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Beatson Institute for Cancer Research, Cancer Research U.K. Beatson Laboratories, Bearsden, Glasgow, United Kingdom
We have previously shown that the 
-chemokine ESkine/CCL27 is
differentially spliced to produce two alternative forms. One is a
secreted chemokine (ESkine), whereas the other (PESKY) lacks a signal
peptide and is translocated to the nucleus. The role of this
nuclear-targeted chemokine has not so far been defined, and it was the
purpose of this study to examine this chemokine variant in more depth.
To identify the region of PESKY involved in the nuclear translocation
we tagged fragments with enhanced green fluorescent protein and
expressed them in Chinese hamster ovary cells. We show PESKY nuclear
translocation to be dependent on C-terminal residues that are shared
with the signal peptide-bearing variant ESkine. Indeed we further
demonstrate that ESkine can also use these C-terminal residues to enter
the nucleus of cells following receptor (CCR10)-mediated
internalization. To examine biological roles for PESKY we have
overexpressed it in 3T3 cells. Such overexpression results in marked
cytoskeletal rearrangements that are coincident with a radical
reorganization of the cellular actin cytoskeleton. Microarray analyses
and Ab neutralization studies indicate that these changes are mediated
in part by insulin-like growth factor-1. Furthermore, monolayer
wounding assays indicate that PESKY expression correlates with markedly
increased migratory capacity. Thus, it is our contention that nuclear
PESKY and ESkine both enter the nucleus by either intracrine or
paracrine mechanisms and may facilitate cellular migration by inducing
actin cytoskeletal relaxation. Therefore, nuclear ESkine/PESKY
represents a novel paradigm for chemokine
function.
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