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MBC in Press, published online ahead of print September 26, 2007
Mol. Biol. Cell 10.1091/mbc.E07-02-0177

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Submitted on February 28, 2007
Revised on August 9, 2007
Accepted on September 17, 2007

Diacylglycerol Kinase-{alpha} Mediates HGF-induced Epithelial Cell Scatter by Regulating Rac Activation and Membrane Ruffling

Federica Chianale,*{dagger} Santina Cutrupi,*{dagger}{ddagger} Elena Rainero,* Gianluca Baldanzi,*{sect} Paolo E. Porporato,* Sara Traini,* Nicoletta Filigheddu,|| Viola F. Gnocchi,* Massimo M. Santoro,¶ Ornella Parolini,{sect} Wim J. van Blitterswijk,# Fabiola Sinigaglia,* and Andrea Graziani*

*Department of Medical Sciences, ||Department of Clinical and Experimental Medicine, and Dipartimento di Scienze dell’Ambiente e della Vita, University of Piemonte Orientale "A. Avogadro," Novara 28100, Italy; {ddagger}Department of Animal and Human Biology, University of Torino, 10123 Torino, Italy; {sect}Centro Ricerche "E. Menni," Ospedale Poliambulanza, Brescia 25124, Italy; #The Netherlands Cancer Institute, Amsterdam, 1066 CX Amsterdam, The Netherlands

Monitoring Editor: J. Silvio Gutkind

Diacylglycerol kinases (Dgk) phosphorylate diacylglycerol (DG) to phosphatidic acid (PA), thus turning off and on, respectively, DG-mediated and PA-mediated signaling pathways. We previously showed that HGF, VEGF and ALK activate Dgk{alpha} in endothelial and leukemia cells through a Src-mediated mechanism, and that activation of Dgk{alpha} is required for chemotactic, proliferative and angiogenic signaling in vitro. Inhere we investigate the downstream events and signaling pathways regulated by Dgk{alpha}, leading to cell scatter and migration upon HGF treatment and v-Src expression in epithelial cells. We report that specific inhibition of Dgk{alpha}, obtained either pharmacologically by R59949 treatment, or by expression of Dgk{alpha} dominant-negative mutant, or by siRNA-mediated down-regulation of endogenous Dgk{alpha}, impairs i) HGF- and v-Src-induced cell scatter and migration, without affecting the loss of intercellular adhesions; ii) HGF-induced cell spreading, lamellipodia formation, membrane ruffling and focal adhesions remodelling; iii) HGF-induced Rac activation and membrane targeting. In summary, we provide evidence that Dgk{alpha}, activated downstream of tyrosine kinase receptors and Src, regulates crucial steps directing Rac activation and Rac-dependent remodelling of actin cytoskeleton and focal contacts in migrating epithelial cells.

{dagger}These authors contributed equally to this work.

Address correspondence to: Andrea Graziani (andrea.graziani{at}med.unipmn.it)




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