The physiological roles of ER stress transducer BBF2H7/CREB3L2 and its potential as a target of disease therapy

BBF2H7 is an endoplasmic reticulum (ER)-resident transmembrane transcription factor, that is cleaved at the transmembrane region in response to physiological and pathophysiological ER stress to generate two fragments; the cytoplasmic N-terminal fragment containing transcription activation and basic leucine zipper (bZIP) domains translocates into the nucleus to act as a transcription factor. Conversely, the luminal C-terminal fragment is extracellularly secreted and promotes the proliferation of neighboring cells via activation of hedgehog (Hh) signaling. In developing cartilage, the dual N- and C-terminal functions of BBF2H7 enable chondrocytes to simultaneously orchestrate distinct cellular events for differentiation and proliferation via the activation of the secretory pathway by the N-terminus and the Hh signaling by the C-terminus. Interestingly, the secreted BBF2H7 C-terminus is involved in cancer cell proliferation by the activation of Hh signaling, which is well known to facilitate tumorigenesis. In this review, we summarize the biological roles of BBF2H7 in developing cartilage and cancer cells, and discuss the potential of BBF2H7 as a novel target for cancer therapy.