Inhibition of PI3K induces Rac Activation and Membrane Ruffling in Proto-Dbl Expressing Cells
Volume 5, Issue 22
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November 15, 2006
Pages 2657 - 2665http://dx.doi.org/10.4161/cc.5.22.3445
Authors: Cristina Vanni, Vincenzo Visco, Alessia Parodi, Catherine Ottaviano, Marzia Ognibene, Andrea D Manazza, Saverio Francesco Retta, Luigi Varesio, Patrizia Mancini, Maria Rosaria Torrisi and Alessandra Eva View affiliations
Proto-Dbl protein, a guanine nucleotide exchange factor (GEF) for Rho GTPases, is tightly regulated by a combination of mechanisms that involve intra- and intermolecular interaction and N- and C-terminal domain-dependent turnover of the protein. Moreover, the interaction of the PH domain of proto-Dbl with phosphoinositides regulates its subcellular localization and biological activity. Here we show that inhibition of the phosphatidylinositol 3-kinase (PI3K) by molecular and pharmacological inhibitors causes a strong inhibition of proto-Dbl-induced cell proliferation and transformation. Conversely, inhibition of PI3K results in the translocation of proto-Dbl to the plasma membrane, Rac activation and increased membrane ruffles and cell motility. Furthermore, we investigated the signaling molecules involved in proto-Dbl-induced cell transformation and motility and observed that inhibition of PI3K in proto-Dbl expressing cells induces an increase in p38 activity and a decrease in ERK phosphorylation. Our results suggest that proto-Dbl activates distinct downstream effectors to induce morphological changes and cell transformation.