The Rho exchange factors Vav2 and Vav3 favor skin tumor initiation and promotion by engaging extracellular signaling loops

The 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 h...

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Published in:PLoS biology 2013-07, Vol.11 (7), p.e1001615-e1001615
Main Authors: Menacho-Márquez, Mauricio, García-Escudero, Ramón, Ojeda, Virginia, Abad, Antonio, Delgado, Pilar, Costa, Clotilde, Ruiz, Sergio, Alarcón, Balbino, Paramio, Jesús M, Bustelo, Xosé R
Format: Article
Language:English
Subjects:
Animals
Biology
Cancer
Cell Proliferation
Enzymes
Epidermal growth factor
Experiments
Genomics
Homeostasis
Keratinocytes - metabolism
Kinases
Lymphoma
Medicine
Mice
Mice, Knockout
Proteins
Proto-Oncogene Proteins c-vav - genetics
Proto-Oncogene Proteins c-vav - metabolism
Signal Transduction - genetics
Signal Transduction - physiology
Skin Neoplasms - genetics
Skin Neoplasms - metabolism
Tumors
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Summary:The 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.
ISSN:1545-7885
1544-9173
1545-7885
DOI:10.1371/journal.pbio.1001615