SH2-containing protein (CIS) had no effect By using chimeric SOCS proteins it was found that the ability of SOCS proteins to inhibit GH-mediated transcription was located in the amino-terminal 40-80 amino acids. In SOCS-3, 46 amino acids C-terminal to the SH2 domain were required for the inhibitory activity, while a truncated SOCS-1 having only 2 amino acids C-terminal to the SH2 domain was able to inhibit GH-mediated transcription. Both SOCS-1 and SOCS-3 were able to inhibit GH-induced STAT5 (signal transducer and activator of transcription) activation. SOCS-1 inhibited the tyrosine kinase activity of Janus kinase 2 (JAK2) directly, while SOCS-3 only inhibited JAK2 when stimulated by the GH receptor. All four SOCS proteins were able to bind to a tyrosine-phosphorylated glutathione-S-transferase-GH receptor fusion protein, and SOCS-3 required the same 46 C-terminal amino acids for GH receptor binding as it did for inhibition of GH-mediated transcription and STAT5 activation. These data suggest that SOCS-1 and -3 can suppress GH-induced transcriptional activity, presumably by inhibiting the kinase activity of JAK2 either directly in the case of SOCS-1 or via binding to the tyrosine-phosphorylated GH receptor in the case of SOCS-3.