Lyn-mediated procaspase 8 dimerization blocks apoptotic signaling in B-cell chronic lymphocytic leukemia

Lyn, a member of the group of tyrosine kinases named the Src family kinases (SFKs), is overexpressed, associated with an aberrant multiprotein complex and constitutively active in B-cell chronic lymphocytic leukemia (B-CLL) cells, resulting in a high level of tyrosine phosphorylation and contributin...

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Bibliographic Details
Published in:Blood 2014-02, Vol.123 (6), p.875-883
Main Authors: Zonta, Francesca, Pagano, Mario Angelo, Trentin, Livio, Tibaldi, Elena, Frezzato, Federica, Gattazzo, Cristina, Martini, Veronica, Trimarco, Valentina, Mazzorana, Marco, Bordin, Luciana, Semenzato, Gianpietro, Brunati, Anna Maria
Format: Article
Language:English
Subjects:
Apoptosis
Blotting, Western
Caspase 8 - chemistry
Caspase 8 - metabolism
Cell Proliferation
Computational Biology
Cytosol - metabolism
Electrophoresis, Gel, Two-Dimensional
Humans
Leukemia, Lymphocytic, Chronic, B-Cell - metabolism
Leukemia, Lymphocytic, Chronic, B-Cell - pathology
Phosphorylation
Protein Multimerization
Proteome - analysis
src-Family Kinases - metabolism
Tumor Cells, Cultured
Tyrosine - metabolism
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Summary:Lyn, a member of the group of tyrosine kinases named the Src family kinases (SFKs), is overexpressed, associated with an aberrant multiprotein complex and constitutively active in B-cell chronic lymphocytic leukemia (B-CLL) cells, resulting in a high level of tyrosine phosphorylation and contributing to their resistance to apoptosis. By using biochemical and bioinformatics tools, we identified procaspase-8 (procasp8), the caspase-8 zymogen, as a cytosolic target for Lyn in B-CLL cells, the phosphorylation of which at Tyr380 promotes the formation of an inactive procasp8 homodimer. This complex remains segregated in the cytosol and appears to be crucial in mediating the antiapoptotic function of Lyn in this disease. The significance of the Lyn-procasp8 axis in impairing apoptosis in B-CLL cells was further confirmed by pharmacological and genetic inhibition of procasp8, which drastically reduced the apoptosis induced by the SFK inhibitors PP2 and dasatinib. Our data highlight that Lyn's dysregulated expression, activity, and localization in B-CLLs support resistance to cell demise by inhibiting an early player of apoptotic signaling, and potentially broaden the perspectives of developing new strategies for the treatment of this disease. •Lyn's overexpression mediates resistance to apoptosis by promoting phosphorylation and dimerization of procaspase 8 in B-CLL cells.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2013-02-485540