Novel phosphorylated TAK1 species with functional impact on NF-κB and β-catenin signaling in human Cutaneous T-cell lymphoma

Fernando Gallardo, Joan Bertran, Erika López-Arribillaga, Jéssica González, Silvia Menéndez, Ignacio Sánchez, Luis Colomo, Mar Iglesias, Marta Garrido, Luis Francisco Santamaría-Babí, Ferran Torres, Ramon M. Pujol, Anna Bigas, Lluís Espinosa

Research output: Contribution to journalArticleResearch

4 Citations (Scopus)

Abstract

© 2018, The Author(s). Cutaneous T-cell lymphomas (CTCLs) represent different subtypes of lymphoproliferative disorders with no curative therapies for the advanced forms of the disease (namely mycosis fungoides and the leukemic variant, Sézary syndrome). Molecular events leading to CTCL progression are heterogeneous, however recent DNA and RNA sequencing studies highlighted the importance of NF-κB and β-catenin pathways. We here show that the kinase TAK1, known as essential in B-cell lymphoma, is constitutively activated in CTCL cells, but tempered by the MYPT1/PP1 phosphatase complex. Blocking PP1 activity, both pharmacologically and genetically, resulted in TAK1 hyperphosphorylation at residues T344, S389, T444, and T511, which have functional impact on canonical NF-κB signaling. Inhibition of TAK1 precluded NF-κB and β-catenin signaling and induced apoptosis of CTCL cell lines and primary Sézary syndrome cells both in vitro and in vivo. Detection of phosphorylated TAK1 at T444 and T344 is associated with the presence of lymphoma in a set of 60 primary human samples correlating with NF-κB and β-catenin activation. These results identified TAK1 as a potential biomarker and therapeutic target for CTCL therapy.
Original languageEnglish
Pages (from-to)2211-2223
JournalLeukemia
Volume32
DOIs
Publication statusPublished - 1 Oct 2018

Fingerprint Dive into the research topics of 'Novel phosphorylated TAK1 species with functional impact on NF-κB and β-catenin signaling in human Cutaneous T-cell lymphoma'. Together they form a unique fingerprint.

Cite this