Distinct Motifs in the Intracellular Domain of Human CD30 Differentially Activate Canonical and Alternative Transcription Factor NF-kB Signaling

The TNF-receptor superfamily member CD30 is expressed on normal and malignant lymphocytes, including anaplastic large cell lymphoma (ALCL) cells. CD30 transmits multiple effects, including activation of NF-kB signaling, cell proliferation, growth arrest and apoptosis. How CD30 generates these pleiotropic effects is currently unknown. Herein we describe ALCL cells expressing truncated forms of the CD30 intracellular domain that allowed us to identify the key regions responsible for transmitting its biological effects in lymphocytes. The first region (CD30519–537) activated both the alternative and canonical NF-kB pathways as detected by p100 and IkBa degradation, IKKb-dependent transcription of both IkBa and the cyclin-dependent kinase inhibitor p21WAF1/CIP1 and induction of cell cycle arrest. In contrast, the second region of CD30 (CD30538– 595) induced some aspects of canonical NF-kB activation, including transcription of IkBa, but failed to activate the alternative NF-kB pathway or drive p21WAF1/CIP1-mediated cell-cycle arrest. Direct comparison of canonical NF-kB activation by the two motifs revealed 4-fold greater p65 nuclear translocation following CD30519–537 engagement. These data reveal that independent regions of the CD30 cytoplasmic tail regulate the magnitude and type of NF-kB activation and additionall