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PNAS 107 (4): 1420-1424

Copyright © 2010 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / CELL BIOLOGY

Anthrax toxin triggers the activation of src-like kinases to mediate its own uptake

Laurence Abrami, Béatrice Kunz, and F. Gisou van der Goot 1

Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland

Edited by Kai Simons, Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany, and approved December 4, 2009 (received for review September 23, 2009)

Abstract: AB-type toxins, like other bacterial toxins, are notably opportunistic molecules. They rely on target cell receptors to reach the appropriate location within the target cell where translocation of their enzymatic subunits occurs. The anthrax toxin, however, times its own uptake, suggesting that toxin binding triggers specific signaling events. Here we show that the anthrax toxin triggers tyrosine phosphorylation of its own receptors, capillary morphogenesis gene 2 and tumor endothelial marker 8, which are not endowed with intrinsic kinase activity. This is required for efficient toxin uptake because endocytosis of the mutant receptor lacking the cytoplasmic tyrosine residues is strongly delayed. Phosphorylation of the receptors was dependent on src-like kinases, which where activated upon toxin binding. Importantly, src-dependent phosphorylation of the receptor was required for its subsequent ubiquitination, which in turn was required for clathrin-mediated endocytosis. Consistently, we found that uptake of the anthrax toxin and processing of the lethal factor substrate MEK1 are inhibited by silencing of src and fyn, as well as in src and fyn knockout cells.

Key Words: endocytosis • CMG2 • TEM8 • ubiquitination

Freely available online through the PNAS open access option.

Author contributions: L.A. and F.G.v.d.G. designed research; L.A. and B.K. performed research; L.A., B.K., and F.G.v.d.G. analyzed data; and L.A. and F.G.v.d.G. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/cgi/content/full/0910782107/DCSupplemental.

1To whom correspondence should be addressed at: Ecole Polytechnique Fédérale de Lausanne, Institute of Global Health, Station 15, 1015 Lausanne, Switzerland. E-mail: gisou.vandergoot{at}epfl.ch.

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