4.8 Article

An α4 integrin-paxillin-Arf-GAP complex restricts Rac activation to the leading edge of migrating cells

Journal

NATURE CELL BIOLOGY
Volume 7, Issue 4, Pages 343-U7

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NATURE PUBLISHING GROUP
DOI: 10.1038/ncb1234

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Formation of a stable lamellipodium at the front of migrating cells requires localization of Rac activation to the leading edge. Restriction of alpha(4) integrin phosphorylation to the leading edge limits the interaction of alpha(4) with paxillin to the sides and rear of a migrating cell. The alpha(4)-paxillin complex inhibits stable lamellipodia, thus confining lamellipod formation to the cell anterior. Here we report that binding of paxillin to the alpha(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 alpha(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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