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

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, Sezary syndrome). Molecular events leading to CTCL progression are heterogeneous, however recent DNA and RNA sequencing studies highlighted the importance of NF-kappa B and beta-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-kappa B signaling. Inhibition of TAK1 precluded NF-kappa B and beta-catenin signaling and induced apoptosis of CTCL cell lines and primary Sezary 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-kappa B and beta-catenin activation. These results identified TAK1 as a potential biomarker and therapeutic target for CTCL therapy.