ADP-ribosylation factor–like 4C binding to filamin-A modulates filopodium formation and cell migration

Abstract

Filamin-A plays a key role in tumorigenesis as well as the metastatic progression of prostate cancer, ovarian cancer, and gastric carcinoma. In this study, we identified filamin-A as a novel effector of Arl4C and showed that binding between Arl4C and FLNa modulates the formation of filopodia and cell migration by promoting activation of Cdc42.

Abstract

Changes in cell morphology and the physical forces that occur during migration are generated by a dynamic filamentous actin cytoskeleton. The ADP-ribosylation factor–like 4C (Arl4C) small GTPase acts as a molecular switch to regulate morphological changes and cell migration, although the mechanism by which this occurs remains unclear. Here we report that Arl4C functions with the actin regulator filamin-A (FLNa) to modulate filopodium formation and cell migration. We found that Arl4C interacted with FLNa in a GTP-dependent manner and that FLNa IgG repeat 22 is both required and sufficient for this interaction. We also show that interaction between FLNa and Arl4C is essential for Arl4C-induced filopodium formation and increases the association of FLNa with Cdc42-GEF FGD6, promoting cell division cycle 42 (Cdc42) GTPase activation. Thus our study revealed a novel mechanism, whereby filopodium formation and cell migration are regulated through the Arl4C-FLNa–mediated activation of Cdc42.