Miquet J G, Sotelo A I, Bartke A, Turyn D
Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET), Facultad de Farmacia y Bioquímica, Junín 956 (1113) Buenos Aires, Argentina.
J Endocrinol. 2005 May;185(2):301-6. doi: 10.1677/joe.1.05943.
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-Bbeta 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-Bbeta 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-Bbeta 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-Bbeta, and especially its association to membranes, are augmented (67% and 13-fold vs normal mice values respectively), suggesting SH2-Bbeta could modulate JAK2 activity in vivo.
过度表达生长激素（GH）的转基因小鼠呈现出明显的GH信号脱敏现象，这表现为酪氨酸激酶JAK2以及信号转导和转录激活因子5（STAT5）的基础磷酸化水平较低，并且这些蛋白质对高剂量GH缺乏反应。为了评估体内高GH水平对JAK2活性调节的相关机制，我们研究了过度表达GH的转基因小鼠中SH2-Bβ的含量和亚细胞分布。SH2-B是衔接蛋白保守家族的成员，其特征在于存在C末端SH2结构域、中央普列克底物蛋白同源（PH）结构域和N末端富含脯氨酸区域。异构体SH2-Bβ通过与磷酸化的酶结合来调节JAK2活性，进一步增加其活性。然而，它也可能通过较低亲和力的结合位点与未磷酸化的无活性JAK2相互作用，防止激酶的异常激活。SH2-Bβ还可能作为衔接蛋白发挥作用，充当GH信号传导介质。我们现在报告，在JAK2未磷酸化的GH过量动物模型中（尽管其在膜组分中增加），SH2-Bβ的水平，尤其是其与膜的结合，均增加（分别比正常小鼠的值高67%和13倍），这表明SH2-Bβ可能在体内调节JAK2活性。
