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Originally published In Press as doi:10.1074/jbc.M110928200 on March 27, 2002

J. Biol. Chem., Vol. 277, Issue 23, 20887-20894, June 7, 2002
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A Fragment of Paxillin Binds the alpha 4 Integrin Cytoplasmic Domain (Tail) and Selectively Inhibits alpha 4-Mediated Cell Migration*

Shouchun LiuDagger §, William B. KiossesDagger , David M. RoseDagger , Marina SlepakDagger , Ravi Salgia, James D. Griffin, Christopher E. Turner||, Martin A. SchwartzDagger , and Mark H. GinsbergDagger **

From the Departments of Dagger  Vascular Biology and ** Cell Biology, The Scripps Research Institute, La Jolla, California 92037, the  Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medial School, Boston, Massachusetts 02115, and the || Department of Cell and Development Biology, SUNY Upstate Medical University, Syracuse, New York 13210

The alpha 4 integrins play important roles in embryogenesis, hematopoiesis, cardiac development, and the immune responses. The alpha 4 integrin subunit is indispensable for these biological processes, possibly because the alpha 4 subunit regulates cellular functions differently from other integrin alpha  subunits. We have previously reported that the alpha 4 cytoplasmic domain directly and tightly binds paxillin, an intracellular signaling adaptor molecule, and this interaction accounts for some of the unusual functional responses to alpha 4 integrin-mediated cell adhesion. We also have identified a conserved 9-amino acid region (Glu983-Tyr991) in the alpha 4 cytoplasmic domain that is sufficient for paxillin binding, and an alanine substitution at either Glu983 or Tyr991 within this region disrupted the alpha 4-paxillin interaction and reversed the effects of the alpha 4 cytoplasmic domain on cell spreading and migration. In the current study, we have mapped the alpha 4-binding site within paxillin using mutational analysis, and examined its effects on the alpha 4 tail-mediated functional responses. Here we report that sequences between residues Ala176 and Asp275 of paxillin are sufficient for binding to the alpha 4 tail. We found that the alpha 4 tail, paxillin, and FAT, the focal adhesion targeting domain of pp125FAK, could form a ternary complex and that the alpha 4-binding paxillin fragment, P(Ala176-Asp275), specifically blocked paxillin binding to the alpha 4 tail more efficiently than it blocked binding to FAT. Furthermore, when expressed in cells, this alpha 4-binding paxillin fragment specifically inhibited the alpha 4 tail-stimulated cell migration. Thus, paxillin binding to the alpha 4 tail leads to enhanced cell migration and inhibition of the alpha 4-paxillin interaction selectively blocks the alpha 4-dependent cellular responses.

* This work was supported by a Scientist Development Grant from the American Heart Association and a Special Fellow Award from the Leukemia & Lymphoma Society (to S. L.), the Juvenile Diabetes Foundation International (to D. M. R.), and National Institutes of Health Grants AR27214, HL31950, and HL48728 (to M. H. G.), and GM47607 (to C. E. T.). This is publication 14505-VB from the Scripps Research Institute.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ To whom correspondence should be addressed: Cardiovascular Research, Millennium Pharmaceuticals, Inc., 256 E. Grand Ave., South San Francisco, CA 94080. Tel.: 650-246-7301; Fax: 650-244-9270; E-mail: shouchun.liu@mpi.com.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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