Repression of Stat3 activity by activation of mitogen-activated protein kinase (MAPK)

STAT proteins are activated by phosphorylation at specific tyrosine residue at the carboxy-terminus which is required for dimer-formation, nuclear tra nslocation, 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 activ ity. Here, we report that ERK2 activated by its upstream kinase, MEK1, repr esses Stat3 transcriptional activity induced by Src or Jak-2, To unravel th e mechanism of repression, we further showed that Stat3 DNA binding activit y and its tyrosine phosphorylation are also inhibited under the same condit ions. ERK2 phosphorylates Stat3 on three serine-containing peptides and dec reases its tyrosine phosphorylation induced by EGF treatment. We also detec ted an association of ERK2 and Stall in vivo which is modulated positively by activation of ERK2, but negatively by Jak2, We propose that MAP kinase c ascade may negatively regulate Stat3 activities by decreasing its tyrosine phosphorylation and also possibly by association.