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Biochemistry - Hematology - Molecular Biology - Oncology

14-3-3? Interacts with Stat3 and Regulates Its Constitutive Activation in Multiple Myeloma Cells
Published: Wednesday, January 18, 2012
Author: Jia Zhang et al.

by Jia Zhang, Fangjin Chen, Wenliang Li, Qian Xiong, Mingkun Yang, Peng Zheng, Chongyang Li, Jianfeng Pei, Feng Ge

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, 14-3-3?, 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 14-3-3? interacting protein. Following our initial finding, in this study, we provide evidence that 14-3-3? interacts physically with Stat3. We further demonstrate that phosphorylation of Stat3 at Ser727 is vital for 14-3-3? interaction and mutation of Ser727 to Alanine abolished 14-3-3?/Stat3 association. Inhibition of 14-3-3? protein expression in U266 cells inhibited Stat3 Ser727 phosphorylation and nuclear translocation, and decreased both Stat3 DNA binding and transcriptional activity. Moreover, 14-3-3? is involved in the regulation of protein kinase C (PKC) activity and 14-3-3? 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 14-3-3? serves as an essential coordinator for different pathways to regulate Stat3 activation and function in MM cells.