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.
Leng
Yumei
Y
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Cao
Cheng
C
Ren
Jian
J
Huang
Lei
L
Chen
Dongshu
D
Ito
Masaki
M
Kufe
Donald
D
D021581:Active Transport, Cell Nucleus / Q000235:genetics; D020816:Amino Acid Motifs; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism*; D018396:Mucin-1; D009077:Mucins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D028861:Nuclear Pore Complex Proteins / Q000235:genetics / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics; D028901:alpha Karyopherins / Q000235:genetics / Q000378:metabolism; D028961:beta Karyopherins / Q000235:genetics / Q000378:metabolism
D000951:Antigens, Neoplasm; C060192:MUC1 protein, human; D008562:Membrane Glycoproteins; D018396:Mucin-1; D009077:Mucins; D028861:Nuclear Pore Complex Proteins; D015513:Oncogene Proteins; D021122:Protein Subunits; D028901:alpha Karyopherins; D028961:beta Karyopherins; C049312:nuclear pore protein p62