Chibby cooperates with 14-3-3 to regulate beta-catenin subcellular distribution and signaling activity.
beta-Catenin functions in both cell-cell adhesion and as a transcriptional coactivator in the canonical Wnt pathway. Nuclear accumulation of beta-catenin is the hallmark of active Wnt signaling and is frequently observed in human cancers. Although beta-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 beta-catenin-mediated transcriptional activation. Here, we identified 14-3-3epsilon and 14-3-3zeta 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 beta-catenin, causing beta-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 beta-catenin, thereby antagonizing beta-catenin signaling.
Li
Feng-Qian
FQ
Department of Pharmacological Sciences and 2Graduate Program in Genetics, State University of New York at Stony Brook, Stony Brook, NY 11794, USA. li@pharm.stonybrook.edu
Mofunanya
Adaobi
A
Harris
Kimberley
K
Takemaru
Ken-Ichi
K
D048948:14-3-3 Proteins / Q000378:metabolism*; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D002467:Cell Nucleus / Q000201:enzymology; D002522:Chlorocebus aethiops; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D020033:Protein Isoforms / Q000378:metabolism; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D013347:Subcellular Fractions / Q000378:metabolism; D013379:Substrate Specificity; D015533:Transcriptional Activation; D051176:beta Catenin / Q000378:metabolism*
D048948:14-3-3 Proteins; C473750:CBY1 protein, human; D002352:Carrier Proteins; D009687:Nuclear Proteins; D020033:Protein Isoforms; D051176:beta Catenin; D051057:Proto-Oncogene Proteins c-akt