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Vol. 19, Issue 4, 1614-1626, April 2008

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STRAD Regulates LKB1 Localization by Blocking Access to Importin-, and by Association with Crm1 and Exportin-7

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

Submitted May 17, 2007; Revised December 17, 2007; Accepted January 24, 2008
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 and MO25. STRAD induces relocalization of LKB1 from the nucleus to the cytoplasm and stimulates its catalytic activity. MO25 stabilizes the STRAD/LKB1 interaction. We investigated the mechanism of nucleocytoplasmic transport of LKB1 in response to its cofactors. Although LKB1 is imported into the nucleus by importin-/β, STRAD and MO25 passively diffuse between the nucleus and the cytoplasm. STRAD induces nucleocytoplasmic shuttling of LKB1. STRAD facilitates nuclear export of LKB1 by serving as an adaptor between LKB1 and exportins CRM1 and exportin7. STRAD inhibits import of LKB1 by competing with importin- for binding to LKB1. MO25 stabilizes the LKB1–STRAD complex but it does not facilitate its nucleocytoplasmic shuttling. Strikingly, the STRADβ, isoform which differs from STRAD 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 multifactored mechanism to control LKB1 localization, and they suggest that the STRADβ-LKB1 complex might possess unique functions in the nucleus.

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

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