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Published online 11 August 2003. doi:10.1083/jcb.200304031
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© The Rockefeller University Press, 0021-9525/2003/8/731 $5.00
The Journal of Cell Biology, Volume 162, Number 4, 731-741

Article

 Spatial restriction of {alpha}4 integrin phosphorylation regulates lamellipodial stability and {alpha}4ß1-dependent cell migration

Lawrence E. Goldfinger1, Jaewon Han1, William B. Kiosses1, Alan K. Howe2 and Mark H. Ginsberg1

1 Department of Cell Biology, Division of Vascular Biology, The Scripps Research Institute, La Jolla, CA 92037
2 Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599

Address correspondence to M.H. Ginsberg, Dept. of Cell Biology, Division of Vascular Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., VB-2 La Jolla, CA 92037. Tel.: (858) 784-7124. Fax: (858) 784-7343. email: ginsberg{at}scripps.edu

Întegrins coordinate spatial signaling events essential for cell polarity and directed migration. Such signals from {alpha}4 integrins regulate cell migration in development and in leukocyte trafficking. Here, we report that efficient {alpha}4-mediated migration requires spatial control of {alpha}4 phosphorylation by protein kinase A, and hence localized inhibition of binding of the signaling adaptor, paxillin, to the integrin. In migrating cells, phosphorylated {alpha}4 accumulated along the leading edge. Blocking {alpha}4 phosphorylation by mutagenesis or by inhibition of protein kinase A drastically reduced {alpha}4-dependent migration and lamellipodial stability. {alpha}4 phosphorylation blocks paxillin binding in vitro; we now find that paxillin and phospho-{alpha}4 were in distinct clusters at the leading edge of migrating cells, whereas unphosphorylated {alpha}4 and paxillin colocalized along the lateral edges of those cells. Furthermore, enforced paxillin association with {alpha}4 inhibits migration and reduced lamellipodial stability. These results show that topographically specific integrin phosphorylation can control cell migration and polarization by spatial segregation of adaptor protein binding.

Key Words: {alpha}4 integrin; paxillin; polarization; lamellipodia; PKA

L.E. Goldfinger and J. Han contributed equally to this work.

Abbreviation used in this paper: PKA, protein kinase A.


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