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PNAS 105 (20): 7188-7193

Copyright © 2008 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / CELL BIOLOGY

The {alpha}9β1 integrin enhances cell migration by polyamine-mediated modulation of an inward-rectifier potassium channel

Gregory W. deHart*, Taihao Jin{dagger}, Diane E. McCloskey{ddagger}, Anthony E. Pegg{ddagger}, and Dean Sheppard*,§

*Lung Biology Center, Department of Medicine, and {dagger}Howard Hughes Medical Institute, Department of Physiology, University of California, San Francisco, CA 94143; and {ddagger}Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA 17033

Edited by Lily Y. Jan, University of California School of Medicine, San Francisco, CA, and approved March 11, 2008

Received for publication August 27, 2007.

Abstract: The {alpha}9β1 integrin accelerates cell migration through binding of spermidine/spermine acetyltransferase (SSAT) to the {alpha}9 cytoplasmic domain. We now show that SSAT enhances {alpha}9-mediated migration specifically through catabolism of spermidine and/or spermine. Because spermine and spermidine are effective blockers of K+ ion efflux through inward-rectifier K+ (Kir) channels, we examined the involvement of Kir channels in this pathway. The Kir channel inhibitor, barium, or knockdown of a single subunit, Kir4.2, specifically inhibited {alpha}9-dependent cell migration. {alpha}9β1 and Kir4.2 colocalized in focal adhesions at the leading edge of migrating cells and inhibition or knockdown of Kir4.2 caused reduced persistence and an increased number of lamellipodial extensions in cells migrating on an {alpha}9β1 ligand. These results identify a pathway through which the {alpha}9 integrin subunit stimulates cell migration by localized polyamine catabolism and modulation of Kir channel function.

Freely available online through the PNAS open access option.

Author contributions: G.W.d. and D.S. designed research; G.W.d. and T.J. performed research; T.J., D.E.M., and A.E.P. contributed new reagents/analytic tools; G.W.d., T.J., D.E.M., and A.E.P. analyzed data; and G.W.d. and D.S. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

See Commentary on page 7109.

This article contains supporting information online at www.pnas.org/cgi/content/full/0708044105/DCSupplemental.

§To whom correspondence should be addressed at: Box 2922, University of California, San Francisco, CA 94143-2922. E-mail: dean.sheppard{at}ucsf.edu

© 2008 by The National Academy of Sciences of the USA

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