title: Inhibition of PI3K induces Rac activation and membrane ruffling in proto-Dbl expressing cells.
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.
authors.affiliation: Laboratorio di Biologia Molecolare, Istituto G. Gaslini, Genova, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Vanni
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Visco
authors.forename: Patrizia
authors.initials: P
authors.lastname: Mancini
authors.forename: Alessia
authors.initials: A
authors.lastname: Parodi
authors.forename: Catherine
authors.initials: C
authors.lastname: Ottaviano
authors.forename: Marzia
authors.initials: M
authors.lastname: Ognibene
authors.forename: Andrea D
authors.initials: AD
authors.lastname: Manazza
authors.forename: Saverio Francesco
authors.initials: SF
authors.lastname: Retta
authors.forename: Luigi
authors.initials: L
authors.lastname: Varesio
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Torrisi
authors.forename: Alessandra
authors.initials: A
authors.lastname: Eva
mesh_terms: D000818:Animals; D019556:COS Cells; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002522:Chlorocebus aethiops; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D051379:Mice; D008856:Microscopy, Fluorescence; D009025:Morpholines / Q000494:pharmacology; D041681:NIH 3T3 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection
chemical_list: D002867:Chromones; D004791:Enzyme Inhibitors; D020662:Guanine Nucleotide Exchange Factors; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; C512843:Mcf2 protein, mouse; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one