Sci. STKE, 12 March 2002
Nucleocytoplasmic Transport The 14-3-3 Shuttle
The signaling molecule 14-3-3 binds to various phosphorylated molecules and presumably regulates their subcellular localization. However, most of the binding partners are located in the nucleus, whereas 14-3-3 is thought to reside mostly in the cytoplasm. Where then does phosphorylation and subsequent binding to 14-3-3 occur, and how is subcellular localization determined? Brunet et al. tackle this hotly debated topic by examining the nucleocytoplasmic transport of Forkhead (FKHRL1), a phosphorylated transcription factor that binds to 14-3-3. The study shows that a sequence in 14-3-3 does not act as a nuclear export signal (NES), as previously suggested, but as a phosphoprotein binding domain. 14-3-3 did not directly interact with components of the nuclear export machinery either. In fact, a mutated form of 14-3-3 that cannot bind to FKHRL1 localized to the nucleus, suggesting that unbound 14-3-3 may normally reside in the nucleus, waiting to bind to a partner protein. FRKHRL1 was phosphorylated within the nucleus, in response to growth factor stimulation of cells, facilitating subsequent interaction with 14-3-3. A NES expressed by FKHRL1 was also required to transport the complex out of the nucleus. The authors speculate that once in the cytoplasm, a nuclear localization signal present in FKHRL1 is masked by association with 14-3-3. Thus, 14-3-3 appears to enhance nuclear export, but just how it accelerates this process remains to be determined.
A. Brunet, F. Kanai, J. Stehn, J. Xu, D. Sarbassova, J. V. Frangioni, S. N. Dalal, J. A. DeCaprio, M. E. Greenberg, M. B. Yaffe, 14-3-3 transits to the nucleus and participates in dynamic nucleocytoplasmic transport. J. Cell Biol. 156, 817-828 (2002).
Citation: The 14-3-3 Shuttle. Sci. STKE 2002, tw101 (2002).
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