14-3-3 Binding and Sumoylation Concur to the Down-Modulation of β-catenin Antagonist Chibby 1 in Chronic Myeloid Leukemia

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2015 Jul 7

PMID 26147002

Citations 5

Authors

Manuela Mancini

Elisa Leo

Ken-Ichi Takemaru

Virginia Campi

Fausto Castagnetti

Simona Soverini

Caterina de Benedittis

Gianantonio Rosti

Michele Cavo

Maria Alessandra Santucci

Giovanni Martinelli

Affiliations

Soon will be listed here.

Abstract

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 14-3-3σ at 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.

Citing Articles

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Chibby 1: a new component of β-catenin-signaling in chronic myeloid leukemia.

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