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EnglishThe 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.
| Titolo: | The Slit/Robo system suppresses hepatocyte growth factor-dependent invasion and morphogenesis | |
| Autori Riconosciuti: | ||
| Autori: | Stella MC; Trusolino L*; Comoglio PM* (Corresponding Authors) | |
| Data di pubblicazione: | 2009 | |
| Abstract: | 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. | |
| Volume: | 20 | |
| Fascicolo: | 2 | |
| Pagina iniziale: | 642 | |
| Pagina finale: | 657 | |
| Digital Object Identifier (DOI): | 10.1091/mbc.E08-03-0321 | |
| URL: | http://www.molbiolcell.org/cgi/pmidlookup?view=long&pmid=19005219 | |
| Parole Chiave: | NEURONAL MIGRATION; SCATTER FACTOR; SLIT PROTEIN; E-CADHERIN; EPIGENETIC INACTIVATION; LEUKOCYTE CHEMOTAXIS; TUMOR-SUPPRESSOR; EPITHELIAL-CELLS; AXON REPULSION; CANCER-CELLS | |
| Rivista: | MOLECULAR BIOLOGY OF THE CELL | |
| Appare nelle tipologie: | 03A-Articolo su Rivista |
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| 2009_The SlitRobo system suppresses hepatocyte growth factor-dependent invasion and morphogenesis.pdf | PDF EDITORIALE | Accesso riservato | Utenti riconosciuti Richiedi una copia | |
| Stella Trusolino Molecular Biol Cell 2009_Aperto.pdf | POSTPRINT (VERSIONE FINALE DELL’AUTORE) | Accesso aperto | Open Access Visualizza/Apri |
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