14-3-3 Ligand Prevents Nuclear Import of c-ABL Protein in Chronic Myeloid Leukemia
Veljković, Nevena V.
Santucci, Maria Alessandra
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Here we demonstrated that the loss of function of not-rearranged c-ABL in chronic myeloid leukemia (CML) is promoted by its cytoplasmic compartmentalization bound to 14-3-3 sigma scaffolding protein. In particular, constitutive tyrosine kinase (TK) activity of p210 BCR-ABL blocks c-Jun N-terminal kinase (JNK) phosphorylation leading to 14-3-3 sigma phosphorylation at a critical residue (Ser(186)) for c-ABL binding in response to DNA damage. Moreover, it is associated with 14-3-3 sigma over-expression arising from epigenetic mechanisms (promoter hyper-acetylation). Accordingly, p210 BCR-ABL TK inhibition by the TK inhibitor Imatinib mesylate (IM) evokes multiple events, including JNK phosphorylation at Thr(183), p38 mitogen-activated protein kinase (MAPK) phosphorylation at Thr(180), c-ABL de-phosphorylation at Ser residues involved in 14-3-3 binding and reduction of 14-3-3 sigma expression, that let c-ABL release from 14-3-3 sigma and nuclear import, and address BCR-ABL-expressing cell...s towards apoptotic death. Informational spectrum method (ISM), a virtual spectroscopy method for analysis of protein interactions based on their structure, and mathematical filtering in cross spectrum (CS) analysis identified 14-3-3 sigma/c-ABL binding sites. Further investigation on CS profiles of c-ABL- and p210 BCR-ABL-containing complexes revealed the mechanism likely involved 14-3-3 precluded phosphorylation in CML cells.
Keywords:Chronic Myeloid Leukemia (CML) / BCR-ABL / Imatinib mesylate (IM) / c-ABL / 14-3-3 sigma / JNK / p38 MAPK
Source:Traffic, 2009, 10, 6, 637-647
- University of Bologna, BolognaAIL and Carisbo Foundation, Dipartimento di Scienze Radiologiche e Istocitopatologiche, Centro Interdipartimentale di Ricerca sul Cancro Giorgio Prodi