14-3-3 ligand prevents nuclear import of c-ABL protein in chronic myeloid leukemia.
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 cells 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.
Mancini
Manuela
M
Istituto di Ematologia e Oncologia Medica Lorenzo e Ariosto Serágnoli, University of Bologna-Medical School, Bologna, Italy. mancini_manu@yahoo.com
Veljkovic
Nevena
N
Corradi
Valentina
V
Zuffa
Elisa
E
Corrado
Patrizia
P
Pagnotta
Eleonora
E
Martinelli
Giovanni
G
Barbieri
Enza
E
Santucci
Maria Alessandra
MA
D048948:14-3-3 Proteins / Q000378:metabolism*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism*; D008024:Ligands; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D010766:Phosphorylation; D021381:Protein Transport; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*
D048948:14-3-3 Proteins; D008024:Ligands; D016315:Proto-Oncogene Proteins c-abl; D048670:MAP Kinase Kinase 4