PMID:23066027

Citation	Dunkel, Y, Ong, A, Notani, D, Mittal, Y, Lam, M, Mi, X and Ghosh, P' (2012) STAT3 Upregulates GIV/Girdin Expression, and GIV Enhances STAT3 Activation in a Positive Feedback Loop during Wound Healing and Tumor Invasion/Metastasis. J. Biol. Chem. '
Abstract	GIV is a guanidine exchange factor (GEF) which 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); the latter commonly known as a central regulator of tumor metastasis. We identified a single STAT3-binding site on the GIV promoter which 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 GEF motif. 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.
Links	PubMed Online version:10.1074/jbc.M112.390781
Keywords
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:STAT3	involved_in	GO:0045893: positive regulation of transcription, DNA-templated	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete

References

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