Jain N, Zhang T, Fong S L, Lim C P, Cao X
Signal Transduction Laboratory, Institute of Molecular and Cell Biology, National University of Singapore.
Oncogene. 1998 Dec 17;17(24):3157-67. doi: 10.1038/sj.onc.1202238.
STAT proteins are activated by phosphorylation at specific tyrosine residue at the carboxy-terminus which is required for dimer-formation, nuclear translocation, DNA binding and transcriptional activity in cells treated with cytokines and growth factors. Recent studies have indicated that STATs are also phosphorylated by MAPK, or extracellular signal-regulated kinase (ERK) on serine. We investigated the role of ERK on the regulation of STAT activity. Here, we report that ERK2 activated by its upstream kinase, MEK1, represses Stat3 transcriptional activity induced by Src or Jak-2. To unravel the mechanism of repression, we further showed that Stat3 DNA binding activity and its tyrosine phosphorylation are also inhibited under the same conditions. ERK2 phosphorylates Stat3 on three serine-containing peptides and decreases its tyrosine phosphorylation induced by EGF treatment. We also detected an association of ERK2 and Stat3 in vivo which is modulated positively by activation of ERK2, but negatively by Jak2. We propose that MAP kinase cascade may negatively regulate Stat3 activities by decreasing its tyrosine phosphorylation and also possibly by association.
信号转导和转录激活因子（STAT）蛋白通过羧基末端特定酪氨酸残基的磷酸化而被激活，这对于细胞在用细胞因子和生长因子处理时的二聚体形成、核转位、DNA结合和转录活性是必需的。最近的研究表明，STAT蛋白也会被丝裂原活化蛋白激酶（MAPK）或细胞外信号调节激酶（ERK）在丝氨酸位点磷酸化。我们研究了ERK在调节STAT活性中的作用。在此，我们报告，由其上游激酶MEK1激活的ERK2会抑制由Src或Jak-2诱导的Stat3转录活性。为了阐明抑制机制，我们进一步表明，在相同条件下，Stat3的DNA结合活性及其酪氨酸磷酸化也受到抑制。ERK2使Stat3在三个含丝氨酸的肽段上磷酸化，并降低其由表皮生长因子（EGF）处理诱导的酪氨酸磷酸化。我们还在体内检测到ERK2与Stat3的关联，这种关联被ERK2的激活正向调节，但被Jak2负向调节。我们提出，MAP激酶级联可能通过降低Stat3的酪氨酸磷酸化以及可能通过关联来负向调节Stat3的活性。
