STRADalpha regulates LKB1 localization by blocking access to importin-alpha, and by association with Crm1 and exportin-7.
LKB1, a serine/threonine kinase, regulates cell polarity, metabolism, and cell growth. The activity and cellular distribution of LKB1 are determined by cofactors, STRADalpha and MO25. STRADalpha induces relocalization of LKB1 from the nucleus to the cytoplasm and stimulates its catalytic activity. MO25 stabilizes the STRADalpha/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-alpha/beta, STRADalpha and MO25 passively diffuse between the nucleus and the cytoplasm. STRADalpha induces nucleocytoplasmic shuttling of LKB1. STRADalpha facilitates nuclear export of LKB1 by serving as an adaptor between LKB1 and exportins CRM1 and exportin7. STRADalpha inhibits import of LKB1 by competing with importin-alpha for binding to LKB1. MO25 stabilizes the LKB1-STRADalpha complex but it does not facilitate its nucleocytoplasmic shuttling. Strikingly, the STRADbeta, isoform which differs from STRADalpha 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 STRADbeta-LKB1 complex might possess unique functions in the nucleus.
Dorfman
Julia
J
Program in Biophysics, Department of Microbiology, University of Virginia School of Medicine, Charlottesville VA 22908-0577, USA.
Macara
Ian G
IG
D000091162:AMP-Activated Protein Kinase Kinases; D021581:Active Transport, Cell Nucleus; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D018076:DNA, Complementary / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D028884:Karyopherins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D028901:alpha Karyopherins / Q000235:genetics / Q000378:metabolism*; D020931:ran GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*; D000097606:Exportin 1 Protein
D000091162:AMP-Activated Protein Kinase Kinases; D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D002352:Carrier Proteins; D018076:DNA, Complementary; D028884:Karyopherins; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; D011994:Recombinant Proteins; D028901:alpha Karyopherins; D020931:ran GTP-Binding Protein; D000097606:Exportin 1 Protein; C417256:RanGTP-binding protein 16; C476400:STRADA protein, human; C109790:STK11 protein, human