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First published online 31 August 2004
doi: 10.1242/jcs.01359
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Research Article |
1 CELL Unit, Christian de Duve Institute of Cellular Pathology, Université catholique de Louvain, UCL 75.41, Avenue Hippocrate, 75, 1200 Bruxelles, Belgium
2 Laboratory of Toxicology, Université Libre de Bruxelles, Boulevard du Triomphe, 1050 Bruxelles, Belgium
* Author for correspondence (e-mail: courtoy{at}cell.ucl.ac.be)
Accepted 14 June 2004
In Rat-1 fibroblasts, v-Src causes a profound remodelling of cortical actin cytoskeleton. This transformation includes membrane ruffling, a hallmark of the leading edge in migrating cells, and results from activation of phosphoinositide 3-kinase (PI 3-kinase), phospholipase C (PLC) and phospholipase D (PLD). We therefore reexamined whether motility is constitutively triggered by v-Src and studied whether this response is controlled by the same signalling pathway. The study was performed using Rat-1/tsLA29 and MDCK/tsLA31 cells, each harbouring a different thermosensitive v-Src kinase, active at 34°C but inactivated at 40°C. In both cell lines, overnight v-Src activation induced transformation and accelerated spontaneous motility by approximately twofold, as evidenced by wound-healing assay and by single-cell track, time-lapse recording in Dunn chambers. Inhibitors of PI 3-kinase, PLC and PLD selectively abrogated acceleration of motility by v-Src. Since mechanisms that co-ordinate spontaneous, as distinct from oriented, cell migration are separable, we further analysed in Dunn chambers chemotactic response of Rat-1/tsLA29 cells to PDGF and of MDCK/tsLA31 cells to EGF. In both cases, v-Src decreased the steady-state level of growth factor receptors at the cell surface twofold, and abrogated movement directionality at comparable level of occupancy as in non-transformed cells. The burst of pinocytosis in response to growth factors was also abolished by v-Src. Altogether, these results indicate that v-Src triggers motility in a PI 3-kinase-, PLC- and PLD-dependent manner, but abrogates directionality by suppressing polarised signalling downstream of growth factor receptors.
Key words: v-Src, Cell migration, PI 3-kinase, PLC, PLD, Chemotaxis
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