Oncogenic activity of BIRC 2 and BIRC 3 mutants independent of nuclear factor‐κB‐activating potential

BIRC 2 and BIRC 3 are closely related members of the inhibitor of apoptosis ( IAP ) family of proteins and play pivotal roles in regulation of nuclear factor‐κB ( NF ‐κB) signaling and apoptosis. Copy number loss for and somatic mutation of BIRC 2 and BIRC 3 have been frequently detected in lymphoid malignancies, with such genetic alterations being thought to contribute to carcinogenesis through activation of the noncanonical NF ‐κB signaling pathway. Here we show that BIRC 2 and BIRC 3 mutations are also present in a wide range of epithelial tumors and that most such nonsense or frameshift mutations confer direct transforming potential. This oncogenic function of BIRC 2/3 mutants is largely independent of their ability to activate NF ‐κB signaling. Rather, all of the transforming mutants lack an intact RING finger domain, with loss of ubiquitin ligase activity being essential for transformation irrespective of NF ‐κB regulation. The serine‐threonine kinase NIK was found to be an important, but not exclusive, mediator of BIRC 2/3‐driven carcinogenesis, although this function was independent of NF ‐κB activation. Our data thus suggest that, in addition to the BIRC 2/3– NIK – NF ‐κB signaling pathway, BIRC 2/3– NIK signaling targets effectors other than NF ‐κB and thereby contributes directly to carcinogenesis. Identification of these effectors may provide a basis for the development of targeted agents for the treatment of lymphoid malignancies and other cancers with BIRC 2/3 alterations.