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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.

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