Abstract
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.
Highlights
G␣-interacting vesicle-associated protein (GIV)/Girdin is a guanine nucleotide exchange factor (GEF) for G␣i and a metastasis-related protein, which is required for cancer invasion
We demonstrate that transcription of GIV is up-regulated during epithelial wound healing and metastatic progression of cancer, and the key finding in this work is the identification of signal transducer and activator of transcription-3 (STAT3) as one of the major and specific transcription factors that up-regulates GIV expression during both processes
Using three different models of epithelial wounding, scratch wounding on a monolayer of HeLa epithelial cells, surgical skin graft wounding in human, and burn injury in murine skin, we showed here that GIV mRNA and protein expression is up-regulated during wound healing
Summary
GIV/Girdin is a GEF for G␣i and a metastasis-related protein, which is required for cancer invasion. G␣-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. (c) A recent study (21) using gene expression profiling in prostate cancer cells showed that STAT3 influences cell migration and proliferation much like GIV (2); i.e. STAT3 inhibits tumor growth (decreases transcription of genes that enhance growth) and favors invasion (increases transcription of genes that are implicated in metastasis). We hypothesized that STAT3 regulates GIV transcription during epithelial wound healing and tumor invasion/ metastasis
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