Regulation of Stat3 activation by MEK kinase 1

Stat3 is a latent transcription factor activated by various cytokines and g rowth factors. Phosphorylation on Tyr-705 is a prerequisite for dimer forma tion, nuclear translocation, binding to its cognate DNA sequences, and regu lation of the target gene transcription. Ser-727 phosphorylation of Stat3 p lays an additional role in the regulation of transcription. MEK kinase 1 (M EKK1) is a mitogen-activated protein kinase (MAPK) kinase kinase (MAPKKK) t hat activates the c-Jun NH2-terminal kinase signaling pathway. Here we repo rt that MEKK1 is involved in the regulation of Stat3 activation by growth f actors. Kinase-inactive MEKK1 inhibits Stat3 phosphorylation on tyrosine an d serine, and its transcriptional activity stimulated by epidermal growth f actor and platelet-derived growth factor in different cell types. In contra st, active MEKK1 induces Stat3 tyrosine and serine phosphorylation leading to a functionally active Stat3 capable of binding DNA and enhancing transcr iption. Ser-727 is phosphorylated by MEKK1 in vitro, whereas Tyr-705 phosph orylation induced by MEKK1 involves Src and Janus kinases in vivo. These da ta demonstrate for the first time a novel role of MEKK1 to modulate tyrosin e kinases that results in the activation of specific members of STAT family .