The role of RelA (p65) threonine 505 phosphorylation in the regulation of cell growth, survival, and migration.

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Msaki A, Sanchez AM, Koh LF, Barre B, Rocha S, Perkins ND, Johnson RF

The role of RelA (p65) threonine 505 phosphorylation in the regulation of cell growth, survival, and migration.

Mol Biol Cell. 2011 Sep;22(17):3032-40. doi: 10.1091/mbc.E11-04-0280. Epub 2011 Jul 7.

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21737676 [ View in PubMed

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Abstract

The NF-kappaB family of transcription factors is a well-established regulator of the immune and inflammatory responses and also plays a key role in other cellular processes, including cell death, proliferation, and migration. Conserved residues in the trans-activation domain of RelA, which can be posttranslationally modified, regulate divergent NF-kappaB functions in response to different cellular stimuli. Using rela(-/-) mouse embryonic fibroblasts reconstituted with RelA, we find that mutation of the threonine 505 (T505) phospho site to alanine has wide-ranging effects on NF-kappaB function. These include previously described effects on chemotherapeutic drug-induced apoptosis, as well as new roles for this modification in autophagy, cell proliferation, and migration. This last effect was associated with alterations in the actin cytoskeleton and expression of cellular migration-associated genes such as WAVE3 and alpha-actinin 4. We also define a new component of cisplatin-induced, RelA T505-dependent apoptosis, involving induction of NOXA gene expression, an effect explained at least in part through induction of the p53 homologue, p73. Therefore, in contrast to other RelA phosphorylation events, which positively regulate NF-kappaB function, we identified RelA T505 phosphorylation as a negative regulator of its ability to induce diverse cellular processes such as apoptosis, autophagy, proliferation, and migration.