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A more recent version of this article appeared on March 1, 2006
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Submitted on August 16, 2005
Revised on November 30, 2005
Accepted on December 5, 2005
*Department of Biochemistry, Institute for Cancer Research, Faculty Division, The Norwegian Radium Hospital, 0310 Oslo, Norway; Department of Molecular Bioscience, University of Oslo, 0316 Oslo, Norway
Monitoring Editor: Suzanne Pfeffer
Shiga toxin (Stx) is composed of an A-moiety that inhibits protein synthesis after translocation into the cytosol, and a B-moiety that binds to Gb3 at the cell surface and mediates endocytosis of the toxin. After endocytosis Stx is transported retrogradely to the ER, and then the A-fragment enters the cytosol. We have in this study investigated whether toxin-induced signaling is involved in its entry. Stx was found to activate Syk, and induce rapid tyrosine phosphorylation of several proteins, one being clathrin heavy chain. Toxin-induced clathrin phosphorylation required Syk activity, and in cells overexpressing Syk a complex containing clathrin and Syk could be demonstrated. Depletion of Syk by siRNA, expression of a dominant negative Syk mutant (Syk KD), or treatment with the Syk inhibitor piceatannol inhibited not only Stx-induced clathrin phosphorylation, but also endocytosis of the toxin. Also Golgi transport of Stx was inhibited under all these conditions. In conclusion, our data suggest that Stx regulates its entry into target cells.
These authors contributed equally to this work.
Address correspondence to:
Kirsten Sandvig (kirsten.sandvig{at}labmed.uio.no)
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