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Molecular and Cellular Biology, May 2006, p. 3478-3491, Vol. 26, No. 9
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.9.3478-3491.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Nucleocytoplasmic Trafficking of the Syk Protein Tyrosine Kinase

Fei Zhou,{dagger} Jianjie Hu,{dagger} Haiyan Ma,{ddagger} Marietta L. Harrison, and Robert L. Geahlen*

Department of Medicinal Chemistry and Molecular Pharmacology and Purdue Cancer Center, Purdue University, West Lafayette, Indiana 47907

Received 29 December 2005/ Returned for modification 25 January 2006/ Accepted 7 February 2006

The protein tyrosine kinase Syk couples the B-cell receptor (BCR) for antigen to multiple intracellular signaling pathways and also modulates cellular responses to inducers of oxidative stress in a receptor-independent fashion. In B cells, Syk is found in both the nuclear and cytoplasmic compartments but contains no recognizable nuclear localization or export signals. Through the analysis of a series of deletion mutants, we identified the presence of an unconventional shuttling sequence near the junction of the catalytic domain and the linker B region that accounts for Syk's subcellular localization. This localization is altered following prolonged engagement of the BCR, which causes Syk to be excluded from the nucleus. Nuclear exclusion requires the receptor-mediated activation of protein kinase C and new protein synthesis. Both of these processes also potentiate the activation of caspase 3 in cells in response to oxidative stress in a manner that is dependent on the localization of Syk outside of the nucleus. In contrast, restriction of Syk to the nucleus greatly diminishes the stress-induced activation of caspase 3.

* Corresponding author. Mailing address: Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 201 S. University St., West Lafayette, IN 47907-2064. Phone: (765) 494-1457. Fax: (765) 494-9193. E-mail: geahlen{at}purdue.edu.

{dagger} F.Z. and J.H. have equal first authorship.

{ddagger} Present address: BioNumerik Pharmaceuticals, Inc., San Antonio, TX 78229.

Molecular and Cellular Biology, May 2006, p. 3478-3491, Vol. 26, No. 9
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.9.3478-3491.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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