Phosphorylation of TTP by MK2 inhibits mRNA decay by 14‐3‐3‐dependent and ‐independent mechanisms

The modulation of mRNA turnover plays a key role in the rapid and dynamic regulation of gene expression in cells. Cell signaling pathways influence mRNA decay, but it is poorly understood how these signals are communicated to the mRNA decay machinery. The RNA‐binding protein Tristetraprolin (TTP) triggers the rapid decay of a class of transiently expressed mRNAs by recruiting enzymes involved in mRNA turnover to these transcripts. Phosphorylation of TTP by the p38 MAPK‐activated kinase MK2 impairs its activity by preventing deadenylase recruitment and leads to the association of the adaptor protein 14‐3‐3. It is unclear, however, whether 14‐3‐3 binding is required to inhibit TTP function. To better understand the role of 14‐3‐3 in the inhibition of TTP we examined the effect of phosphorylation‐independent 14‐3‐3 association on the ability of TTP to recruit mRNA decay enzymes and to stimulate mRNA decay in cells. We found that 14‐3‐3 association was sufficient to prevent deadenylase recruitment and slowed deadenylation of target transcripts. However, this defect was not as severe as when TTP was phosphorylated. These results support a role for 14‐3‐3 in preventing deadenylase recruitment to TTP and suggest that phosphorylation of TTP by MK2 may impair its function via 14‐3‐3‐dependent and ‐independent mechanisms. Supported by American Cancer Society grants RSG‐GMC 111896 to JL and PF‐06‐156‐01‐GMC to SLC.