Nucleocytoplasmic trafficking of the Syk protein tyrosine kinase.
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.
Zhou
Fei
F
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 201 S. University St., West Lafayette, IN 47907-2064, USA.
Hu
Jianjie
J
Ma
Haiyan
H
Harrison
Marietta L
ML
Geahlen
Robert L
RL
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology; D001402:B-Lymphocytes / Q000187:drug effects / Q000201:enzymology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D020134:Catalytic Domain; D002467:Cell Nucleus / Q000201:enzymology*; D002478:Cells, Cultured; D003593:Cytoplasm / Q000201:enzymology*; D004252:DNA Mutational Analysis; D004789:Enzyme Activation; D049452:Green Fluorescent Proteins / Q000032:analysis / Q000235:genetics; D007075:Immunoglobulin M / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D019913:Nuclear Localization Signals / Q000235:genetics*; D014176:Protein Biosynthesis; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism; D021381:Protein Transport / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D017384:Sequence Deletion; D000072377:Syk Kinase; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000888:Antibodies, Anti-Idiotypic; D007075:Immunoglobulin M; D047908:Intracellular Signaling Peptides and Proteins; D019913:Nuclear Localization Signals; D049452:Green Fluorescent Proteins; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; D011493:Protein Kinase C; D053148:Caspase 3; D020169:Caspases; D013755:Tetradecanoylphorbol Acetate