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MBC in Press, published online ahead of print February 6, 2008
Mol. Biol. Cell 10.1091/mbc.E07-05-0454

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Submitted on May 17, 2007
Revised on December 17, 2007
Accepted on January 24, 2008

STRAD{alpha} Regulates LKB1 Localization by Blocking Access To Importin-{alpha}, and by Association With Crm1 and Exportin-7

Julia Dorfman and Ian G. Macara

Program in Biophysics, Department of Microbiology, University of Virginia School of Medicine, Charlottesville VA 22908-0577

Monitoring Editor: Susan Wente

LKB1, a serine/threonine kinase, regulates cell polarity, metabolism, and cell growth. The activity and cellular distribution of LKB1 are determined by cofactors, STRAD{alpha} and MO25. STRAD{alpha} induces relocalization of LKB1 from the nucleus to the cytoplasm and stimulates its catalytic activity. MO25 stabilizes the STRAD{alpha}/LKB1 interaction. We investigated the mechanism of nucleo-cytoplasmic transport of LKB1 in response to its cofactors. While LKB1 is imported into the nucleus by importin-{alpha}/{beta}, STRAD{alpha} and MO25 passively diffuse between the nucleus and the cytoplasm. STRAD{alpha} induces nucleo-cytoplasmic shuttling of LKB1. STRAD{alpha} facilitates nuclear export of LKB1 by serving as an adaptor between LKB1 and exportins CRM1 and exportin7. STRAD{alpha} inhibits import of LKB1 by competing with importin{alpha} for binding to LKB1. MO25 stabilizes the LKB1-STRAD{alpha} complex but does not facilitate its nucleo-cytoplasmic shuttling. Strikingly, the STRAD{beta}, isoform, which differs from STRAD{alpha} in the N-and C-terminal domains that are responsible for interaction with export receptors, does not efficiently relocalize LKB1 from the nucleus to the cytoplasm. These results identify a multi-factored mechanism to control LKB1 localization, and suggest that the STRAD{beta}-LKB1 complex might possess unique functions in the nucleus.

Address correspondence to: Ian G. Macara (igm9c{at}virginia.edu)




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