Regulation of Stat3 activation by MEK kinase 1.
Stat3 is a latent transcription factor activated by various cytokines and growth factors. Phosphorylation on Tyr-705 is a prerequisite for dimer formation, nuclear translocation, binding to its cognate DNA sequences, and regulation of the target gene transcription. Ser-727 phosphorylation of Stat3 plays an additional role in the regulation of transcription. MEK kinase 1 (MEKK1) is a mitogen-activated protein kinase (MAPK) kinase kinase (MAPKKK) that activates the c-Jun NH(2)-terminal kinase signaling pathway. Here we report that MEKK1 is involved in the regulation of Stat3 activation by growth factors. Kinase-inactive MEKK1 inhibits Stat3 phosphorylation on tyrosine and serine, and its transcriptional activity stimulated by epidermal growth factor and platelet-derived growth factor in different cell types. In contrast, active MEKK1 induces Stat3 tyrosine and serine phosphorylation leading to a functionally active Stat3 capable of binding DNA and enhancing transcription. Ser-727 is phosphorylated by MEKK1 in vitro, whereas Tyr-705 phosphorylation induced by MEKK1 involves Src and Janus kinases in vivo. These data demonstrate for the first time a novel role of MEKK1 to modulate tyrosine kinases that results in the activation of specific members of STAT family.
Institute of Molecular and Cell Biology, Singapore 117609, Singapore.
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D000209:Acute-Phase Proteins / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D006801:Humans; D048728:MAP Kinase Kinase Kinase 1; D008954:Models, Biological; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection
D000209:Acute-Phase Proteins; D004268:DNA-Binding Proteins; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D004815:Epidermal Growth Factor; D017346:Protein Serine-Threonine Kinases; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human