Drosophila Naked cuticle (Nkd) engages the nuclear import adaptor Importin-α3 to antagonize Wnt/β-catenin signaling

Laboratory of Molecular Pathology, Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390-9072, USA.
Developmental Biology (Impact Factor: 3.64). 07/2008; 318(1):17-28. DOI: 10.1016/j.ydbio.2008.02.050
Source: PubMed

ABSTRACT Precise control of Wnt/beta-catenin signaling is critical for animal development, stem cell renewal, and prevention of disease. In the fruit fly Drosophila melanogaster, the naked cuticle (nkd) gene limits signaling by the Wnt ligand Wingless (Wg) during embryo segmentation. Nkd is an intracellular protein that is composed of separable membrane- and nuclear-localization sequences (NLS) as well as a conserved EF-hand motif that binds the Wnt receptor-associated scaffold protein Dishevelled (Dsh), but the mechanism by which Nkd inhibits Wnt signaling remains a mystery. Here we identify a second NLS in Nkd that is required for full activity and that binds to the canonical nuclear import adaptor Importin-alpha3. The Nkd NLS is similar to the Importin-alpha3-binding NLS in the Drosophila heat-shock transcription factor (dHSF), and each Importin-alpha3-binding NLS required intact basic residues in similar positions for nuclear import and protein function. Our results provide further support for the hypothesis that Nkd inhibits nuclear step(s) in Wnt/beta-catenin signaling and broaden our understanding of signaling pathways that engage the nuclear import machinery.

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    ABSTRACT: The Notch signaling pathway controls diverse cell-fate specification events throughout development. The versatility of this pathway to influence different aspects of development comes from its multiple levels of regulation. Upon ligand-induced Notch activation, the Notch intracellular domain (Notch-ICD) is released from the membrane and translocates to the nucleus, where it transduces Notch signals by regulating the transcription of downstream target genes. But the exact mechanism of translocation of Notch-ICD into the nucleus is not clear. Here, we implicate Importin-α3 (also known as karyopherin-α3) in the nuclear translocation of Notch-ICD in Drosophila. Our present analyses reveal that Importin-α3 can directly bind to Notch-ICD and loss of Importin-α3 function results in cytoplasmic accumulation of the Notch receptor. Using MARCM (Mosaic Analysis with a Repressible Cell Marker) technique, we demonstrate that Importin-α3 is required for nuclear localization of Notch-ICD. These results reveal that the nuclear transport of Notch-ICD is mediated by the canonical Importin-α3/Importin-β transport pathway. In addition, co-expression of both Notch-ICD and Importin-α3 displays synergistic effects on cell proliferation. Taken together, our results suggest that Importin-α3 mediated nuclear import of Notch-ICD may play important role in regulation of Notch signaling.
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