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

PLoS Biol. 2013 Jul;11(7):e1001615. doi: 10.1371/journal.pbio.1001615. Epub 2013 Jul 23.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation
  • Keratinocytes / metabolism
  • Mice
  • Mice, Knockout
  • Proto-Oncogene Proteins c-vav / genetics
  • Proto-Oncogene Proteins c-vav / metabolism*
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • Skin Neoplasms / genetics
  • Skin Neoplasms / metabolism*


  • Proto-Oncogene Proteins c-vav
  • Vav2 protein, mouse
  • Vav3 protein, mouse

Grants and funding

This work was supported by grants from the Spanish Ministry of Economy and Competitiveness to XRB (SAF2009-07172, SAF2012-3171, RD06/0020/0001 and RD12/0036/0002), BA (RD06/0020/1002, RD12/0036/0075), and JMP (SAF2011-26122-C02-01, RD06/0020/0029, RD12/0036/0009); a cooperative grant to XRB and BA from the Spanish Cancer Association; and a grant from the Madrid Autonomous Government to JMP (S2006/BIO-0232). Spanish government funding to XRB has been co-sponsored by the European Regional Development Fund. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript