Details

Autor(en) / Beteiligte

• Dunkel, Ying
• Ong, Andrew
• Notani, Dimple
• Mittal, Yash
• Lam, Michael
• Mi, Xiaoyi
• Ghosh, Pradipta

Titel

STAT3 Protein Up-regulates Gα-interacting Vesicle-associated Protein (GIV)/Girdin Expression, and GIV Enhances STAT3 Activation in a Positive Feedback Loop during Wound Healing and Tumor Invasion/Metastasis

Ist Teil von

• The Journal of biological chemistry, 2012-12, Vol.287 (50), p.41667-41683

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2012

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• Gα-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. Background: GIV/Girdin is a GEF for Gαi and a metastasis-related protein, which is required for cancer invasion. Results: STAT3 directly binds the GIV promoter and triggers GIV transcription. The GEF function of GIV enhances activation of STAT3. Conclusion: STAT3 up-regulates GIV transcription, and GIV enhances STAT3 activation. Significance: Insights gained are crucial for devising both therapeutic and prognostic options at the crossroads between STAT3 and GIV.