title: Serine phosphorylation and negative regulation of Stat3 by JNK.
abstract: STATs are activated by various cytokines and growth factors via tyrosine phosphorylation, which leads to sequential dimer formation, nuclear translocation, binding to specific DNA sequences, and regulation of gene expression. Recently, serine phosphorylation of Stat3 on Ser-727 by ERK has been identified in response to epidermal growth factor (EGF). Here, we report that Ser-727 phosphorylation of Stat3 can also be induced by JNK and activated either by stress or by its upstream kinase and that various stress treatments induce serine phosphorylation of Stat3 in the absence of tyrosine phosphorylation. Inhibitors of ERK and p38 did not inhibit UV-induced Stat3 serine phosphorylation, suggesting that neither of them is involved. We further demonstrate that JNK1, activated by its upstream kinase MKK7, negatively regulated the tyrosine phosphorylation and DNA binding and transcriptional activities of Stat3 stimulated by EGF. Correspondingly, pretreatment of cells with UV reduced the EGF-stimulated tyrosine phosphorylation and phosphotyrosine-dependent activities of Stat3. The inhibitory effect was not observed for Stat1. Our results suggest that Stat3 is a target of JNK that may regulate Stat3 activity via both Ser-727 phosphorylation-dependent and -independent mechanisms.
authors.affiliation: Signal Transduction Laboratory, Institute of Molecular and Cell Biology, National University of Singapore, Singapore 117609.
authors.forename: C P
authors.initials: CP
authors.lastname: Lim
authors.forename: X
authors.initials: X
authors.lastname: Cao
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D019556:COS Cells; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000502:physiology* / Q000528:radiation effects; D007093:Imidazoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D017354:Point Mutation; D011725:Pyridines / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D050796:STAT3 Transcription Factor; D012694:Serine; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015534:Trans-Activators / Q000378:metabolism*; D014162:Transfection; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D011725:Pyridines; D011993:Recombinant Fusion Proteins; D050796:STAT3 Transcription Factor; D015534:Trans-Activators; D010768:Phosphoserine; D012694:Serine; D004815:Epidermal Growth Factor; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one