Increased SH2-Bbeta content and membrane association in transgenic mice overexpressing GH

MIQUET JG, SOTELO AI, BARTKE A, TURYN D

JOURNAL OF ENDOCRINOLOGY

Society for Endocrinology

Año: 2005 vol. 185 p. 301 - 306

0022-0795

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-Bb 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-Bb modulates JAK2 activity by binding to the phosphorylated enzyme, further increasing its activity. However, it may also interact with nonphosphorylated inactive JAK2 via lower affinity binding sites, preventing abnormal activation of the kinase. SH2-Bb 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-Bb, and especially its association to membranes, are augmented (67% and 13-fold vs normal mice values respectively), suggesting SH2-Bb could modulate JAK2 activity in vivo. Journal of Endocrinology (2005) 185, 301–306