The Slit/Robo system suppresses hepatocyte growth factor-dependent invasion and morphogenesis.
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.
Stella
Maria Cristina
MC
Division of Molecular Oncology, Institute for Cancer Research and Treatment, University of Torino School of Medicine, 10060 Candiolo, Torino, Italy.
Trusolino
Livio
L
Comoglio
Paolo M
PM
D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology*; D004789:Enzyme Activation; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D009024:Morphogenesis / Q000502:physiology*; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein
D006023:Glycoproteins; D017228:Hepatocyte Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D011971:Receptors, Immunologic; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein; C120566:slit protein, vertebrate