期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 287, 期 50, 页码 41667-41683出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M112.390781
关键词
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资金
- National Institutes of Health [5 T32 GM007198, T32 GM008666]
- Burroughs Wellcome Fund
- Doris Duke Charitable Foundation
- American Cancer Society Grant [ACS-IRG 70-002]
- United States Department of Defense Postdoctoral Fellowship Award [BC103858]
- Sarah Rogers Fellowship (University of California, San Diego)
- Specialized Research Fund for the Doctoral Program of Higher Education of China Grant [20112104110017]
G alpha-interacting vesicle-associated protein (GIV) is a guanine nucleotide exchange factor that modulates key signaling pathways during a diverse set of biological processes, e.g. wound healing, macrophage chemotaxis, tumor angiogenesis, vascular repair, and cancer invasion/metastasis. We recently demonstrated that GIV is a metastasis-related protein, which serves both as a therapeutic target and as a biomarker for prognostication in cancer patients. Here we report the discovery that GIV is a direct target of the transcription factor signal transducer and activator of transcription-3 (STAT3), which is commonly known as a central regulator of tumor metastasis. We identified a single STAT3-binding site on the GIV promoter that was necessary and sufficient for transcriptional activation of GIV during wound healing and cancer invasion. Immunohistochemical analysis of breast carcinomas showed significant correlation between STAT3 activation and elevated GIV expression. Furthermore, we provide evidence that GIV positively autoregulates its own transcription by enhancing STAT3 activation via its guanine nucleotide exchange factor activity. Our findings provide mechanistic insights into how STAT3 activation is directly integrated with the receptor tyrosine kinase-GIV-G protein signaling axis. The forward feedback regulation we describe here between GIV and STAT3 may have profound therapeutic implications for cancer and epithelial regeneration/repair and could help invent novel approaches in treating and prognosticating cancer.
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