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Abstract
Ames dwarf mice that do not express growth hormone (GH) or prolactin (PRL) genes were used to study the effects of GH deficiency on the presence and the characteristics of GH-binding protein (GHBP) in serum. Chromatographic techniques were used to allow characterization of biological rather than immunological activity of GHBP. Two GH-binding fractions were found in dwarf mice serum, one with low affinity and high capacity (GHBPI) and one with high affinity, low capacity and lower molecular mass (GHBPII). Serum concentration of the high-affinity GHBP was 0·73 ± 0·03 nm with a K d of 6·3 ± 1·7 nm. Since Ames dwarf mice have no GH in the circulation, all the GHBP is free. Interestingly, the concentration of GHBP in dwarf mice was similar to the levels of free GHBP measured in normal mice from the same line. Moreover, this value (0·7 nm) closely resembles the concentration of free GHBP in the serum of transgenic mice overexpressing GH, in which peripheral GH levels are grossly elevated. These observations can be interpreted as evidence that the levels of free GHBP in mouse serum are independent of GH concentration, and that GH influences only the levels of bound GHBP in peripheral circulation.
Journal of Endocrinology (1997) 153, 319–325
Department of Physiology and Internal Medicine, School of Medicine, Southern Illinois University, Springfield, IL, USA
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Department of Physiology and Internal Medicine, School of Medicine, Southern Illinois University, Springfield, IL, USA
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Department of Physiology and Internal Medicine, School of Medicine, Southern Illinois University, Springfield, IL, USA
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Department of Physiology and Internal Medicine, School of Medicine, Southern Illinois University, Springfield, IL, USA
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Transgenic mice overexpressing GH present a marked GH signaling desensitization, reflected by low basal phosphorylation levels of the tyrosine kinase JAK2, and signal transducer and activator of transcription-5 (STAT5) and a lack of response of these proteins to a high GH dose. To evaluate the mechanisms involved in the regulation of JAK2 activity by high GH levels in vivo, the content and subcellular distribution of SH2-Bβ were studied in GH-overexpressing transgenic mice. SH2-B is a member of a conserved family of adapter proteins characterized by the presence of a C-terminal SH2 domain, a central pleckstrin homology (PH) domain, and an N-terminal proline rich region. The isoform SH2-Bβ modulates JAK2 activity by binding to the phosphorylated enzyme, further increasing its activity. However, it may also interact with non-phosphorylated inactive JAK2 via lower affinity binding sites, preventing abnormal activation of the kinase. SH2-Bβ may also function as an adapter protein, acting as a GH signaling mediator.
We now report that, in an animal model of GH excess in which JAK2 is not phosphorylated, although it is increased in the membrane-fraction, both the level of SH2-Bβ, and especially its association to membranes, are augmented (67% and 13-fold vs normal mice values respectively), suggesting SH2-Bβ could modulate JAK2 activity in vivo.
Geriatrics Research, Departments of Internal Medicine and Physiology, School of Medicine, Southern Illinois University, Springfield, Illinois 62794, USA
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Geriatrics Research, Departments of Internal Medicine and Physiology, School of Medicine, Southern Illinois University, Springfield, Illinois 62794, USA
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Geriatrics Research, Departments of Internal Medicine and Physiology, School of Medicine, Southern Illinois University, Springfield, Illinois 62794, USA
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Geriatrics Research, Departments of Internal Medicine and Physiology, School of Medicine, Southern Illinois University, Springfield, Illinois 62794, USA
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Geriatrics Research, Departments of Internal Medicine and Physiology, School of Medicine, Southern Illinois University, Springfield, Illinois 62794, USA
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Geriatrics Research, Departments of Internal Medicine and Physiology, School of Medicine, Southern Illinois University, Springfield, Illinois 62794, USA
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To investigate the influence of chronic GH deficiency on GH signaling in vivo, we have analyzed Janus kinase (JAK) 2/signal transducers and activators of transcription (STAT) 5 GH signaling pathway, and its regulation by the suppressors of the cytokine signaling SOCS and by the JAK2-interacting protein SH2-Bβ, in liver of Ames dwarf (Prop1 df /Prop1 df ) mice, which are severely deficient in GH, prolactin and TSH, and of their normal littermates. Prop1df/Prop1df mice displayed unaltered GH receptor, JAK2 and STAT5a/b protein levels. No significant differences in the basal tyrosine-phosphorylation levels of JAK2 and STAT5a/b were found between both groups of animals. After in vivo administration of a high GH dose (5 μg/g body weight (BW)), the tyrosine-phosphorylation levels of JAK2 and STAT5a/b increased significantly, reaching similar values in normal and dwarf mice. However, after stimulation with lower GH doses (50 and 15 ng/g BW) the tyrosine-phosphorylation level of STAT5a/b was higher in dwarf mice. The protein content of CIS, a SOCS protein that inhibits STAT5 signaling, was approximately 80% lower in dwarf mice liver, while SOCS-2 and SOCS-3 levels were unaltered. The content of SH2-Bβ, a modulator of JAK2 activity, was reduced by approximately 30% in dwarf mice, although this was associated with normal JAK2 response to a high GH dose. In summary, Prop1df/Prop1df mice display increased hepatic sensitivity to GH, an effect that could be related to the lower abundance of CIS in this tissue. Furthermore, the lower CIS content found in this model of GH deficiency suggests that CIS protein levels are regulated by GH in vivo.
