Mechanism of inhibition of growth hormone receptor signaling by suppressor of cytokine signaling proteins
Research output: Contribution to journal › Journal article › Research › peer-review
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.
Original language | English |
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Journal | Molecular endocrinology (Baltimore, Md.) |
Volume | 13 |
Issue number | 11 |
Pages (from-to) | 1832-43 |
Number of pages | 12 |
ISSN | 0888-8809 |
Publication status | Published - Nov 1999 |
- Amino Acid Sequence, Animals, CHO Cells, Carrier Proteins, Cricetinae, DNA-Binding Proteins, Growth Hormone, Janus Kinase 2, Milk Proteins, Molecular Sequence Data, Phosphorylation, Protein-Tyrosine Kinases, Proteins, Proto-Oncogene Proteins, Receptors, Somatotropin, STAT5 Transcription Factor, Signal Transduction, Trans-Activators, Transcription, Genetic, src Homology Domains
Research areas
ID: 47972582