Dynamic trafficking of STAT5 depends on an unconventional nuclear localization signal
Dynamic trafficking of STAT5 depends on an unconventional nuclear localization signal
复制标题
DOI：
10.1242/jcs.123042
复制
发表时间：
2013-08-01
影响因子：
4
通讯作者：
Reich, Nancy C.
中科院分区：
文献类型：
--
作者：
Shin, Ha Youn;Reich, Nancy C.
信号转导子和转录激活子 5 (STAT5) 对于造血、肝脏代谢和乳腺发育等生理过程至关重要。然而，STAT5 的异常持续活性与人类白血病和实体瘤的形成存在因果关系。作为一种受调控的转录因子，STAT5 的精确细胞定位至关重要。传统的核定位信号由短段的碱性氨基酸组成。在这项研究中，我们提供的证据表明 STAT5 核输入依赖于在广泛的卷曲螺旋结构域内发挥作用的非常规核定位信号。体外结合和体内功能测定均表明，STAT5 核输入是由 importin-α 3/β 1 系统介导的，独立于酪氨酸磷酸化引起的 STAT5 激活。卷曲螺旋结构域的完整性对于 STAT5 在催乳素刺激后转录诱导 β-酪蛋白基因及其与糖皮质激素受体协同作用的能力至关重要。糖皮质激素受体响应催乳素在细胞核中积聚，这种向核输入依赖于 STAT5 向核输入。 STAT5 不断地进出细胞核，活细胞成像表明 STAT5 核输出是由染色体区域维护 1 (Crm1) 依赖性和 Crm1 独立途径介导的。在 STAT5 N 末端发现了 Crm1 依赖性核输出信号。这些发现深入了解了调节STAT5核运输以及与糖皮质激素受体合作的基本机制，并为STAT5功能在疾病中的临床干预提供了基础。
Signal transducer and activator of transcription 5 (STAT5) is crucial for physiological processes that include hematopoiesis, liver metabolism and mammary gland development. However, aberrant continual activity of STAT5 has been causally linked to human leukemias and solid tumor formation. As a regulated transcription factor, precise cellular localization of STAT5 is essential. Conventional nuclear localization signals consist of short stretches of basic amino acids. In this study, we provide evidence that STAT5 nuclear import is dependent on an unconventional nuclear localization signal that functions within the conformation of an extensive coiled-coil domain. Both in vitro binding and in vivo functional assays reveal that STAT5 nuclear import is mediated by the importin-alpha 3/beta 1 system independently of STAT5 activation by tyrosine phosphorylation. The integrity of the coiled-coil domain is essential for STAT5 transcriptional induction of the beta-casein gene following prolactin stimulation as well as its ability to synergize with the glucocorticoid receptor. The glucocorticoid receptor accumulates in the nucleus in response to prolactin and this nuclear import is dependent on STAT5 nuclear import. STAT5 continually shuttles in and out of the nucleus and live cell imaging demonstrates that STAT5 nuclear export is mediated by both chromosome region maintenance 1 (Crm1)-dependent and Crm1-independent pathways. A Crm1-dependent nuclear export signal was identified within the STAT5 N-terminus. These findings provide insight into the fundamental mechanisms that regulate STAT5 nuclear trafficking and cooperation with the glucocorticoid receptor and provide a basis for clinical intervention of STAT5 function in disease.