Modulatory role of the anti-apoptotic protein kinase CK2 in the sub-cellular localization of Fas associated death domain protein (FADD)

Abstract

The Fas associated death domain protein (FADD) is the key adaptor molecule of the apoptotic signal triggered by death receptors of the TNF-R1 superfamily. Besides its crucial role in the apoptotic machinery, FADD has proved to be important in many biological processes like tumorigenesis, embryonic development or cell cycle progression. In a process to decipher the regulatory mechanisms underlying FADD regulation, we identified the anti-apoptotic kinase, CK2, as a new partner and regulator of FADD sub-cellular localization. The blockade of CK2 activity induced FADD re-localization within the cell. Moreover, cytoplasmic FADD was increased when CK2β was knocked down. In vitro kinase and pull down assays confirmed that FADD could be phosphorylated by the CK2 holoenzyme. We found that phosphorylation is weak with CK2α alone and optimal in the presence of stoichiometric amounts of CK2α catalytic and CK2β regulatory subunit, showing that FADD phosphorylation is undertaken by the CK2 holoenzyme in a CK2β-driven fashion. We found that CK2 can phosphorylate FADD on the serine 200 and that this phosphorylation is important for nuclear localization of FADD. Altogether, our results show for the first time that multifaceted kinase, CK2, phosphorylates FADD and is involved in its sub-cellular localization. This work uncovered an important role of CK2 in stable FADD nuclear localization.

The size-speed-force relationship governs migratory cell response to tumorigenic factors

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Beclin-1-mediated Autophagy Protects Against Cadmium-activated Apoptosis via the Fas/FasL Pathway in Primary Rat Proximal Tubular Cell Culture

“…FADD has been described as a crucial element in many important biological processes including embryonic development, proliferation, cell cycle, innate immunity, tumor development, and autophagy 27, 40–42 . Many studies have focused on the role of FADD in autophagy 43, 44 . Thorburn et al .…”

CIGB-300, an anti-CK2 peptide, inhibits angiogenesis, tumor cell invasion and metastasis in lung cancer models

“…The overexpression of CK2 confers tumor cells the ability to evade apoptosis through the activation of pro-survival signaling pathways [2]. Recently, Vilmont et al [3] reported a novel CK2-dependent apoptosis evasion mechanism by modulation of Fas associated death domain protein (FADD) localization. When FADD is phosphorylated by CK, this protein remains in the nucleus, impairing the association with other pro-apoptotic components in the cytosol and, consequently, apoptosis.…”