Cytokine-inducible SH2 protein up-regulation is associated with desensitization of GH signaling in GHRH-transgenic mice.
The effects of continuous high GH levels on GH signal transduction through the GH receptor (GHR)/Janus kinase 2 (JAK2)/signal transducer and activator of transcription 5 (STAT5) pathway as well as the desensitization of this pathway by suppressors of cytokine signaling (SOCS) were studied in transgenic mice overexpressing GHRH. In transgenic mice, hepatic GHR levels were 4.5-fold higher than in normal animals, whereas the protein contents of JAK2, STAT5a, and STAT5b did not vary. This same pattern was found for basal tyrosine phosphorylation (PY-): PY-GHR was 4.5-fold increased in transgenic mice, whereas there were no differences in PY-JAK2 and PY-STATs between normal and transgenic animals. After GH administration, tyrosine phosphorylation of GHR, JAK2, and STAT5s increased 3- to 7-fold in normal mice, but no significant changes were found in transgenic mice, indicating a decreased GH sensitivity in these animals. The content of cytokine-inducible SH2 protein, a member of the SOCS family, was 18-fold higher in GHRH-transgenic than in normal mice. Conversely, SOCS-3, present in normal mice, was hardly seen in transgenic animals, whereas SOCS-2 levels did not vary. These findings suggest that cytokine-inducible SH2 protein, significantly induced by continuously elevated GH levels, may be the SOCS protein responsible for the GH signaling desensitization in transgenic animals.
González
L
L
Instituto de Química y Fisicoquímica Biológicas, Facultad de Farmacia y Bioquímica, Junín 956, 1113 Buenos Aires, Argentina.
Miquet
J G
JG
Sotelo
A I
AI
Bartke
A
A
Turyn
D
D
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D016207:Cytokines / Q000502:physiology*; D005260:Female; D013006:Growth Hormone / Q000502:physiology*; D013007:Growth Hormone-Releasing Hormone / Q000235:genetics*; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis*; D015151:Immunoblotting; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D011233:Precipitin Tests; D011986:Receptors, Somatotropin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D050826:Suppressor of Cytokine Signaling Proteins; D014443:Tyrosine / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*
D016207:Cytokines; D013006:Growth Hormone; D013007:Growth Hormone-Releasing Hormone; D017874:Immediate-Early Proteins; D011986:Receptors, Somatotropin; D050826:Suppressor of Cytokine Signaling Proteins; D014443:Tyrosine