title: Lyn-mediated procaspase 8 dimerization blocks apoptotic signaling in B-cell chronic lymphocytic leukemia.
abstract: 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.
authors.affiliation: Department of Molecular Medicine, and.
authors.forename: Francesca
authors.initials: F
authors.lastname: Zonta
authors.forename: Mario Angelo
authors.initials: MA
authors.lastname: Pagano
authors.forename: Livio
authors.initials: L
authors.lastname: Trentin
authors.forename: Elena
authors.initials: E
authors.lastname: Tibaldi
authors.forename: Federica
authors.initials: F
authors.lastname: Frezzato
authors.forename: Cristina
authors.initials: C
authors.lastname: Gattazzo
authors.forename: Veronica
authors.initials: V
authors.lastname: Martini
authors.forename: Valentina
authors.initials: V
authors.lastname: Trimarco
authors.forename: Marco
authors.initials: M
authors.lastname: Mazzorana
authors.forename: Luciana
authors.initials: L
authors.lastname: Bordin
authors.forename: Gianpietro
authors.initials: G
authors.lastname: Semenzato
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Brunati
mesh_terms: D017209:Apoptosis; D015153:Blotting, Western; D053181:Caspase 8 / Q000737:chemistry* / Q000378:metabolism; D049109:Cell Proliferation; D019295:Computational Biology; D003600:Cytosol / Q000378:metabolism; D015180:Electrophoresis, Gel, Two-Dimensional; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D055503:Protein Multimerization; D020543:Proteome / Q000032:analysis; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D020543:Proteome; D014443:Tyrosine; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D053181:Caspase 8