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.
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.
Department of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
Ying
Y
Dunkel
Andrew
A
Ong
Dimple
D
Notani
Yash
Y
Mittal
Michael
M
Lam
Xiaoyi
X
Mi
Pradipta
P
Ghosh
D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D008840:Microfilament Proteins / Q000096:biosynthesis* / Q000235:genetics; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D015854:Up-Regulation; D033921:Vesicular Transport Proteins / Q000096:biosynthesis* / Q000235:genetics; D014945:Wound Healing
C502451:CCDC88A protein, human; D008840:Microfilament Proteins; D009363:Neoplasm Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D033921:Vesicular Transport Proteins