Inhibition of PI3K induces Rac activation and membrane ruffling in proto-Dbl expressing cells

Cristina Vanni, Vincenzo Visco, Patrizia Mancini, Alessia Parodi, Catherine Ottaviano, Marzia Ognibene, Andrea D. Manazza, Saverio Francesco Retta, Luigi Varesio, Maria Rosaria Torrisi, Alessandra Eva

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)2657-2665
Number of pages9
JournalCell Cycle
Volume5
Issue number22
Publication statusPublished - Nov 15 2006

Keywords

  • GEF
  • GTPase
  • MAPK
  • Motility
  • Proliferation
  • Proto-Dbl
  • Transformation

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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    Vanni, C., Visco, V., Mancini, P., Parodi, A., Ottaviano, C., Ognibene, M., Manazza, A. D., Retta, S. F., Varesio, L., Torrisi, M. R., & Eva, A. (2006). Inhibition of PI3K induces Rac activation and membrane ruffling in proto-Dbl expressing cells. Cell Cycle, 5(22), 2657-2665.