Nuclear import of the MUC1-C oncoprotein is mediated by nucleoporin Nup62.

The MUC1 heterodimeric transmembrane protein is aberrantly overexpressed by most human carcinomas. The MUC1 C-terminal subunit (MUC1-C) is devoid of a classical nuclear localization signal and is targeted to the nucleus by an unknown mechanism. The present results demonstrate that MUC1-C associates with importin beta and not importin alpha. The ...
results also show that, like importin beta, MUC1-C binds to Nup62 (nucleoporin p62). MUC1-C binds directly to the Nup62 central domain and indirectly to the Nup62 C-terminal alpha-helical coiled-coil domain. We demonstrate that MUC1-C forms oligomers and that oligomerization is necessary for binding to Nup62. The MUC1-C cytoplasmic domain contains a CQC motif that when mutated to AQA abrogates oligomerization and binding to Nup62. Stable expression of MUC1 with the CQC --> AQA mutations was associated with targeting to the cell membrane and cytosol and attenuation of nuclear localization. The results further show that expression of MUC1(CQC-AQA) attenuates MUC1-induced (i) transcriptional coactivation, (ii) anchorage-independent growth, and (iii) tumorigenicity. These findings indicate that the MUC1-C oncoprotein is imported to the nucleus by a pathway involving Nup62.
Mesh Terms:
Active Transport, Cell Nucleus, Amino Acid Motifs, Antigens, Neoplasm, Cell Line, Tumor, Cell Nucleus, Gene Expression, Humans, Membrane Glycoproteins, Mucin-1, Mucins, Mutation, Neoplasms, Nuclear Pore Complex Proteins, Oncogene Proteins, Protein Binding, Protein Structure, Tertiary, Protein Subunits, Transcriptional Activation, alpha Karyopherins, beta Karyopherins
J. Biol. Chem.
Date: Jul. 06, 2007
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