Desensitization of growth hormone (GH) signaling in GH releasing hormone transgenic mice

GONZÁLEZ L, SOTELO AI, MIQUET JG, BARTKE A, TURYN D

Denver, Colorado, USA

Congreso; The Endocrine Society, 83rd Annual Meeting; 2001

The Endocrine Society

GH signaling is initiated by receptor (GHR) dimerization and activation of the GHR-associated tyrosine-kinase JAK2, which in turn phosphorylates cytoplasmic tirosina (PY) on GHR. These PY form docking sites for the transcriptional activators STAT5a and STAT5b, as well as for other signaling molecules. Termination includes cytokine-receptor –JAK2 kinase signal inhibitory molecules, the SOCS/CIS proteins. CIS is a STAT5-inducible negative regulator implied in the GH desensitization mechanism, that binds to phosphorylated GHR. To study the effects oh high continuous mouse GH levels on GH signal transduction in vivo, transgenic mice expressing GH-releasing hormone were used. A 3-fold increase in GHR concentration in transgenic mice liver over normal animals was found, while there was not significant difference in JAK2, STAT5a or STAT5b content. Basal GHR phosphorylation was 4.5 fold higher for transgenic mice liver over control, whereas GH injection caused a 3.5 fold increase in the GHR phosphorylation level in normal mice liver but not in transgenic animals. Basal JAK2, STAT5a and STAT5b phosphotylation was slightly increased in GHRH-mice. After GH administration, phosphorylation of these proteins increased 5, 6 and 7 folds, respectively, in normal mice liver, while no significant changes were found for transgenic mice. The content of CIS was more than 40 fold higher in transgenic mice liver extracts than in normal ones, where it was almost not detectable. In conclusion, high and continuous GH concentration cause an increase in GHR levels while not in JAK2, STAT5a and STAT5b. Basal phosphorylation of these proteins is slightly increased in transgenic animals, but it is not further increased by GH injection, as it is in normal controls, indicating a decreased sensibility to GH in these mice. The inducible protein CIS would be constutive in these transgenic mice and could be related to the inhibition of GH tyrosine phosphorylation of JAK2 and STATs, resulting in a desensitization of GH signal transduction.