Regulation of STAT1 nuclear export by Jak1

Signal transducer and activator of transcription 1 (STAT1) mediates gene ex pression in response to cytokines and growth factors. Activation of STAT1 i s achieved through its tyrosine phosphorylation, a process that involves Ja k tyrosine kinases. Here we show that STAT1, although phosphorylated on Y70 1, is unable to localize in the nucleus in the absence of Jak1 or Jak1 kina se activity. In contrast, the nuclear accumulation of STAT1 in Tyk2-deficie nt 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 leuc ine-rich nuclear export signal (NES). An L-->A mutation within the NES rest ored nuclear retention of STAT1 in Jak1-deficient cells. Impaired binding o f the transcriptional coactivator CBP to tyrosine-phosphorylated STAT1 deri ved from Jak1-deficient cells offers a model for the intermolecular regulat ion of the nuclear export sequence.