title: STAT3 regulates Nemo-like kinase by mediating its interaction with IL-6-stimulated TGFbeta-activated kinase 1 for STAT3 Ser-727 phosphorylation.
abstract: Signal transducer and activator of transcription 3 (STAT3) is activated by the IL-6 family of cytokines and growth factors. STAT3 requires phosphorylation on Ser-727, in addition to tyrosine phosphorylation on Tyr-705, to be transcriptionally active. In IL-6 signaling, the two major pathways that derive from the YXXQ and the YSTV motifs of gp130 cause Ser-727 phosphorylation. Here, we show that TGF-beta-activated kinase 1 (TAK1) interacts with STAT3, that the TAK1-Nemo-like kinase (NLK) pathway is efficiently activated by IL-6 through the YXXQ motif, and that this is the YXXQ-mediated H7-sensitive pathway that leads to STAT3 Ser-727 phosphorylation. Because NLK was recently shown to interact with STAT3, we explored the role of STAT3 in activating this pathway. Depletion of STAT3 diminished the IL-6-induced NLK activation by >80% without inhibiting IL-6-induced TAK1 activation or its nuclear entry. We found that STAT3 functioned as a scaffold for TAK1 and NLK in vivo through a region in its carboxyl terminus. Furthermore, the expression of the STAT3(534-770) region in the nuclei of STAT3-knockdown cells enhanced the IL-6-induced NLK activation in a dose-dependent manner but not the TGFbeta-induced NLK activation. TGFbeta did not cause STAT3 Ser-727 phosphorylation, even when the carboxyl region of STAT3 was expressed in the nuclei. Together, these results indicate that STAT3 enhances the efficiency of its own Ser-727 phosphorylation by acting as a scaffold for the TAK1-NLK kinases, specifically in the YXXQ motif-derived pathway.
authors.affiliation: Department of Immunology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.
authors.forename: Hirotada
authors.initials: H
authors.lastname: Kojima
authors.forename: Takanori
authors.initials: T
authors.lastname: Sasaki
authors.forename: Tohru
authors.initials: T
authors.lastname: Ishitani
authors.forename: Shun-ichiro
authors.initials: S
authors.lastname: Iemura
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.forename: Shuhei
authors.initials: S
authors.lastname: Kaneko
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kunimoto
authors.forename: Tohru
authors.initials: T
authors.lastname: Natsume
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Koichi
authors.initials: K
authors.lastname: Nakajima
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004247:DNA / Q000235:genetics; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D051550:I-kappa B Kinase; D015850:Interleukin-6 / Q000494:pharmacology; D020930:MAP Kinase Kinase Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D046912:Multiprotein Complexes; D010766:Phosphorylation; D034622:RNA Interference; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D050796:STAT3 Transcription Factor; D012694:Serine / Q000737:chemistry; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D002352:Carrier Proteins; D004247:DNA; D004268:DNA-Binding Proteins; D051550:I-kappa B Kinase; D015850:Interleukin-6; D020930:MAP Kinase Kinase Kinases; D046912:Multiprotein Complexes; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; D012694:Serine; D015534:Trans-Activators; D000099151:MAP Kinase Kinase Kinase 7; C491731:IKBKG protein, human; C494086:STAT3 protein, human