title: 14-3-3ζ interacts with stat3 and regulates its constitutive activation in multiple myeloma cells.
abstract: The 14-3-3 proteins are a family of regulatory signaling molecules that interact with other proteins in a phosphorylation-dependent manner and function as adapter or scaffold proteins in signal transduction pathways. One family member, 14-3-3ζ, is believed to function in cell signaling, cycle control, and apoptotic death. A systematic proteomic analysis done in our laboratory has identified signal transducers and activators of transcription 3 (Stat3) as a novel 14-3-3ζ interacting protein. Following our initial finding, in this study, we provide evidence that 14-3-3ζ interacts physically with Stat3. We further demonstrate that phosphorylation of Stat3 at Ser727 is vital for 14-3-3ζ interaction and mutation of Ser727 to Alanine abolished 14-3-3ζ/Stat3 association. Inhibition of 14-3-3ζ protein expression in U266 cells inhibited Stat3 Ser727 phosphorylation and nuclear translocation, and decreased both Stat3 DNA binding and transcriptional activity. Moreover, 14-3-3ζ is involved in the regulation of protein kinase C (PKC) activity and 14-3-3ζ binding to Stat3 protects Ser727 dephosphorylation from protein phosphatase 2A (PP2A). Taken together, our findings support the model that multiple signaling events impinge on Stat3 and that 14-3-3ζ serves as an essential coordinator for different pathways to regulate Stat3 activation and function in MM cells.
authors.affiliation: Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Zhang
authors.forename: Fangjin
authors.initials: F
authors.lastname: Chen
authors.forename: Wenliang
authors.initials: W
authors.lastname: Li
authors.forename: Qian
authors.initials: Q
authors.lastname: Xiong
authors.forename: Mingkun
authors.initials: M
authors.lastname: Yang
authors.forename: Peng
authors.initials: P
authors.lastname: Zheng
authors.forename: Chongyang
authors.initials: C
authors.lastname: Li
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Pei
authors.forename: Feng
authors.initials: F
authors.lastname: Ge
mesh_terms: D048948:14-3-3 Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D021581:Active Transport, Cell Nucleus; D000465:Algorithms; D000595:Amino Acid Sequence; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009154:Mutation; D010766:Phosphorylation; D011485:Protein Binding; D011493:Protein Kinase C / Q000378:metabolism; D017434:Protein Structure, Tertiary; D050796:STAT3 Transcription Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013816:Thermodynamics; D015533:Transcriptional Activation
chemical_list: D048948:14-3-3 Proteins; D050796:STAT3 Transcription Factor; D012694:Serine; D011493:Protein Kinase C