title: Mechanism of inhibition of growth hormone receptor signaling by suppressor of cytokine signaling proteins.
abstract: 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.
authors.affiliation: Hagedorn Research Institute, Gentofte, Denmark.
authors.forename: J A
authors.initials: JA
authors.lastname: Hansen
authors.forename: K
authors.initials: K
authors.lastname: Lindberg
authors.forename: D J
authors.initials: DJ
authors.lastname: Hilton
authors.forename: J H
authors.initials: JH
authors.lastname: Nielsen
authors.forename: N
authors.initials: N
authors.lastname: Billestrup
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D013006:Growth Hormone / Q000378:metabolism / Q000494:pharmacology; D053614:Janus Kinase 2; D008894:Milk Proteins; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D011986:Receptors, Somatotropin / Q000378:metabolism*; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D018909:src Homology Domains
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D008894:Milk Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D011986:Receptors, Somatotropin; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D013006:Growth Hormone; D011505:Protein-Tyrosine Kinases; D053614:Janus Kinase 2