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Title

The Rho Exchange Factors Vav2 and Vav3 Favor Skin Tumor Initiation and Promotion by Engaging Extracellular Signaling Loops

AuthorsMenacho-Márquez, Mauricio ; García-Escudero, Ramón; Ojeda, Virginia; Abad, Antonio; Delgado, Pilar ; Costa, Clotilde; Ruiz Macías, Sergio; Alarcón, Balbino ; Paramio, Jesús M.; Bustelo, Xosé R.
Issue Date2013
PublisherPublic Library of Science
CitationPLoS Biology 11(7): e1001615 (2013)
AbstractThe catalytic activity of GDP/GTP exchange factors (GEFs) is considered critical to maintain the typically high activity of Rho GTPases found in cancer cells. However, the large number of them has made it difficult to pinpoint those playing proactive, nonredundant roles in tumors. In this work, we have investigated whether GEFs of the Vav subfamily exert such specific roles in skin cancer. Using genetically engineered mice, we show here that Vav2 and Vav3 favor cooperatively the initiation and promotion phases of skin tumors. Transcriptomal profiling and signaling experiments indicate such function is linked to the engagement of, and subsequent participation in, keratinocyte-based autocrine/paracrine programs that promote epidermal proliferation and recruitment of pro-inflammatory cells. This is a pathology-restricted mechanism because the loss of Vav proteins does not cause alterations in epidermal homeostasis. These results reveal a previously unknown Rho GEF-dependent pro-tumorigenic mechanism that influences the biology of cancer cells and their microenvironment. They also suggest that anti-Vav therapies may be of potential interest in skin tumor prevention and/or treatment. © 2013 Menacho-Márquez et al.
DescriptionThis is an open-access article distributed under the terms of the Creative Commons Attribution License.
Publisher version (URL)http://dx.doi.org/10.1371/journal.pbio.1001615
URIhttp://hdl.handle.net/10261/99540
DOI10.1371/journal.pbio.1001615
Identifiersissn: 1545-7885
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