Abstract
TRIP6 is an adaptor protein that regulates cell motility and antiapoptotic signaling. Although it has been implicated in tumorigenesis, the underlying mechanism remains largely unknown. Here we provide evidence that TRIP6 promotes tumorigenesis by serving as a bridge to promote the recruitment of p27(KIP1) to AKT in the cytosol. TRIP6 regulates the membrane translocation and activation of AKT and facilitates AKT-mediated recognition and phosphorylation of p27(KIP1) specifically at T157, thereby promoting the cytosolic mislocalization of p27(KIP1). This is required for p27(KIP1) to enhance lysophosphatidic acid (LPA)-induced ovarian cancer cell migration. TRIP6 also promotes serum-induced reduction of nuclear p27(KIP1) expression levels through Skp2-dependent and -independent mechanisms. Consequently, knockdown of TRIP6 in glioblastoma or ovarian cancer xenografts restores nuclear p27(KIP1) expression and impairs tumor proliferation. As TRIP6 is upregulated in gliomas and its levels correlate with poor clinical outcomes in a dose-dependent manner, it may represent a novel prognostic marker and therapeutic target in gliomas.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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ATPases Associated with Diverse Cellular Activities
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Adaptor Proteins, Signal Transducing / genetics*
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Adaptor Proteins, Signal Transducing / metabolism*
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Animals
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Cell Growth Processes / physiology
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Cell Line, Tumor
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Cell Movement / genetics
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Cell Nucleus / genetics
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Cell Nucleus / metabolism
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Cell Transformation, Neoplastic / genetics*
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Cyclin-Dependent Kinase Inhibitor p27 / genetics*
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Cyclin-Dependent Kinase Inhibitor p27 / metabolism*
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Cytosol / metabolism
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Female
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Glioblastoma / genetics
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Glioblastoma / metabolism
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Glioma / genetics
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Glioma / metabolism
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HEK293 Cells
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Humans
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LIM Domain Proteins / genetics*
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LIM Domain Proteins / metabolism*
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LIM-Homeodomain Proteins / genetics
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LIM-Homeodomain Proteins / metabolism
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Mice
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Mice, Nude
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Ovarian Neoplasms / genetics
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Ovarian Neoplasms / metabolism
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Phosphorylation
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Proteasome Endopeptidase Complex
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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S-Phase Kinase-Associated Proteins / genetics
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S-Phase Kinase-Associated Proteins / metabolism
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Transcription Factors / genetics*
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Transcription Factors / metabolism*
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Transplantation, Heterologous
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Up-Regulation
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Zyxin / genetics
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Zyxin / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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CDKN1B protein, human
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LHX1 protein, human
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LIM Domain Proteins
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LIM-Homeodomain Proteins
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PSMC5 protein, human
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S-Phase Kinase-Associated Proteins
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Transcription Factors
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ZYX protein, human
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Zyxin
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Cyclin-Dependent Kinase Inhibitor p27
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AKT1 protein, human
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Proto-Oncogene Proteins c-akt
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Proteasome Endopeptidase Complex
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ATPases Associated with Diverse Cellular Activities