Formation of a stable lamellipodium at the front of migrating cells requires localization of Rac activation to the leading edge. Restriction of 4 integrin phosphorylation to the leading edge limits the interaction of 4 with paxillin to the sides and rear of a migrating cell. The 4−paxillin complex inhibits stable lamellipodia, thus confining lamellipod formation to the cell anterior. Here we report that binding of paxillin to the 4 integrin subunit inhibits adhesion-dependent lamellipodium formation by blocking Rac activation. The paxillin LD4 domain mediates this reduction in Rac activity by recruiting an ADP-ribosylation factor GTPase-activating protein (Arf-GAP) that decreases Arf activity, thereby inhibiting Rac. Finally, the localized formation of the 4−paxillin−Arf-GAP complex mediates the polarization of Rac activity and promotes directional cell migration. These findings establish a mechanism for the spatial localization of Rac activity to enhance cell migration.
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4 integrin−paxillin−Arf-GAP complex restricts Rac activation to the leading edge of migrating cells
4 integrin phosphorylation to the leading edge limits the interaction of 
