Posttranslational Regulation of Tristetraprolin Subcellular Localization and Protein Stability by p38 Mitogen-Activated Protein Kinase and Extracellular Signal-Regulated Kinase Pathways

• DOI: 10.1128/mcb.26.6.2408-2418.2006
• Publication Date: 2006-03-01T00:02:41Z
• Authors: Matthew Brook; Carmen R. Tchen; Tomas Santalucia; Joanne McIlrath; J. Simon C. Arthur; Jeremy Saklatvala; Andrew R. Clark
• Keywords: Tristetraprolin

The p38 mitogen-activated protein kinase (MAPK) signaling pathway, acting through the downstream MK2, regulates stability of many proinflammatory mRNAs that contain adenosine/uridine-rich elements (AREs). It is thought to do this by modulating expression or activity ARE-binding proteins regulate mRNA turnover. MK2 phosphorylates and mRNA-destabilizing tristetraprolin (TTP) at serines 52 178. Here we show MAPK pathway subcellular localization TTP protein. A inhibitor causes rapid dephosphorylation TTP, relocalization from cytoplasm nucleus, degradation 20S/26S proteasome. Hence, continuous required maintain phosphorylation status, cytoplasmic localization, regulation both dependent on integrity Furthermore, extracellular signal-regulated (ERK) synergizes with TTP. This effect independent kinases are known be synergistically activated ERK MAPK. We present a model for actions during distinct phases inflammatory response.