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A more recent version of this article appeared on March 1, 2003
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Submitted on March 27, 2002
Revised on October 17, 2002
Accepted on November 22, 2002
mediates the regulated nuclear targeting of Serum and Glucocorticoid inducible protein kinase (Sgk) by recognition of a nuclear localization signal in the kinase central domain
1 Dept. of Molecular and Cell Biology and The Cancer Research Laboratory, University of California at Berkeley, Berkeley, CA 94720-3200
* Corresponding author. E-mail address: glfire{at}uclink4.berkeley.edu.
The transcriptionally regulated serum and glucocorticoid inducible protein kinase (Sgk) is localized to the nucleus in a serum dependent manner, and a yeast two hybrid genetic screen uncovered a specific interaction between Sgk and the importin-
nuclear import receptor. In vitro GST pull down assays demonstrated a strong and direct association of importin- with endogenous Sgk and exogenously expressed HA-tagged Sgk, while both components co-immunoprecipitate, and co-localize to the nucleus following serum stimulation. Consistent with an active mechanism of nuclear localization, the nuclear import of HA-Sgk in permeabilized cells required ATP, cytoplasm and a functional nuclear pore complex. Ectopic addition of a 107 amino acid carboxy-terminal fragment of importin-, which contains the Sgk binding region, competitively inhibited the ability of endogenous importin- to import Sgk into nuclei in vitro. Mutagenesis of lysines by alanine substitution defined a KKAILKKKEEK sequence within the central domain of Sgk between amino acids 131-141 that functions as a nuclear localization signal (NLS) required for the in vitro interaction with importin-, and for nuclear import of full length Sgk in cultured cells. The serum induced nuclear import of Sgk requires the NLS-dependent recognition of Sgk by importin- as well as the PI3-kinase-dependent phosphorylation of Sgk. Our results define a new role importin- in the stimulus dependent control of signal transduction by nuclear localized protein kinases.
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