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A more recent version of this article appeared on June 1, 2003
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Submitted on August 27, 2002
Revised on December 17, 2002
Accepted on January 30, 2003
1 Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037
2 Department of Pathophysiology, The First Military Medical University, Guangzhou, China
* Corresponding author. E-mail address: jhan{at}scripps.edu.
The p38 mitogen activated protein kinase (MAPK) pathway plays an important role in cellular responses to inflammatory stimuli and environmental stress. p38 regulated/activated protein kinase [PRAK, also known as mitogen activated protein kinase activated protein kinase 5 (MAPKAPK5)] functions downstream of p38
and p38
in mediating the signaling of the p38 pathway. Immunostaining revealed that endogenous PRAK was predominantly localized in the cytoplasm. Interestingly, ectopically expressed PRAK was localized in the nucleus and can be redistributed by co-expression of p38 or p38 to the locations of p38 and p38. Mutations in the docking groove on p38/p38? or the p38-docking site in PRAK, disrupted the PRAK-p38 interaction and impaired the ability of p38?and?p38 to redistribute ectopically expressed PRAK, indicating that the location of PRAK could be controlled by its docking interaction with p38 and p38. Although the majority of PRAK molecules were detected in the cytoplasm, PRAK is consistently shuttling between the cytoplasm and the nucleus. A sequence analysis of PRAK shows that PRAK contains both a putative nuclear export sequence (NES) and a nuclear localization sequence (NLS). The shuttling of PRAK requires NES and NLS motifs in PRAK and can be regulated through cellular activation induced by stress stimuli. The nuclear content of PRAK was reduced after stimulation, which resulted from a decrease in the nuclear import of PRAK and an increase in the nuclear export of PRAK. The nuclear import of PRAK is independent from p38 activation, but the nuclear export requires p38-mediated phosphorylation of PRAK. Thus, the subcellular distribution of PRAK is determined by multiple factors including its own NES and NLS, docking interactions between PRAK and docking proteins, phosphorylation of PRAK, and cellular activation status. The p38 MAPKs not only regulate PRAK activity and PRAK activation-related translocation, but also dock PRAK to selected subcellular locations in resting cells.
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