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Pàgina inicial > Articles > Articles publicats > Novel phosphorylated TAK1 species with functional impact on NF-κB and β-catenin signaling in human Cutaneous T-cell lymphoma |
Data: | 2018 |
Resum: | 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. |
Ajuts: | Instituto de Salud Carlos III PT13-0002-002 Instituto de Salud Carlos III PT13-0010-0005 Instituto de Salud Carlos III PI13-00448 Instituto de Salud Carlos III PI16-00437 Ministerio de Economía y Competitividad SAF2016-75613-R |
Nota: | Altres ajuts: Fundació la Marató de TV3 (20131210); and the "Xarxa de Bancs de tumors sponsored by Pla Director d'Oncologia de Catalunya (XBTC). |
Drets: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades. |
Llengua: | Anglès |
Document: | Article ; recerca ; Versió publicada |
Matèria: | Humans ; Lymphoma, T-Cell, Cutaneous ; Metabolism ; NF-kappa B ; Phosphorylation ; Physiology ; Receptors, Neuropeptide Y ; Sezary Syndrome ; Signal Transduction ; Skin Neoplasms |
Publicat a: | Leukemia, Vol. 32 (february 2018) , p. 2211-2223, ISSN 1476-5551 |
13 p, 3.1 MB |