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Originally published as MBC in Press, 10.1091/mbc.E08-03-0321 on November 12, 2008

Vol. 20, Issue 2, 642-657, January 15, 2009

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The Slit/Robo System Suppresses Hepatocyte Growth Factor-dependent Invasion and Morphogenesis

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

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

Submitted March 27, 2008; Revised August 11, 2008; Accepted November 4, 2008
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. Short hairpin RNA-mediated depletion of SLIT-2 or ectopic expression of a soluble decoy Robo enhance hepatocyte growth factor (HGF)-induced migration, matrix invasion, and tubulogenesis, concomitantly with the up-regulation 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 antimigratory 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.

This was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E08-03-0321) on November 12, 2008.

Address correspondence to: Maria Cristina Stella (mariacristina.stella{at}ircc.it) or Livio Trusolino (livio.trusolino{at}ircc.it)




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