The NPM-ALK oncoprotein abrogates CD30 signaling and constitutive NF-kappaB activation in anaplastic large cell lymphoma.
NPM-ALK characterizes anaplastic large cell lymphoma (ALCL), as does the high expression of CD30, a feature shared with H-RS cells of classic Hodgkin's lymphoma. In H-RS cells, ligand-independent signaling by overexpressed CD30 drives constitutive NF-kappaB activation, which is absent in ALCL cells. Here we show that NPM-ALK impedes CD30 signaling and NF-kappaB activation, dependent on both ALK kinase activity and the N-terminal NPM domain. NPM-ALK transduction into H-RS cell lines abrogates recruitment and aggregation of TRAF proteins, inducing an ALCL-like morphology and phenotype. TRAF2 associates with NPM-ALK at a consensus binding motif located in the kinase domain. Thus, NPM-ALK abrogates CD30-driven NF-kappaB activation and can also induce an ALCL phenotype, distinguishing ALCL cells from H-RS cells of T cell origin.
Horie
Ryouichi
R
Fourth Department of Internal Medicine, Faculty of Medicine, Kitasato University, 1-15-1 Kitasato, Sagamihara, Kanagawa 228-8555, Japan.
Watanabe
Mariko
M
Ishida
Takaomi
T
Koiwa
Tsukasa
T
Aizawa
Shigemi
S
Itoh
Kinji
K
Higashihara
Masaaki
M
Kadin
Marshall E
ME
Watanabe
Toshiki
T
D020816:Amino Acid Motifs; D002478:Cells, Cultured; D016384:Consensus Sequence; D003593:Cytoplasm / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D017730:Ki-1 Antigen / Q000235:genetics / Q000378:metabolism*; D017728:Lymphoma, Large-Cell, Anaplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D010766:Phosphorylation; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2; D014443:Tyrosine / Q000378:metabolism
D020672:I-kappa B Proteins; D017730:Ki-1 Antigen; D016328:NF-kappa B; D015514:Oncogene Proteins, Fusion; D011506:Proteins; D047992:TNF Receptor-Associated Factor 2; D014443:Tyrosine; C107023:p80(NPM-ALK) protein; D011505:Protein-Tyrosine Kinases