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Vol. 14, Issue 6, 2603-2616, June 2003
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* Department of Immunology, The Scripps Research Institute, La Jolla, California
92037;
Department of Pathophysiology, The First Military Medical University,
Guangzhou, China
Submitted August 27, 2002;
Revised December 17, 2002;
Accepted February 5, 2003
Monitoring Editor: Suzanne R. Pfeffer
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 coexpression 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.
Corresponding author. E-mail address:
jhan{at}scripps.edu.
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