Journal
EXPERIMENTAL CELL RESEARCH
Volume 317, Issue 13, Pages 1787-1795Publisher
ELSEVIER INC
DOI: 10.1016/j.yexcr.2011.05.008
Keywords
Rho GTPases; MgcRacGAP; Stat3
Categories
Funding
- Canadian Institutes of Health Research (CIHR)
- Canadian Breast Cancer Foundation (Ontario Chapter)
- Natural Sciences and Engineering Research Council of Canada (NSERC)
- Ontario Centers of Excellence
- Breast Cancer Action Kingston
- Clare Nelson bequest fund
- Canadian Breast Cancer Research Alliance
- Ontario Council of Graduate Studies
- Queen's University
- MITACS
- Ministry of Research and Innovation
- province of Ontario
- US Army
- National Cancer Institute [CA128865]
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The signal transducer and activator of transcription-3 (Stat3) is a member of the STAT family of cytoplasmic transcription factors. Overactivation of Stat3 is detected with high frequency in human cancer and is considered a molecular abnormality that supports the tumor phenotype. Despite concerted investigative efforts, the molecular mechanisms leading to the aberrant Stat3 activation and Stat3-mediated transformation and tumorigenesis are still not clearly defined. Recent evidence reveals a crosstalk close relationship between Stat3 signaling and members of the Rho family of small GTPases, including Rac1, Cdc42 and RhoA. Specifically, Rac1, acting in a complex with the MgcRacGAP (male germ cell RacGAP), promotes tyrosine phosphorylation of Stat3 by the IL6-receptor family/jak kinase complex, as well as its translocation to the nucleus. Studies have further revealed that the mutational activation of Rac1 and Cdc42 results in Stat3 activation, which occurs in part through the upregulation of IL6 family cytokines that in turn stimulates Stat3 through the Jak kinases. Interestingly, evidence also shows that the engagement of cadherins, cell to cell adhesion molecules, specifically induces a striking increase in Rac1 and Cdc42 protein levels and activity, which in turn results in Stat3 activation. In this review we integrate recent findings clarifying the role of the Rho family GTPases in Stat3 activation in the context of malignant progression. (C) 2011 Elsevier Inc. All rights reserved.
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