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 language | English |
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Pages (from-to) | 2657-2665 |
Number of pages | 9 |
Journal | Cell Cycle |
Volume | 5 |
Issue number | 22 |
Publication status | Published - Nov 15 2006 |
Keywords
- GEF
- GTPase
- MAPK
- Motility
- Proliferation
- Proto-Dbl
- Transformation
ASJC Scopus subject areas
- Biochemistry
- Cell Biology
- Molecular Biology