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MBC in Press, published online ahead of print November 12, 2008
Mol. Biol. Cell 10.1091/mbc.E08-03-0321

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Submitted on March 27, 2008
Revised on August 11, 2008
Accepted on November 4, 2008

The Slit/Robo System Suppresses HGF-dependent Invasion and Morphogenesis

Maria Cristina Stella, Livio Trusolino, and Paolo M. Comoglio

Division of Molecular Oncology, IRCC, Institute for Cancer Research and Treatment, University of Torino School of Medicine, 10060 Candiolo (Torino), Italy

Monitoring Editor: Richard O. Hynes

The Slit protein acts through the Roundabout receptor as a paracrine chemorepellent in axon guidance and as an inhibitor in leukocyte chemotaxis, but its role in epithelial cell motility and morphogenesis remains largely unexplored. We report that nontransformed epithelial cells and cancerous cells empower the Slit-2/Robo1 signaling system to limit outward migration in response to motogenic attractants and to remain positionally confined within their primitive location. shRNA-mediated depletion of SLIT-2 or ectopic expression of a soluble decoy Robo enhance HGF-induced migration, matrix invasion and tubulogenesis, concomitantly with the upregulation of Cdc-42 and the down-modulation of Rac-1 activities. Accordingly, autocrine overexpression or exogenous administration of Slit-2 prevent HGF-triggered motile responses, reduce Cdc-42 activation, and stimulate Rac-1. This anti-migratory activity of Slit-2 derives from the inhibition of actin-based protrusive forces and from an increased adhesive strength of cadherin-mediated intercellular contacts. These results disclose a novel function for Slit and Robo in the inhibition of growth factor-mediated epithelial cell motility and morphogenesis, invoking a critical role for both molecules as natural antagonists of neoplastic invasive growth.

Address correspondence to: Paolo M. Comoglio (livio.trusolino{at}ircc.it)






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