title: An alpha4 integrin-paxillin-Arf-GAP complex restricts Rac activation to the leading edge of migrating cells.
abstract: Formation of a stable lamellipodium at the front of migrating cells requires localization of Rac activation to the leading edge. Restriction of alpha4 integrin phosphorylation to the leading edge limits the interaction of alpha4 with paxillin to the sides and rear of a migrating cell. The alpha4-paxillin complex inhibits stable lamellipodia, thus confining lamellipod formation to the cell anterior. Here we report that binding of paxillin to the alpha4 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 alpha4-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.
authors.affiliation: Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0726, USA.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Nishiya
authors.forename: William B
authors.initials: WB
authors.lastname: Kiosses
authors.forename: Jaewon
authors.initials: J
authors.lastname: Han
authors.forename: Mark H
authors.initials: MH
authors.lastname: Ginsberg
mesh_terms: D020727:ADP-Ribosylation Factors / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D016764:Cell Polarity / Q000187:drug effects / Q000502:physiology; D006224:Cricetinae; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D039441:Integrin alpha4 / Q000378:metabolism*; D019012:Integrin beta1 / Q000378:metabolism*; D008024:Ligands; D046911:Macromolecular Substances / Q000378:metabolism; D008954:Models, Biological; D051419:Paxillin; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary / Q000502:physiology; D011554:Pseudopodia / Q000187:drug effects / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D020744:rac GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D003598:Cytoskeletal Proteins; D020690:GTPase-Activating Proteins; D019012:Integrin beta1; D008024:Ligands; D046911:Macromolecular Substances; D051419:Paxillin; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D039441:Integrin alpha4; D020727:ADP-Ribosylation Factors; D020744:rac GTP-Binding Proteins