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A correction to this article has been published: J. Cell Biol. 157 (3) 533
Published online 25 February 2002. doi:10.1083/jcb.200112059
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© The Rockefeller University Press, 0021-9525/2002/3/817 $5.00
The Journal of Cell Biology, Volume 156, Number 5, March 4, 2002 817-828

Article

14-3-3 transits to the nucleus and participates in dynamic nucleocytoplasmic transport



Anne Brunet3, Fumihiko Kanai1,2, Justine Stehn1, Jian Xu2, Dilara Sarbassova1,2, John V. Frangioni4, Sorab N. Dalal5, James A. DeCaprio5, Michael E. Greenberg3 and Michael B. Yaffe1,2,6

1 Center for Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139
2 Division of Signal Transduction, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215
3 Division of Neuroscience, Children's Hospital, and Department of Neurobiology, Harvard Medical School, Boston, MA 02115
4 Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, MA 02215
5 Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115
6 Department of Surgery, Beth Israel Deaconess Medical Center, Boston, MA 02215

Address correspondence to Michael B. Yaffe, Center for Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Ave., E18-580 Cambridge, MA 02139. Tel.: (617) 452-2442. Fax: (617) 452-4978. E-mail: myaffe{at}mit.edu

14-3-3 proteins regulate the cell cycle and prevent apoptosis by controlling the nuclear and cytoplasmic distribution of signaling molecules with which they interact. Although the majority of 14-3-3 molecules are present in the cytoplasm, we show here that in the absence of bound ligands 14-3-3 homes to the nucleus. We demonstrate that phosphorylation of one important 14-3-3 binding molecule, the transcription factor FKHRL1, at the 14-3-3 binding site occurs within the nucleus immediately before FKHRL1 relocalization to the cytoplasm. We show that the leucine-rich region within the COOH-terminal {alpha}-helix of 14-3-3, which had been proposed to function as a nuclear export signal (NES), instead functions globally in ligand binding and does not directly mediate nuclear transport. Efficient nuclear export of FKHRL1 requires both intrinsic NES sequences within FKHRL1 and phosphorylation/14-3-3 binding. Finally, we present evidence that phosphorylation/14-3-3 binding may also prevent FKHRL1 nuclear reimport. These results indicate that 14-3-3 can mediate the relocalization of nuclear ligands by several mechanisms that ensure complete sequestration of the bound 14-3-3 complex in the cytoplasm.

Key Words: 14-3-3; FKHRL1; phosphoserine; nuclear export; Crm1


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