title: Cooperative phosphorylation of FADD by Aur-A and Plk1 in response to taxol triggers both apoptotic and necrotic cell death.
abstract: Administration of the antimitotic chemotherapeutic taxol is known to cause accumulation of the mitotic kinase Aurora-A (Aur-A). Here, we report that Aur-A phosphorylates S203 of the Fas associated with death domain protein (FADD) in response to taxol treatment. In addition, polo-like kinase 1 (Plk1) failed to phosphorylate the Aur-A-unphosphorylatable FADD substitution mutant S203A, indicating that phosphorylation of S203 by Aur-A serves to prime FADD for Plk1-mediated phosphorylation at S194. The double-phosphorylation-mimicking mutant form of FADD, FADD-S194D/S203D (FADD-DD), recruited caspase-8, activating the caspase-dependent cell death pathway. FADD-DD also dissociated the cell death protein RIP1 from FADD, resulting in activation of RIP1 and triggering of caspase-independent cell death. Consistent with its death-promoting potential, FADD-DD showed robust tumor suppressor activity. However, single-phosphorylation-mimicking mutant forms of FADD, FADD-S194D/S203A (FADD-DA) and FADD-S194A/S203D (FADD-AD), were incapable of carrying out such functions, indicating that double phosphorylation of FADD is critical for the execution of cell death and tumor suppression. Collectively, our data show the existence of cooperative actions between Aur-A and Plk1 mitotic kinases in response to taxol, providing a molecular explanation for the action mechanism of taxol.
authors: College of Biological Sciences and Biotechnology, Chungnam National University, Daejeon, Korea.
authors: Moon-Sun
authors: MS
authors: Jang
authors: Su-Jin
authors: SJ
authors: Lee
authors: Nam Sook
authors: NS
authors: Kang
authors: Eunhee
authors: E
authors: Kim
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D064127:Aurora Kinases; D053181:Caspase 8 / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D009154:Mutation; D009336:Necrosis; D028861:Nuclear Pore Complex Proteins / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism; D000097869:Polo-Like Kinase 1
chemical_list: D064127:Aurora Kinases; D053181:Caspase 8; D018797:Cell Cycle Proteins; D053200:Fas-Associated Death Domain Protein; D028861:Nuclear Pore Complex Proteins; D017239:Paclitaxel; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D016601:RNA-Binding Proteins; D019014:fas Receptor; D000097869:Polo-Like Kinase 1; C119724:AGFG1 protein, human; C505533:FADD protein, human