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Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET), Facultad de Farmacia y Bioquímica, Junín 956 (1113) Buenos Aires, Argentina
¹ Department of Physiology and Internal Medicine, School of Medicine, Southern Illinois University, Springfield, IL, USA

(Requests for offprints should be addressed to D Turyn; Email: dturyn{at}qb.ffyb.uba.ar)

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-Bß 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-Bß 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-Bß 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-Bß, and especially its association to membranes, are augmented (67% and 13-fold vs normal mice values respectively), suggesting SH2-Bß could modulate JAK2 activity in vivo.

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				J. G Miquet, L. Gonzalez, M. N Matos, C. E Hansen, A. Louis, A. Bartke, D. Turyn, and A. I Sotelo Transgenic mice overexpressing GH exhibit hepatic upregulation of GH-signaling mediators involved in cell proliferation J. Endocrinol., August 1, 2008; 198(2): 317 - 330. [Abstract] [Full Text] [PDF]

				J G Miquet, A I Sotelo, F P Dominici, M S Bonkowski, A Bartke, and D Turyn Increased sensitivity to GH in liver of Ames dwarf (Prop1df/Prop1df) mice related to diminished CIS abundance J. Endocrinol., December 1, 2005; 187(3): 387 - 397. [Abstract] [Full Text] [PDF]

				J. G. Miquet, A. I. Sotelo, A. Bartke, and D. Turyn Desensitization of the JAK2/STAT5 GH signaling pathway associated with increased CIS protein content in liver of pregnant mice Am J Physiol Endocrinol Metab, October 1, 2005; 289(4): E600 - E607. [Abstract] [Full Text] [PDF]