TY - JOUR
T1 - 14-3-3 binding and SUMOylation concur to the down-modulation of β-catenin antagonist Chibby 1 in chronic myeloid leukemia
AU - Mancini, Manuela
AU - Leo, Elisa
AU - Takemaru, Ken Ichi
AU - Campi, Virginia
AU - Castagnetti, Fausto
AU - Soverini, Simona
AU - De Benedittis, Caterina
AU - Rosti, Gianantonio
AU - Cavo, Michele
AU - Santucci, Maria Alessandra
AU - Martinelli, Giovanni
N1 - Publisher Copyright:
© 2015 Mancini et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2015/7/6
Y1 - 2015/7/6
N2 - The down-modulation of the β-catenin antagonist Chibby 1 (CBY1) associated with the BCR-ABL1 fusion gene of chronic myeloid leukemia (CML) contributes to the aberrant activation of β-catenin, particularly in leukemic stem cells (LSC) resistant to tyrosine kinase (TK) inhibitors. It is, at least partly, driven by transcriptional events and gene promoter hyper-methylation. Here we demonstrate that it also arises from reduced protein stability upon binding to 14-3-3σ adapter protein. CBY1/14-3-3σ interaction in BCR-ABL1+ cells is mediated by the fusion protein TK and AKT phosphorylation of CBY1 at critical serine 20, and encompasses the 14-3-3σ binding modes I and II involved in the binding with client proteins. Moreover, it is impaired by c-Jun N-terminal kinase (JNK) phosphorylation of 14-3-3σat serine 186, which promotes dissociation of client proteins. The ubiquitin proteasome system UPS participates in reducing stability of CBY1 bound with 14-3-3σ through enhanced SUMOylation. Our results open new routes towards the research on molecular pathways promoting the proliferative advantage of leukemic hematopoiesis over the normal counterpart.
AB - The down-modulation of the β-catenin antagonist Chibby 1 (CBY1) associated with the BCR-ABL1 fusion gene of chronic myeloid leukemia (CML) contributes to the aberrant activation of β-catenin, particularly in leukemic stem cells (LSC) resistant to tyrosine kinase (TK) inhibitors. It is, at least partly, driven by transcriptional events and gene promoter hyper-methylation. Here we demonstrate that it also arises from reduced protein stability upon binding to 14-3-3σ adapter protein. CBY1/14-3-3σ interaction in BCR-ABL1+ cells is mediated by the fusion protein TK and AKT phosphorylation of CBY1 at critical serine 20, and encompasses the 14-3-3σ binding modes I and II involved in the binding with client proteins. Moreover, it is impaired by c-Jun N-terminal kinase (JNK) phosphorylation of 14-3-3σat serine 186, which promotes dissociation of client proteins. The ubiquitin proteasome system UPS participates in reducing stability of CBY1 bound with 14-3-3σ through enhanced SUMOylation. Our results open new routes towards the research on molecular pathways promoting the proliferative advantage of leukemic hematopoiesis over the normal counterpart.
UR - https://www.scopus.com/pages/publications/84940195656
U2 - 10.1371/journal.pone.0131074
DO - 10.1371/journal.pone.0131074
M3 - Article
C2 - 26147002
AN - SCOPUS:84940195656
SN - 1932-6203
VL - 10
JO - PLoS ONE
JF - PLoS ONE
IS - 7
M1 - e0131074
ER -