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

Nature Cell Biology volume 7, pages 343–352 (2005)Cite this article

An Erratum to this article was published on 01 May 2005

Abstract

Formation of a stable lamellipodium at the front of migrating cells requires localization of Rac activation to the leading edge. Restriction of α4 integrin phosphorylation to the leading edge limits the interaction of α4 with paxillin to the sides and rear of a migrating cell. The α4–paxillin complex inhibits stable lamellipodia, thus confining lamellipod formation to the cell anterior. Here we report that binding of paxillin to the α4 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 α4–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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Figure 1: Paxillin association with the α4 integrin subunit reduces local Rac activity at the cell periphery.
Figure 2: Paxillin association with an 'irrelevant' integrin α subunit inhibits adhesion-dependent Rac activation and cell spreading.
Figure 3: Integrin-associated paxillin LD4 domain leads to inhibition of adhesion-dependent Rac activation and cell spreading.
Figure 4: Paxillin mediates GIT1 binding to the α4 cytoplasmic domain.
Figure 5: Paxillin-mediated association of Arf-GAP activity with integrins inhibits adhesion-dependent Rac activation.
Figure 6: Disruption of the paxillin–Arf-GAP complex increases α4β1-mediated Rac activity at the cell periphery.
Figure 7: Disruption of the α4–paxillin–Arf-GAP complex inhibits α4β1-mediated motility.
Figure 8: Model for the regulation of Rac activity by α4-associated paxillin.

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Acknowledgements

We thank Dr Miguel A. Del Pozo, Dr Larry E. Goldfinger and Dr Sergio Lizano for valuable discussions, and Dr Christopher E. Turner for critical review of the manuscript. This work was supported by grants from the National Institutes of Health. N.N. was supported by The Naito Foundation and then by a postdoctoral fellowship from the American Heart Association. J.H. was an advanced Fellow of the National Multiple Sclerosis Society.

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  1. Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, 92093-0726, CA, USA

    Naoyuki Nishiya, Jaewon Han & Mark H. Ginsberg

  2. The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, 92037, CA, USA

    William B. Kiosses

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Nishiya, N., Kiosses, W., Han, J. et al. An α4 integrin–paxillin–Arf-GAP complex restricts Rac activation to the leading edge of migrating cells. Nat Cell Biol 7, 343–352 (2005). https://doi.org/10.1038/ncb1234

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