WIP participates in actin reorganization and ruffle formation induced by PDGF

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Abstract
Platelet-derived growth factor (PDGF) is a chemotactic factor for fibroblasts that triggers actin cytoskeleton reorganization by increasing the level of GTP-Rac, the activated form of a small Rho family GTPase. GTP-Rac induces membrane ruffling and lamellipodium formation that are required for adhesion, migration and macropinocytosis, among other functions. We have shown that WIP interacts with members of the Wiskott-Aldrich syndrome protein family and is essential for filopodium formation regulated by Cdc42 GTPase. In this report, we show that WIP participates in the actin reorganization that leads to ruffle formation. WIP overexpression in murine fibroblasts (3T3 cells)enhances ruffle formation in response to PDGF stimulation, as shown by immunofluorescence and electron and video microscopy. More importantly,microinjection of anti-WIP antibody or absence of WIP in murine fibroblasts results in decreased ruffle formation in response to PDGF treatment. Finally,overexpression of a modified form of WIP lacking the actin-binding site blocks PDGF-induced membrane ruffling. These data suggest a role for WIP in actin reorganization to form PDGF-induced ruffles. This is the first in vivo evidence in mammalian cells for a function of WIP dependent on its ability to bind actin.