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A more recent version of this article appeared on June 1, 2004
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Submitted on November 28, 2003
Revised on February 16, 2004
Accepted on March 1, 2004
1 Department of Tumor Virology, Research Institute for Microbial Diseases, Osaka University, Yamadaoka, Suita-shi, Osaka 565-0871, Japan
* Corresponding author. E-mail address: matsudam{at}biken.osaka-u.ac.jp.
RalA, a member of the Ras-family GTPases, regulates various cellular functions such as filopodia formation, endocytosis, and exocytosis. On epidermal growth factor (EGF) stimulation, activated Ras recruits guanine nucleotide exchange factors (GEFs) for RalA, followed by RalA activation. By using FRET-based probes for RalA activity, we found that the EGF-induced RalA activation in Cos7 cells was restricted at the EGF-induced nascent lamellipodia, whereas under a similar condition both Ras activation and Ras-dependent translocation of Ral GEFs occurred more diffusely at the plasma membrane. This EGF-induced RalA activation was not observed when lamellipodial protrusion was suppressed by a dominant negative mutant of Rac1, a GAP for Cdc42, inhibitors of PI 3-kinase, or inhibitors of actin polymerization. On the other hand, EGF-induced lamellipodial protrusion was inhibited by microinjection of the RalA-binding domains (RBD) of RalBP1 and Sec5. Furthermore, we found that RalA activity was high at the lamellipodia of migrating MDCK cells and that the migration of MDCK cells was perturbed by the microinjection of RalBP1-RBD. Thus, RalA activation is required for the induction of lamellipodia and, conversely, lamellipodial protrusion seems to be required for the RalA activation, suggesting the presence of a positive feedback loop between RalA activation and lamellipodial protrusion. Our observation also demonstrates that the spatial regulation of RalA is conducted by a mechanism distinct from the temporal regulation conducted by Ras-dependent plasma membrane recruitment of Ral GEFs.
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