Mowen K, David M
Department of Biology, University of California at San Diego, La Jolla, California 92093, USA.
Mol Cell Biol. 2000 Oct;20(19):7273-81. doi: 10.1128/MCB.20.19.7273-7281.2000.
Signal transducer and activator of transcription 1 (STAT1) mediates gene expression in response to cytokines and growth factors. Activation of STAT1 is achieved through its tyrosine phosphorylation, a process that involves Jak tyrosine kinases. Here we show that STAT1, although phosphorylated on Y701, is unable to localize in the nucleus in the absence of Jak1 or Jak1 kinase activity. In contrast, the nuclear accumulation of STAT1 in Tyk2-deficient cells remains intact. Nuclear presence of tyrosine-phosphorylated STAT1 could be restored in Jak1-deficient cells by leptomycin B, an inhibitor of nuclear export. Amino acids 197 to 205 of STAT1 were found to encode a leucine-rich nuclear export signal (NES). An L-->A mutation within the NES restored nuclear retention of STAT1 in Jak1-deficient cells. Impaired binding of the transcriptional coactivator CBP to tyrosine-phosphorylated STAT1 derived from Jak1-deficient cells offers a model for the intermolecular regulation of the nuclear export sequence.
信号转导及转录激活因子1（STAT1）介导细胞因子和生长因子应答中的基因表达。STAT1的激活通过其酪氨酸磷酸化来实现，这一过程涉及Jak酪氨酸激酶。在此我们表明，STAT1尽管在Y701位点发生了磷酸化，但在缺乏Jak1或Jak1激酶活性的情况下无法定位于细胞核。相比之下，STAT1在Tyk2缺陷细胞中的核积累保持完整。通过核输出抑制剂雷帕霉素B，可以使Jak1缺陷细胞中酪氨酸磷酸化的STAT1恢复核内存在。发现STAT1的197至205位氨基酸编码一个富含亮氨酸的核输出信号（NES）。NES内的L→A突变恢复了Jak1缺陷细胞中STAT1的核保留。转录共激活因子CBP与源自Jak1缺陷细胞的酪氨酸磷酸化STAT1的结合受损，为核输出序列的分子间调控提供了一个模型。
