Mechanism of inhibition of growth hormone receptor signaling by suppressor of cytokine signaling proteins

Mol Endocrinol. 1999 Nov;13(11):1832-43. doi: 10.1210/mend.13.11.0368.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • CHO Cells / metabolism
  • Carrier Proteins / metabolism*
  • Cricetinae
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Growth Hormone / metabolism
  • Growth Hormone / pharmacology
  • Janus Kinase 2
  • Milk Proteins*
  • Molecular Sequence Data
  • Phosphorylation
  • Protein-Tyrosine Kinases / metabolism
  • Proteins / metabolism*
  • Proto-Oncogene Proteins*
  • Receptors, Somatotropin / metabolism*
  • STAT5 Transcription Factor
  • Signal Transduction
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transcription, Genetic
  • src Homology Domains

Substances

  • Carrier Proteins
  • DNA-Binding Proteins
  • Milk Proteins
  • Proteins
  • Proto-Oncogene Proteins
  • Receptors, Somatotropin
  • STAT5 Transcription Factor
  • Trans-Activators
  • Growth Hormone
  • Protein-Tyrosine Kinases
  • Janus Kinase 2