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J. Biol. Chem., Vol. 281, Issue 32, 23227-23236, August 11, 2006

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Anthrax Toxin Receptor 1/Tumor Endothelium Marker 8 Mediates Cell Spreading by Coupling Extracellular Ligands to the Actin Cytoskeleton^*

Erica Werner¹, Andrew P. Kowalczyk, and Victor Faundez

From the Departments of Cell Biology and Dermatology, Emory University, Atlanta, Georgia 30322-3030

Tumor endothelial marker 8 (TEM8) is induced in tumor-associated vasculature and acts as a receptor for Protective Antigen (PA), the cell-binding component of the anthrax toxin determinant for toxin entrance into cells. However, the normal function for TEM8 remains unknown. We show that TEM8 functions as an adhesion molecule mediating cell spreading on immobilized PA and collagen I. The mechanism for TEM8 interaction with collagen I was cell type-specific, because binding to collagen I was abrogated by 1 integrin function blocking antibody in HEK293 cells, but not in primary synovial rabbit fibroblasts. Binding to PA remained unaffected by the addition of 1 integrin function blocking antibody. Whereas the extracellular and transmembrane domains of TEM8 were sufficient to provide cell attachment, the intracellular domain was critical for spreading. Fusion of the cytosolic domain of TEM8 to the IL-2 receptor, conferred cell-spreading capability on IL-2 receptor antibody substrates. The cytoplasmic domain mediated linkage with the actin cytoskeleton as it co-precipitated actin and determined partitioning of TEM8 to the actin-containing detergent insoluble cellular fraction. TEM8 anchorage to actin was relevant as spreading was inhibited by the cytoskeleton-disrupting drug cytochalasin D, but persisted in the presence of the microtubule-depolymerizing drug nocodazole, and in cells lacking intermediate filaments. Thus, our results indicate that TEM8 is a new adhesion molecule linking collagen I or PA to the actin cytoskeleton.

Received for publication, April 17, 2006 , and in revised form, June 6, 2006.

^* This work was supported by the Emory University Research Committee and the American Heart Association (to E. W.), and National Institutes of Health Grants R01AR050501 (to A. P. K.) and R01NS42599 (to V. F.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. A and B.

¹ To whom correspondence should be addressed: Dept. of Cell Biology. Whitehead Biomedical Research Bldg, Rm 455, 615 Michael St., Atlanta, GA 30322-3030. Tel.: 404-727-6277; E-mail: ericaw{at}cellbio.emory.edu.

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