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PMID: 16508015 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Posttranslational regulation of tristetraprolin subcellular localization and protein stability by p38 mitogen-activated protein kinase and extracellular signal-regulated kinase pathways.

Molecular and cellular biology ·Vol. 26 ·No. 6 ·2006-03-00 ·Pages 2408-18

Brook M, Tchen CR, Santalucia T, McIlrath J, Arthur JS, Saklatvala J, Clark AR

Abstract

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

MeSH Terms
Animals Cell Nucleus/metabolism Cells, Cultured Cytoplasm/metabolism Enzyme Inhibitors/pharmacology Extracellular Signal-Regulated MAP Kinases/metabolism Humans Lipopolysaccharides/pharmacology Mice Phosphoprotein Phosphatases/metabolism Phosphorylation Proteasome Endopeptidase Complex/metabolism Protein Processing, Post-Translational Serine/metabolism Signal Transduction Tristetraprolin/drug effects,genetics,metabolism p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors,genetics,metabolism
Chemicals
Enzyme Inhibitors Lipopolysaccharides Tristetraprolin Zfp36 protein, mouse Serine Extracellular Signal-Regulated MAP Kinases p38 Mitogen-Activated Protein Kinases Phosphoprotein Phosphatases Proteasome Endopeptidase Complex
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Brook Matthew
Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College London, 1 Aspenlea Rd., Hammersmith, London W6 8LH, United Kingdom.
Tchen Carmen R
Santalucia Tomas
McIlrath Joanne
Arthur J Simon C
Saklatvala Jeremy
Clark Andrew R
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.26.6.2408-2418.2006
Published
2006-03-00
Pages
2408-18
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC1430283
Subset
IM
Grants
Medical Research Council · G8623776 · United Kingdom
Medical Research Council · MC_U127081014 · United Kingdom
External Links
PubMed source DOI: 10.1128/MCB.26.6.2408-2418.2006 PMC Full Text View journal details
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