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.
Highlights
Antimitotic drugs comprise several classes of molecules that kill cancer cells via different cell death pathways [1]
Fas associated with death domain protein (FADD) interacts with Aurora-A kinase (Aur-A) It is known that FADD expression increases in cancer cells and tissues treated with anticancer agents [23,24,25, 28], suggesting that FADD might participate in the action of these agents
We report that FADD is double phosphorylated by the sequential action of Aur-A and Polo-like kinase 1 (Plk1) upon taxol treatment and show that dP-FADD activates both caspase-dependent and caspaseindependent pathways, leading to cell death
Summary
Antimitotic drugs comprise several classes of molecules that kill cancer cells via different cell death pathways [1]. Antimitotic drugs such as taxol bind to microtubules and cause kinetic suppression of microtubule dynamics [2]. The consequent cell-cycle arrest at mitotic phases by taxol leads to cell death. The mechanism by which taxol induces cell death may differ depending on cell type and taxol concentration, both caspase-independent and caspase-dependent pathways are involved [3,4,5,6,7]. The molecular mechanism leading from cell-cycle arrest to cell death is not well understood. Polo-like kinase 1 (Plk1) and Aurora-A kinase (Aur-A) are the most extensively studied mitotic kinases [8, 9]. Plk has 2 functional domains: a kinase domain and polo-box domain
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