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J. Biol. Chem., Vol. 278, Issue 40, 38707-38714, October 3, 2003

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Crucial Role of the Specificity-determining Loop of the Integrin ₄ Subunit in the Binding of Cells to Laminin-5 and Outside-in Signal Transduction^*

Daisuke Tsuruta , Susan B. Hopkinson , Kimberly D. Lane, Michael E. Werner, Vincent L. Cryns and Jonathan C. R. Jones 

From the Departments of Cell and Molecular Biology and Medicine, Feinberg School of Medicine at Northwestern University, Chicago, Illinois 60611

Within each hemidesmosome, ₆₄ integrin plays a crucial role in hemidesmosome assembly by binding to laminin-5 in the basement membrane zone of epithelial tissue. Recent analyses have implicated "specificity-determining loops" (SDLs) in the I-like domain of integrin in regulating ligand binding. Here, we investigated the function of an SDL-like motif within the extracellular I-like domain of ₄ integrin. We generated point mutations within the SDL of ₄ integrin tagged with green fluorescent protein (GFP-₄K150A and GFP-₄Q155L). We also generated a mutation within the I-like domain of the ₄ integrin, lying outside the SDL region (GFP-₄V284E). We transfected constructs encoding the mutated ₄ integrins and a GFP-conjugated wild type ₄ integrin (GFP-₄WT) into 804G cells, which assemble hemidesmosomes, and human endothelial cells, which express little endogenous ₄ integrin. In transfected 804G cells, GFP-₄WT and GFP-₄V284E colocalize with hemidesmosome proteins, whereas hemidesmosomal components in cells expressing GFP-₄K150A and GFP-₄Q155L are aberrantly localized. In endothelial cells, GFP-₄WT and mutant proteins are co-expressed at the cell surface with ₆ integrin. When transfected endothelial cells are plated onto laminin-5 matrix, GFP-₄WT and GFP-₄V284E localize with laminin-5, whereas GFP-₄K150A and GFP-₄Q155L do not. GFP-₄WT and GFP-₄V284E expressed in endothelial cells associate with the adaptor protein Shc when the cells are stimulated with laminin-5. However, GFP-₄K150A and GFP-₄Q155L fail to associate with Shc even when laminin-5 is present, thus impacting downstream signaling. These results provide evidence that the SDL segment of the ₄ integrin subunit is required for ligand binding and is involved in outside-in signaling.

Received for publication, February 14, 2003 , and in revised form, July 1, 2003.

^* This work is supported by National Institutes of Health Grant RO1(24) DK60589 (to J. C. R. J.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These two authors contributed equally to this work.

To whom correspondence should be addressed: Dept. of Cell and Molecular Biology, Morton 4-616, Feinberg School of Medicine at Northwestern University, 303 E. Chicago Ave., Chicago, IL 60611. Tel.: 312-503-1412; Fax: 312-503-6475; E-mail: j-jones3{at}northwestern.edu.

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