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Vol. 17, Issue 3, 1096-1109, March 2006

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Shiga Toxin Regulates Its Entry in a Syk-dependent Manner

Silje Ugland Lauvrak ^* , Sébastien Wälchli ^* , Tore-Geir Iversen ^*, Hege Holte Slagsvold ^*, Maria Lyngaas Torgersen ^*, Bjørn Spilsberg ^*, and Kirsten Sandvig ^* 

^* Department of Biochemistry, Institute for Cancer Research, Faculty Division The Norwegian Radium Hospital, 0310 Oslo, Norway; Department of Molecular Biosciences, University of Oslo, 0316 Oslo, Norway

Submitted August 16, 2005; Revised November 30, 2005; Accepted December 5, 2005
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 endoplasmic reticulum, and then the A-fragment enters the cytosol. In this study, we have 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 protein 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 small interfering RNA, 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.

Abbreviations used: Stx, Shiga toxin; TGN, trans-Golgi network.

These authors contributed equally to this work.

Address correspondence to: Kirsten Sandvig (kirsten.sandvig{at}labmed.uio.no).

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