期刊
MOLECULAR AND CELLULAR BIOLOGY
卷 27, 期 24, 页码 8683-8697出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00157-07
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资金
- NCI NIH HHS [R01 CA116356] Funding Source: Medline
- NHLBI NIH HHS [P01 HL045100, HL45100] Funding Source: Medline
- NIGMS NIH HHS [R01 GM029860, GM29860] Funding Source: Medline
Net1 is a RhoA-specific guanine nucleotide exchange factor which localizes to the nucleus at steady state. A deletion in its N terminus redistributes the protein to the cytosol, where it activates RhoA and can promote transformation. Net1 contains a PDZ-binding motif at the C terminus which is essential for its transformation properties. Here, we found that Nett interacts through its PDZ-binding motif with tumor suppressor proteins of the Dig family, including Dlg1/SAP97, SAP102, and PSD95. The interaction between Net1 and its PDZ partners promotes the translocation of the PDZ proteins to nuclear subdomains associated with PML bodies. Interestingly, the oncogenic mutant of Nett is unable to shuttle the PDZ proteins to the nucleus, although these proteins still associate as clusters in the cytosol. Our results suggest that the ability of oncogenic Net1 to transform cells may be in part related to its ability to sequester tumor suppressor proteins like Dlg1 in the cytosol, thereby interfering with their normal cellular function. In agreement with this, the transformation potential of oncogenic Net1 is reduced when it is coexpressed with Dlg1 or SAP102. Together, our results suggest that the interaction between Net1 and Dlg1 may contribute to the mechanism of Net1-mediated transformation.
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