Background: Control of the nuclear localization of specific proteins is an important mechanism for regulating many signal transduction pathways. Upon activation of the Wnt signaling pathway, β-catenin localizes into the nucleus and interacts with TCF/LEF-1 (T-cell factor/lymphocyte enhancer factor-1) transcription factors, triggering activation of downstream genes. The role of regulated nuclear localization in β-catenin signaling is still unclear. β-catenin has no nuclear localization sequence (NLS). Although it has been reported that β-catenin can piggyback into the nucleus by binding to TCF/LEF-1, there is evidence that its import is independent of TCF/LEF-1 in vivo. Therefore, the mechanism for β-catenin nuclear localization remains to be established.

Results: We have analyzed β-catenin nuclear import in an in vitro assay using permeabilized cells. β-catenin docks specifically onto the nuclear envelope in the absence of other cytosolic factors. Docking is not inhibited by an NLS peptide and does not require importins/karyopherins, the receptors for classical NLS substrates. Rather, docking is specifically competed by importin-β/β-karyopherin, indicating that β-catenin and importin-β/β-karyopherin both interact with common nuclear pore components. Nuclear translocation of β-catenin is energy dependent and is inhibited by nonhydrolyzable GTP analogs and by a dominant-negative mutant form of the Ran GTPase. Cytosol preparations contain inhibitory activities for β-catenin import that are distinct from the competition by importin-β/β-karyopherin and may be involved in the physiological regulation of the pathway.

Conclusions:β-catenin is imported into the nucleus by binding directly to the nuclear pore machinery, similar to importin-β/β-karyopherin or other importin-β-like import factors, such as transportin. These findings provide an explanation for how β-catenin localizes to the nucleus without an NLS and independently of its interaction with TCF/LEF-1. This is a new and unusual mechanism for the nuclear import of a signal transduction protein. The lack of β-catenin import activity in the presence of normal cytosol suggests that its import may be regulated by upstream events in the Wnt signaling pathway.