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Published online June 23, 2008
doi:10.1083/jcb.200709091
The Journal of Cell Biology, Vol. 181, No. 7, 1141-1154
The Rockefeller University Press, 0021-9525 $30.00
© 2008 Li et al.
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Article

 Chibby cooperates with 14-3-3 to regulate β-catenin subcellular distribution and signaling activity

Feng-Qian Li1, Adaobi Mofunanya1,2, Kimberley Harris1, and Ken-Ichi Takemaru1

1 Department of Pharmacological Sciences and 2 Graduate Program in Genetics, State University of New York at Stony Brook, Stony Brook, NY 11794

Correspondence to Feng-Qian Li: li{at}pharm.stonybrook.edu; or Ken-Ichi Takemaru: takemaru{at}pharm.stonybrook.edu

β-Catenin functions in both cell–cell adhesion and as a transcriptional coactivator in the canonical Wnt pathway. Nuclear accumulation of β-catenin is the hallmark of active Wnt signaling and is frequently observed in human cancers. Although β-catenin shuttles in and out of the nucleus, the molecular mechanisms underlying its translocation remain poorly understood. Chibby (Cby) is an evolutionarily conserved molecule that inhibits β-catenin–mediated transcriptional activation. Here, we identified 14-3-3{epsilon} and 14-3-3{zeta} as Cby-binding partners using affinity purification/mass spectrometry. 14-3-3 proteins specifically recognize serine 20 within the 14-3-3–binding motif of Cby when phosphorylated by Akt kinase. Notably, 14-3-3 binding results in sequestration of Cby into the cytoplasm. Moreover, Cby and 14-3-3 form a stable tripartite complex with β-catenin, causing β-catenin to partition into the cytoplasm. Our results therefore suggest a novel paradigm through which Cby acts in concert with 14-3-3 proteins to facilitate nuclear export of β-catenin, thereby antagonizing β-catenin signaling.

Abbreviations used in this paper: APC, adenomatous polyposis coli; Cby, Chibby; CRM-1, chromosome region maintenance protein 1; DN-14-3-3, dominant-negative 14-3-3; GSK3, glycogen synthase kinase 3; hRluc, synthetic Renilla luciferase; KD, kinase-dead; Lef, lymphoid enhancer factor; MBP, maltose-binding protein; NES, nuclear export signal; OA, okadaic acid; rPP2A, recombinant protein phosphatase 2A; Tcf, T cell factor; WT, wild-type.


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