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Originally published as MBC in Press, 10.1091/mbc.E05-04-0358 on October 5, 2005

Vol. 16, Issue 12, 5773-5783, December 2005

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Plasma Membrane Organization Is Essential for Balancing Competing Pseudopod- and Uropod-promoting Signals during Neutrophil Polarization and Migration{boxd}{boxv}

Stéphane Bodin, and Matthew D. Welch

Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720

Submitted April 28, 2005; Revised September 24, 2005; Accepted September 26, 2005
Monitoring Editor: Clare Waterman-Storer

Exposure of neutrophils to chemoattractant induces cell polarization and migration. These behaviors require the asymmetric activation of distinct signaling pathways and cytoskeletal elements in the protruding pseudopod at the front of cells and the retracting uropod at the rear. An important outstanding question is, how does the organization of the plasma membrane participate in establishing asymmetry during polarization and migration? To answer this question, we investigated the function of cholesterol, a lipid known to influence membrane organization. Using controlled cholesterol depletion, we found that a cholesterol-dependent membrane organization enabled cell polarization and migration by promoting uropod function and suppressing ectopic pseudopod formation. At a mechanistic level, we showed that cholesterol was directly required for suppressing inappropriate activation of the pseudopod-promoting Gi/PI3-kinase signaling pathway. Furthermore, cholesterol was required for dampening Gi-dependent negative feedback on the RhoA signaling pathway, thus enabling RhoA activation and uropod function. Our findings suggest a model in which a cholesterol-dependent membrane organization plays an essential role in the establishment of cellular asymmetry by balancing the activation and segregating the localization of competing pseudopod- and uropod-inducing signaling pathways during neutrophil polarization and migration.

This article was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E05-04-0358) on October 5, 2005.

{boxd}{boxv} The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Address correspondence to: Matthew Welch (welch{at}berkeley.edu) or Stéphane Bodin (stbodin{at}uclink.berkeley.edu).




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